Psychiatric disorders, including depression and schizophrenia, affect millions of individuals worldwide. However, the precise neurobiology of psychiatric disorders remains unclear. Accumulating evidence suggests that various inflammatory processes play a key role in depression and schizophrenia, and that anti-inflammatory drugs exert a therapeutic effect in patients with psychiatric disorders. Epoxyeicosatrienoic acids (EETs) and epoxydocosapentaenoic acids (EDPs) have potent anti-inflammatory properties. These mediators are broken down into their corresponding diols by soluble epoxide hydrolase (sEH), and inhibition of sEH enhances the anti-inflammatory effects of EETs. Therefore, sEH may play a key role in inflammation, which is involved in psychiatric disorders. Recent studies have shown that abnormal levels of sEH may be involved in the pathogenesis of certain psychiatric diseases, and that sEH inhibitors exhibit antidepressant and antipsychotic activity. The present review discusses the extensive evidence supporting sEH as a therapeutic target for psychiatric diseases, and the clinical value of sEH inhibitors as therapeutic or prophylactic drugs. Depression and schizophrenia are severe and chronic debilitating psychiatric diseases that affect millions of individuals worldwide, with >300 million individuals of all ages affected by depression and nearly 800,000 dying each year from suicide . SimilarThere is ample evidence that inflammation plays a central role in the pathophysiology of depression and schizophrenia . In patiExtensive evidence suggests that biological substances in the arachidonate cascade, such as enzymes and eicosanoid metabolites, are involved in the etiology and pathology of inflammatory disease. Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), are metabolized by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs) . The COXvia increased BDNF-TrkB signaling and synaptogenesis. Furthermore, data reported by other groups are in agreement with these results. Wu et al. reported that the sEH inhibitor TPPU decreased depression-like behavior in the novelty-suppressed feeding test, which is a test of stress-induced anxiety/depression (As discussed above, inflammation is associated with psychiatric disorders such as depression and schizophrenia, and sEH plays a role in the pathogenesis of inflammatory-related diseases. Therefore, it is possible that sEH contributes to the pathophysiology of these disorders. Recently, our study of postmortem brains revealed that the protein levels of sEH in the parietal cortex of patients with major depressive disorder, schizophrenia, and bipolar disorder were significantly elevated compared with those in the parietal cortex of healthy individuals . In studpression . Moreovepression , 2019. Tpression .via regulation of the BDNF-TrkB signaling pathway. There is ample evidence suggesting that oxidative stress also plays an important role in the pathophysiology of schizophrenia, and antioxidant agents have demonstrated antipsychotic effects in animal models of schizophrenia (As mentioned above, patients with schizophrenia exhibit higher sEH protein levels in the parietal cortex than controls. Meanwhile, another study investigating alterations of eicosanoids in the serum of patients with schizophrenia reported that 11,12-DHETs and 14,15-DHETs were increased in patients compared with controls and were decreased post-treatment . This evophrenia , 2015. Mophrenia . Recentlophrenia ; howeverophrenia . Additioophrenia . Other sophrenia . These fIn this minireview, we highlighted recent studies that have demonstrated the potential of sEH as a therapeutic target in psychiatric disorders. Crucial data from Several hypotheses have postulated that inflammation may play a causative role in depression and schizophrenia . HoweverCollectively, these studies described a potential mechanism for sEH in the pathophysiology of depression and schizophrenia. This evidence suggests that sEH inhibitors exert an antidepressant and antipsychotic effect, and may attenuate the appearance of oxidative and ER stress, dysregulation of neurotrophic and dysfunction of dopaminergic neurons in the brain . NeverthQR wrote the manuscript and prepared the figures.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Few differences in SFA sources were identified between sexes, age groups, education levels, and body mass index (BMI) categories. These data show that the mean SFA consumption is greater than the 10% E cut-off previously proposed in Canada. Future studies should examine which food substitution is most likely to contribute to a greater reduction in SFA intake at the population level.The 2019 revised version of Canada’s Food Guide (CFG) recommends limiting the consumption of processed foods that are high in saturated fatty acids (SFA). Yet, the contributions of each CFG group to the total SFA intake of Canadians are not specifically known. The objectives of this study were to quantify the total SFA intake of Canadians, determine the sources of SFA consumed by Canadian adults, and identify potential differences in these sources. A nation representative sample from the Canadian Community Health Survey (CCHS – Nutrition 2015) was used for these analyses. Dietary intakes were measured using a single 24-h recall. Food sources of SFA were classified according to the revised 2019 CFG categories. We have also examined the contribution of foods not included in these three categories to total SFA intake. Among Canadian adults, total SFA contributed to 10.4 ± 0.1% (SE) of total energy intake (E). The “Protein foods” (47.7 ± 0.5% with 23.2 ± 0.4% from  Dietary saturated fatty acids (SFA) increase low-density lipoprotein (LDL) cholesterol (LDL-C) when compared with carbohydrates and polyunsaturated fats . AccordiTherefore, the objectives of this study were to quantify the SFA intakes of Canadian adults, determine the sources of SFA consumed by Canadian adults, and identify how these vary according to various sociodemographic characteristics and body weight status. We hypothesized that the mean SFA intake of Canadian adults is above current recommendations, and that foods not included in any of the three new CFG categories are the most important contributors to SFA consumption in Canadian adults. We also hypothesized that men consume more SFA from protein foods than women, that body weight is positively associated with total SFA intake, and that age is inversely associated with the proportion of SFA from foods not included in the CFG categories.Data from the nutrition component of the 2015 Canadian Community Health Survey (CCHS Nutrition) was used for this study. The CCHS Nutrition is a sample survey with a cross-sectional design providing information on the eating habits and dietary intakes of Canadians aged 1 year old and over living in the 10 Canadian provinces. People living on reserves and other Aboriginal settlements, full-time members of the Canadian Forces, and institutionalized individuals were excluded from the survey’s coverage. The sampling method, based on age, sex, geography, and socioeconomic status was designed in order to generate a sample representative of the Canadian population. For the present analyses, only Canadian adults were included . Weight status was qualified according to body mass index (BMI). The present study objectives were pre-specified in contract #17-SSH-LAVAL-5405 with Statistics Canada.Dietary data were obtained using a single computer-assisted 24-h recall administered by trained interviewers using the Automated Multiple-Pass Method (AMPM) . The AMPmeats and alternatives and milk and alternatives. The contribution to total SFA intake of “All other foods”, i.e., all foods not included in the three new food categories of the CFG such as fruit juices, refined grains, and salty snacks, was also examined.SFA food sources were classified according to the new 2019 CFG categories: (1) vegetables and fruits (excluding fruit and/or vegetable juices), (2) whole grain foods (excluding refined grains), and (3) protein foods, which include the previous CFG categories p-values lower than 0.05 were considered statistically significant.All the analyses were undertaken using survey-specific procedures to account for the CCHS Nutrition design and balanced repeated replication (BRR) for variance estimation. The sampling weights and 500 bootstrap weights provided by Statistics Canada were used to achieve the representativeness of the study sample. Thus, the results presented here are representative of the entire adult Canadian population aged 19 to 70 years with exclusion of the aforementioned groups. Means, medians, and variances of continuous variables were obtained using PROC SURVEYMEANS. Proportions/variances of categorical variables were computed using PROC SURVEYFREQ. Potential differences among sociodemographic characteristics and weight statuses were assessed using general linear models in PROC SURVEYREG with Tukey–Kramer adjustment for multiple comparisons when appropriate. SAS (v. 9.4) was used for all the analyses. 2), 34.1% were overweight (BMI 25–30 kg/m2), and 26.6% were obese (BMI >30 kg/m2).The mean age (±SE) of the sample used for analyses was 45.0 ± 0.3 years, with 50.2% of respondents being female and 48.3% having a household income greater than $80,000/year. The sample was evenly distributed among education levels, with 33.9% having a high school diploma or no diploma, 31.0% having a CEGEP, college, or trade school certificate, and 34.4% with a University degree. CEGEP is a pre-university and technical college institution that is specific to the Province of Quebec. Over one-third (39.3%) of Canadian adults were in the normal weight category (BMI <25 kg/mp = 0.05). Canadians with a CEGEP, college, or trade certificate consumed more SFA than Canadians with a high school diploma or no diploma, or with a University degree . There were only small differences in total SFA consumption among the 10 Canadian provinces  among Canadian adults in 2015 . No diffrovinces .milk and alternatives and meats and alternatives, to total SFA intake. “Protein foods”  and “All other foods”  were the main sources of SFA in the diet of Canadian adults in 2015. Milk and alternatives and meats and alternatives equally contributed to SFA from the “Protein foods” category. Whole grain foods were the least important contributor to total SFA intake .meats and alternatives than women . No differences were found between age groups for the “Protein foods” category. However, younger adults (19–30 years old) consumed more SFA from milk and alternatives and less from meats and alternatives than older adults (31–50 years old and 51–70 years old). Inversely, older adults (51–70 years old) consumed more SFA from whole grain foods than younger adults (19–30 years old). We also found that Canadians with a CEGEP, college, or trade certificate consumed less SFA from whole grain foods than Canadians with a high school diploma or no diploma, or Canadians with a University degree (p < 0.05). Respondents living in Newfoundland and Labrador and in Prince Edward Island had a higher proportion of their SFA coming from the “All other foods” category than Canadians from Quebec, Ontario, and British Columbia  currently recommends limiting the intake of SFA at a maximum of 10% E per day . Here, wMultiple studies have observed intakes higher than the WHO recommendation at a population level. For example, Huth et al. 2013) found that Americans aged 2 years or older consume a mean of 11.4% E as SFA . Among E found thp = 0.002); respondents with a CEGEP, college, or trade certificate consumed more SFA than respondents with a lower education (high school diploma or no diploma) or a higher education (University degree). This “non-linear” association between SFA intake and education level is unclear. Also, very few studies have examined the potential associations between SFA consumption and education level, making comparison difficult. However, Hiza et al. (2012) found that American adults with no diploma had higher Healthy Eating Index (HEI) subscores for SFA than those with a higher education level, reflecting a lower intake [Data from the present study suggest a weak association between education level and SFA intake (r intake . Therefop = 0.05), which is consistent with previous data in the American adult population and in the Canadian population [No difference in total SFA intake, which is reported relative to total energy intake, was identified between sexes and age groups in the present study, which is consistent with the available literature on the subject ,15,16. Tpulation ,18. HoweAs expected, “Protein foods” (47.8%), and “All other foods” not included in the 2019 CFG (44.2%) were the two main sources of SFA in the diet of Canadian adults in 2015. To our knowledge, this is the first study to evaluate the contribution of each 2019 CFG category to total SFA intake, since most studies available to date have reported data using more specific dietary sources of SFA such as milk, cheese, or red meat. While comparison with data from previous studies is limited by our use of this novel classification of food groups, data are nevertheless consistent with results from studies available on the subject ,13,19. Fmeats and alternatives category .Very few studies have documented the associations between food sources of SFA and sociodemographic characteristics. Kirkpatrick et al. 2019) have shown, based on data from the CCHS Nutrition 2015, that the main singular food sources of SFA in the Canadian diet were red meat mixed dishes, unflavored milk, cheese, egg dishes, and dairy-based desserts [19 have smeats and alternatives and more from milk and alternatives than older adults . This can be due to either a lower consumption of meat or consumption of meat with a lower fat content among younger adults in Canada. A lower consumption of meat among younger adults is unlikely, based on findings by Tugault-Lafleur and Black (2019) [meats and alternatives has increased by 0.3 servings/day in Canadian adults 18–54 years old between 2004–2015 [meats and alternatives is not due to the consumption of meat per se [When looking at potential differences in SFA sources between age groups, we found that younger adults (19–30 years old) consumed less SFA from k (2019) . Indeed,004–2015 . Howevert per se . Additiot per se .Finally, the proportion of SFA from each 2019 CFG category was similar across all BMI categories. This result was unexpected, considering that obese individuals generally report consuming more foods that have a low nutritive value than non-obese individuals . It is pTo our knowledge, this is the first study to assess SFA dietary sources using the new 2019 CFG food categories. The assessment of potential differences in SFA intakes and dietary sources between sexes, age groups, education levels, and weight statuses is also a strength, as few studies are currently available on the subject. The use of survey-specific procedures applied to data from CCHS 2015 implies that results are representative of all Canadian adults, which is an important strength. Dietary data was obtained using a 24-h recall, which is affected by within-person variation, mostly caused by the day-to-day variation of food intakes . As a reThese findings suggest that dietary intake of SFA among Canadian adults in 2015 was in average above the 10% E recommendation. Similar results from previous surveys in Canada also suggest that SFA intake has not changed significantly over the past years, despite public health efforts aimed at improving the diet quality of Canadians. Unsurprisingly, almost half of SFA consumed by Canadians in 2015 came from foods that are not recommended and/or not included in the CFG. Therefore, even if the main sources of total SFA intake are protein foods, future health policies should focus primarily on reducing the population’s intake of processed foods and/or foods not included in the CFG, as they are an important source of SFA. Such focus on low nutritive quality foods are entirely in line with Canada’s most recent dietary guidelines, in which a reduction in the intake of processed foods high in sodium, sugar, and SFA is strongly recommended. Future studies should examine which food substitutions are likely to contribute the most to the reduction of SFA consumption in Canada.


Branched polymers are a valuable class of polymeric materials. In the present study, anionic polymerization techniques were employed for the synthesis of low molecular weight poly(ethylene oxide) (PEO) macromonomers bearing norbornenyl end groups. The macromonomers were characterized by SEC, MALDI-TOF and NMR spectroscopy. Subsequent ring opening metathesis polymerization (ROMP) of the macromonomers using ruthenium catalysts  afforded the corresponding polymacromonomers. The effects of the macromonomer molecular weight, the type of the catalyst, the nature of the solvent, the monomer concentration and the polymerization temperature on the molecular characteristics of the branched polymers were examined in detail. The crystallization behavior of the macromonomers and the corresponding polymacromonomers were studied by Differential Scanning Calorimetry (DSC). The thermal stability and the kinetics of the thermal decomposition of the samples were also studied by Thermogravimetric Analysis (TGA). The activation energies of the thermal decomposition were analyzed using the Ozawa–Flynn–Wall and Kissinger methodologies. Great effort has been devoted to the synthesis of multifunctional and architecturally demanding polymers and the study of their properties ,5,6,7,8.Poly(ethylene oxide) (PEO) is a neutral, non-toxic, biocompatible and water soluble polymer which has found numerous applications, such as in conductive composites with carbon black, cosmetology , gene therapy, pharmaceutical products, etc. ,22,23,24Norbornene is a bicyclic compound with a high ring strain, which allows it to proceed in ROMP reaction in a robust and rapid manner ,33,34. PHerein, we describe the synthesis of PEO bottlebrushes, varying in branch size as well as backbone length. The synthesis of these structures was realized through the combination of two different polymerization techniques, those of anionic polymerization and ring opening metathesis polymerization (ROMP). Adopting the grafting through method, the synthetic process involved the use of a PEO macromonomer functionalized with a norbornene group on one end. The macromonomers were subjected to ROMP using the well-defined, ruthenium-based, Grubbs catalysts resulting in the desired brush-like structures with branches comprised of PEO homopolymers and a backbone of a polynorbornene chain. The crystallization behavior of these materials, the thermal stability and the kinetics of thermal decomposition were also studied by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA), respectively.4) and then fractionally distilled into ampoules under vacuum. Dichloromethane (CH2Cl2) was stirred overnight in the presence of a small amount of calcium hydride (CaH2) and then fractionally distilled in a flame dried flask containing 3 Å molecular sieves. Dichlorobenzene (DCBz) was stirred overnight in the presence of a small amount of CaH2 and then fractionally distilled in a flame dried flask containing pieces of sodium. 5-Norbornene-2-methanol (Sigma-Aldrich) was used as provided. Ethylene oxide monomer was purified according to the standards of anionic polymerization [All reagents were purchased from Sigma-Aldrich  and used as received, unless described otherwise. Tetrahydrofurane  and Toluene  were purified according to the standards of anionic polymerization high vacuum techniques described elsewhere . Methanorization . Grubbs rization .The synthesis of the macromonomers was realized via anionic polymerization. Prior to the polymerization process, the preparation of a norbornenyl oxyanion initiator was necessary . For thew/v. All polymerization reactions led to the desired molecular weights and to quantitative yields. Initially, the ampoule containing the initiator was introduced by rupturing the appropriate break-seal in the reactor. The temperature of the reaction solution was then raised to 40 °C and then the break seal of the ampoule containing the monomer was carefully ruptured. Prudence is necessary since the gassy nature of the monomer EO might prove hazardous, hence prior to smashing the seal, the monomer was chilled using liquid nitrogen. After rupturing the break-seal of the monomer ampoule EO was slowly and cautiously liquefied. After the complete addition of the monomer the reactor was left in the water bath (40 °C) for 2–3 days depending on the molecular weight. After the completion of the polymerization the terminating agent  was added by breaking the break-seal of the appropriate ampoule. The solution was then left to react for 30 min. Finally, the polymer was precipitated in petroleum ether, filtered and dried under vacuum for 24 h.Ethylene oxide was polymerized under high-vacuum in THF using break-seal techniques, and the norbornenyl oxyanion as the initiator. The polymerization reaction  was perf2Cl2, DCBz, or Toluene). The desired type of Grubbs catalyst was then dissolved in THF or CH2Cl2 (0.5 mg/mL) under stirring. After complete dissolution, employing the conventional method, the desired volume of the catalyst solution was added in a vial or a Schlenk flask already containing the macromonomer solution. Employing the seeding process, the catalyst solution was initially added in a vial or a Schlenk flask followed by the addition of a small amount of the macromonomer solution. After 10–15 s, the remaining macromonomer solution was added in the reaction mixture for the completion of the polymerization. In both cases, the polymerization was allowed to proceed for 30 min to 4 h, depending on the targeted molecular weight. Finally, the catalyst was quenched with the addition of a few droplets of ethyl vinyl ether, and the bottlebrush was precipitated in a non-solvent (diethyl ether or petroleum ether), filtered, washed with diethyl ether and vacuum dried. Residual amounts of the catalyst were removed via the use of a soxhlet apparatus and diethyl ether as the refluxing solvent.As previously mentioned, the preparation of the polymacromonomers involved the use of ruthenium Grubbs type catalysts. The ROMP process was conducted under inert argon atmosphere, either in a glove box or on an argon-vacuum line according to principles mentioned elsewhere ,39,40. G6 to 103 Å. The columns were housed in an oven thermostatted at 40 °C. THF was the carrier solvent at a flow rate of 1 mL/min. The system was calibrated with seven PS standards having MWs between 1000 and 900,000 g·mol−1.SEC experiments were conducted at 40 °C using a modular instrument consisting of a Waters Model 510 pump, a Waters Model U6K sample injector, a Waters Model 401 differential refractometer, a Waters Model 486 UV spectrophotometer , and a set of 4 μ-Styragel columns with a continuous porosity range from 10Nuclear magnetic resonance (NMR) spectra were recorded in chloroform-d and deuterated dimethylsulfoxide DMSO-d6 at 25 °C with a Varian Unity Plus 300/54 NMR spectrometer and Liquid State Varian Mercury Vx 300 MHz spectrometer . Mass spectra were obtained on a Bruker UltrafleXtreme matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) spectrometer  using 2,5-Dihydroxybenzoic acid (DHB) as matrix. 2 at heating rates of 3, 5, 7, 10, 15 and 20 °C/min.The glass-transition temperatures were obtained by differential scanning calorimetry (DSC) using a 2910 modulated DSC model from TA instruments . The samples were heated or cooled at a rate of 10 °C/min. The second heating results were obtained in all cases. The thermal stability of the copolymers and the kinetics of their thermal decompostion was studied by thermogravimetric analysis (TGA) employing a Q50 TGA model from TA instruments. The samples were heated from ambient temperatures up to 700 °C in a 60 mL/min flow of NThe macromonomers were synthesized employing a functional norbornenyl oxyanionic initiator. This method holds the benefit of ensuring functionalization on the polymer chain end. In addition, through the use of a suitable electrophilic terminating agent, there is an ability to introduce functionality on the ω-chain end as well, thus finally creating α, ω bifunctional telechelic polymers. The synthesis of macromonomers through modification of the PEO’s end-group employing post-polymerization reactions is not always the desired method because it is difficult to achieve quantitative functionalization reactions. Finally, the product is a macromonomer contaminated with amounts of non-functionalized PEO chains. In order to force the post-polymerization reaction to completion, special reagents in a large excess are required. This excess has to be removed before proceeding further with the synthesis of the bottlebrushes, thus adding more steps in the synthesis of the desired products. 3C−+K) solution. This method, although experimentally more convenient, cannot be easily performed under high vacuum. Moreover, the titration process ceases after the slight presence of the characteristic red color of (Ph)3C−+K solution. The excess (Ph)3C−+K acts as initiator for ethylene oxide thus generating macromolecules without a functional norbornenyl end-groups. The preparation of PEO macromonomers using a similar methodology (oxyanionic polymerization) has been previously presented ,42,43,442 covalently bonded on a norbornene moiety has also been reported [The use of commercially available ω-hydroxy-PEOs in PEO macromonomer is not advised, since these compounds are known to contain traces of dihydroxy species as well. A method involving the use of commercially available PEO-NHreported . Howeverreported . The prereported ,48,49,50The macromonomer synthesis was conducted in dilute THF solutions at 40 °C. Since the preparation of the initiator involved the use of potassium, a known pyrophoric substance, judicious planning and extreme caution is necessary before handling the metal. Immediately after the addition of the alcohol solution to the potassium, mirror bubbling and a quick decay of the mirror are visible. To achieve quantitative yields, degassing of the solution is necessary. This procedure was applied twice before the termination of the living polymer. Precipitation was realized in chilled diethyl ether, under constant stirring; before pouring the solution in the non-solvent part of the solvent was removed, via evaporation, for better precipitation. After that the macromonomers were filtered, washed with diethyl ether and freeze dried with benzene, in order to remove moister traces from the polymers. This final process is necessary to provide dry samples suitable in the latter step for ROMP reaction. The polymers were then stored and weighted in a glove box. In all cases, the mass of the macromonomers indicated quantitative polymerization yields and characterization with NMR , MALDI TI1) of the norbornene double bond (δ 5.8–6.2 ppm) when integrated, compared with the intensity of the peak corresponding to the protons (I2) of the etheric carbons of PEO (δ 3.5–3.7 ppm), were found in close agreement with the equation I2 = 2The α-functionality of the macromonomers was confirmed from the NMR spectra. The intensity of the characteristic peaks of the protons  and gave better spectra results in the absence of added ionizer. All data confirm that well defined macromonomers with narrow molecular weight distributions are obtained through this oxyanionic polymerization.d-orbitals of the ruthenium metal of the catalyst, thus hindering the ROMP process. After the addition of the catalyst to the monomer solution, the solution color changes initially from green (G 3rd), violet red (G 2nd) or purple (G 1st), depending on the catalyst, to orange, and within a few seconds into red to dark red, indicating the possible interaction of the oxygen atoms with the catalyst transition metal [The synthesis of the PEO macromonomers with the desired molecular characteristics was no trivial task. Other than the possible decomposition of the catalyst to monohydride species from the ω-hydroxyl groups, mentioned previously, the unpaired electors of the oxygen atoms in each repeated monomer unit may also interact with unoccupied on metal . There iAll three generations of the well-defined Grubbs catalysts were used in various solvents and temperatures, in an attempt to define the optimum polymerization conditions. Grubbs 1st generation catalyst demonstrated poor results with low polymerization yields, broad molecular weight distributions  and non-reproducible molecular weights. The problem was more pronounced for the higher molecular weight macromonomers. Grubbs 2nd generation gave, in most cases, quantitative yields, however with poor control over the molecular characteristics. Bimodal distributions were a common result and only when toluene was used as the solvent monomodal distributions were realized. Much better results, as expected, were obtained with the use of Grubbs 3rd generation catalyst. Quantitative yields were obtained, however reproducible results and monomodal distributions were difficult to acquire in sequential ROMP reaction, showing no dependence on solvent nature or monomer concentration. The addition process was proved to be of great significance; specifically ROMP reactions carried out through the seeding process gave reproducible results and monomodal distributions. According to this procedure, a small amount of the macromonomer  is initially added to the catalyst solution and after 10–15 s the remaining amount of macromonomer is added and left for polymerization. With this methodology the initiation step is technically separated from the propagation step. The initial addition of the small amount of macromonomer assures that all the catalyst species are activated at the same time and that they are ready to promote the propagation step, upon the subsequent addition of the remaining quantity of macromonomer, with the same rate leading to uniform polymerization reaction. Molecular characteristics of polymacromonomers prepared by the conventional addition of the catalyst to the macromonomer solution are given in the Supporting Information Section , whereasOverall, the synthesis of the PEO polymacromonomers is accompanied by many synthetic challenges. Against all expectations the key factor was neither the solvent nor the monomer concentration but the addition method. The seeding process ensures reproducible results and the optimum molecular characteristics. Nevertheless, all factors have minor effects on the ROMP reactions. From our observations, the primary factors are the following:Molecular weight dependency• d-orbitals of the catalyst metal. Reproducibility was also a difficult factor to ensure, probably due to the presence of such phenomena. Quantitative yields and monomodal distributions were constantly obtained for macromonomers with molecular weights up to 3 kDa. Polymacromonomers with branch sizes up to 5 kDa were produced, however quantitative yields and monomodal distributions were difficult or impossible to achieve. It was found that repeatable results were only possible when the seeding process was followed. For macromonomers with molecular weights <3 kDa repeatable results, with decreased polydispersity, were obtained via seeding polymerization. For macromonomers with molecular weights >3 kDa improved results in polydispersity and reaction yields, were observed. The declining results, as the molecular weight of the macromonomers increases, is reasonable since the “density” of the oxygen atoms (possible complexing factors) increases. In other words, keeping in mind that the macromonomer, in solution, adopts a bundle like entangled formation, the coordination of the ruthenium catalyst with the targeted norbornene group is confronted with more oxygen atoms in each chain, as well as the solution in general.By increasing the length of the macromonomer chain, a decrease over polymerization control was observed. Bimodal distributions were obtained and, in spite of the presence of the norbornene functional group, quantitative yields were not received. This was attributed to coordination phenomena that occur between the electron rich oxygen atoms of the repeating units and the unoccupied Catalyst dependency• Grubbs 1st generation gave satisfactory and repeating results for macromonomers up to 2 kDa. However, for molecular weight higher than 2 kDa bimodal distributions and non-quantitative yields were acquired. Grubbs 2nd generation, being more tolerant to functional groups gave in all cases quantitative yields, however did not give reproducible results. Grubbs 3rd generation catalyst, gave improved and in general much better results; combining the two major qualities of the other two catalysts, fast initiation rate compared to propagation (G 3rd is 1000 times faster compared to G 1st) and functional group tolerance .Mw= mass of macromonomer in g/moles of catalyst, even though complete metathesis was achieved in both cases. G 1st generation catalyst gave larger molecular weights compared to G 3rd. This result could be attributed to the high reactivity and functional group tolerance, leading to rapid polymerization without any obstructions due to coordination phenomena. In comparative experiments between G 1st and G 3rd catalysts using the same amounts of the same macromonomer, results showed that G 3rd catalysts produced polymacromonomers in better agreement with the equation Solvent and concentration dependency• Various solvents were used in a range of concentrations and in different reaction temperatures. Even though large concentrations are favorable for ROMP reactions , in the case of ROMP using macromonomers was not as crucial. On the contrary, lower concentrations were found to give better results. Polar solvents and specifically solvents with greater dielectric constant gave better initiation to propagation rates. With G 2nd catalyst better results were obtained in toluene resulting, in most cases, to monomodal distributions and quantitative yields. Dichloromethane (DCM) was a most reliable solvent for ROMP, however, for ROMP preformed in higher temperatures, dichlorobenzene (DCBz) was found to be the best choice, having a high boiling point and high dielectric constant. ROMP preformed at higher temperatures, up to 70 °C, gave better results in cases were low yields were obtained, increasing the polymerization yields. This was ascribed to the fact that at higher temperatures coordination phenomena between the catalyst and oxygen of the monomeric units become weaker ,52.Mw= g macromonomer/moles of catalyst. There have been reports in literature [2Cl2 in a 65/35 ratio. However, this solvent mixture did not give the best results in our experiments, since the presence of primary alcohols may have a destructive effect causing decomposition of the catalyst to monohydride species [In general the solvents of choice were THF and DCM, giving polymacromonomers in agreement with the equation terature  stating terature  on the u species ,48,49,50The thermal properties of the polymacromonomers were also investigated and the samples bearing the optimum molecular characteristics were subjected to Differential Scanning Calorimetry (DSC) measurements.The number and letter code describing the polymacromonomer samples in Tg value [Due to the ionic conductivity that PEO presents, there has been much interest in their employment in electrochemical devices. However, PEO aids in ion transportation only in the amorphous phase, and, being a semi-crystalline polymer, presents crystallinity at room temperatures; thus, their use in such applications has been limited. Hence, the design-criterion for PEO-based electrolytes has been focused on the suppression of PEO crystallinity and the increase of the amorphous percentage. Crystallinity (for PEO) is normally increased with molecular weight: up to 1000 Daltons, it remains a viscous liquid with glass transition temperatures below room temperature. Our scope was to study the effect of the total brush and branch molecular weight on crystallinity. For that reason, a series of polymacromonomers differing in branch and backbone size were prepared. During the building process of the polymacromonomers, due to the polymer chain congestion and repulsive forces present, the side chains adopt a rod-like conformation leading to a final cylindrical structure. The backbone of the PEO bottlebrushes consisted of norbornene units. Polynorbornene is a rather flexible chain, judging from their low Tg value ,56, thusThe tailoring of PEO macromonomers at the significantly dense backbone extensions results in the PEO chains adopting an entropically unfavourable chain conformation, with hydrodynamic volumes much smaller than that of their random coil structures ,57. ThesΗM values or in other words a substantial reduction of the crystallinity compared to the corresponding macromonomers from which they were synthesized. If the difference in molecular weight between the macromonomers and their polymacromonomers is taken into account then the reduction of crystallinity is even more pronounced. Analyzing the DSC results for the linear PEO macromonomers, it is observed that both the melting point and the degree of crystallinity increase upon increasing the molecular weight of the macromonomer. This result is quite reasonable in view of the low molecular weight of the macromonomers. On the contrary, polymacromonomers showed much smaller ΔThe samples 1-15-3, 2-15-3 and 3-15-3 have similar total molecular weights but different number of branches. It is obvious that a decrease of the number of branches leads to an increase of both the crystallinity and the melting point, extending the effect of the macromolecular architecture on the thermal properties of the materials. Similar results are extracted from the comparison of the samples 1-47-1, 2-45-3, and 3-50-3. PEO bottlebrushes have been previously synthesized by many groups and their thermal properties have been studied. According to the literature, the crystallinity increases upon increasing the total molecular weight of the PEO bottlebrush (backbone) ,59,60. SThe PEO macromonomers with molecular weights 1k, 2k, 3k and three of the polymacromonomers, namely 1-205-3-THF, 2-45-3-THF and 3-50-3-THF, were thermally degraded at different heating rates under inert atmosphere. The samples 2-45-3-THF and 3-50-3-THF were selected because they have similar total molecular weight but differ in the number of branches and branch molecular weight. Sample 1-205-3-THF was chosen, since it has a very high number of branches. The temperatures where the thermal decomposition is initiated and completed along with the temperatures at the maximum rate of thermal decomposition are provided in Tp) is similar for the macromonomers PEO 1k and PEO 2k, whereas a slightly higher value is observed for macromonomer PEO 5k. It is obvious that, for these low molecular weight semicrystalline polymers, an increase in molecular weight should result in an increase of the intermolecular interactions leading to higher thermal stability. The difference in molecular weight for samples PEO 1k and PEO 2k is rather low to observe this effect. However, PEO 5k has a substantially higher molecular weight leading to higher Tp value. For all macromonomers a simple and symmetrical peak is obtained in DTG with a rather short range of decomposition temperatures thus indicating the presence of a relatively simple decomposition mechanism. The residue of the thermal decomposition is lower than 5%. However, an even lower value (less than 3%) is obtained for PEO 5k. This is a manifestation of the effect of the norbornene end groups. It is known that in polynorbornene from ROMP reactions a high residue is obtained after the thermal decomposition in inert atmosphere [The temperature of the thermal decomposition at the peak of DTG . Since the chain end is chemically connected to the PNBE backbone, its thermal stability is substantially increased. However, DTG reveals that the Comparing the polymacromonomers, it is concluded that samples 1-205-3-THF and 2-45-3-THF have similar ranges of temperatures for their thermal decomposition. However, sample 3-50-3-THF has increased temperatures of decomposition, which reflects the higher thermal stability of PEO 3k compared to the other macromonomers.Ea, of mass loss upon heating was calculated using both the isoconversional Ozawa–Flynn–Wall (OFW) [F(α), where α is the conversion, does not change upon altering of the heating rate, β, for all values of α. The OFW method involves the measurement of the temperatures corresponding to fixed values of α from experiments at different heating rates β. Therefore, plotting lnβ vs. 1/T in the form:The kinetics of the thermal decomposition of the samples was studied by TGA measurements. The activation energy, ll (OFW) ,64 and Kll (OFW) ,66 methoT is the absolution temperature. A is the pre-exponential factor (min−1) and R is the gas constant (8.314 J/K·mol). If the determined activation energy is the same for the various values of α, then a single-step degradation reaction can be concluded. The OFW method is the most useful method for the kinetic interpretation of thermogravimetric data, obtained from complex processes like the thermal degradation of polymers. This method can be applied without knowing the reaction order. This should result in straight lines with slopes directly proportional to the activation energy where Ea was also calculated from plots of the logarithm of the heating rate vs. the inverse of temperature at the maximum reaction rate in constant heating experiments, according to the Kissinger method. The equation for the Kissinger method is the following:n is the reaction order. The Ea values can be calculated from the slope of the plots of ln(β/Τp2) vs. 1/Tp. The activation energy Ea, of the samples resulting from the OFW method are displayed in The activation energy values, Ea values for the macromonomers do not vary substantially with the conversion α (OFW method) indicating that the decomposition mechanism is rather simple, in agreement with the DTG results. Upon increasing the molecular weight of the macromonomer the Ea values are decreased, meaning that a lower energy barrier is required for the thermal decomposition of the higher molecular weight macromonomers. This result reflects the effect of the norbornene end-group in fortifying the thermal stability of the polymers. The lower the molecular weight of the macromonomer, the higher is the effect of the norbornene end-group and thus the higher the thermal stability. Similar conclusions were drawn by DTG. The Ea values obtained from the Kissinger method are qualitatively in close agreement with those obtained from the OFW method. However, as it is common in the literature, the Kissinger approach leads to lower Ea values than the OFW approach. The Ea values, according to the OFW analysis, vary slightly with the conversion as a manifestation of the more complex mechanism of thermal decomposition. This variation is more pronounced for sample 1-205-3-THF, obviously due to the higher norbornene content of this sample. However, in contrast with the macromonomers, the Ea values are decreased upon decreasing the molecular weight of the macromonomer. The higher the number of end groups in the structure, the lower is the energy barrier that is required for the thermal decomposition. Combination of the branch molecular weight and the degree of polymerization of the bottlebrush leads to an increase of end groups in the order: 3-50-3-THF < 2-45-3-THF < 1-205-3-THF.In the case of the polymacromonomers the A combination of anionic and ring opening metathesis polymerization techniques were used in order to produce poly(ethylene oxide) (PEO) macromonomers and the corresponding polymacromonomers. SEC, MALDI-TOF and NMR spectroscopy were used to characterize these materials. Parameters such as the molecular weight of the macromonomer, the structure of the catalyst, the nature of the solvent, the monomer concentration and the polymerization temperature were examined in order to achieve the best control over the molecular characteristics of the polymer brushes. Above all of these factors, the most important was to adopt the seeding polymerization method. According to this, a small amount of the macromonomer is added to the catalyst solution, followed after 10–15 s with the addition of the remaining amount of macromonomer. This way, technically, the initiation and the propagation steps are separated in time leading to the best control over the polymerization kinetics and to reproducibility of the results. DSC analysis revealed that the crystallinity of the polymacromonomers is substantially reduced due to the architectural constraints of the structure, which prevent the organization in crystalline domains. The thermal stability of the samples and the kinetics of the thermal decomposition were studied by TGA measurements. The activation energies of the thermal decomposition were analyzed using the Ozawa–Flynn–Wall and Kissinger methodologies. The polynorbornene backbone offers increased thermal stability to the polymer brushes. Upon increasing the molecular weight of the macromonomer, the Ea values were found to decrease. The opposite effect was observed for the polymacromonomers.


In this work, we developed and fabricated a paper-based anisotropic magneto-resistive sensor using a sputtered permalloy (Ni Due to its low cost, biodegradability, and renewability, among other properties, paper is being investigated as a functional material for disruptive applications such as interactive surfaces , skin-liIn our previous work ,16), we , we 16])Conventionally, AMR sensors and Nier poles , to direarticles  for bio-urfaces ,21)..81Fe19 tTo develop a paper-based AMR sensor, we proceed as follows: First, we develop a computational model to understand the empirically observed AMR response of thin NiAs a first example of application of the sensor, we consider educational clickers that are used to engage the classroom in the teaching and learning experience. With clickers, teachers can conveniently collect answers to a question from all students in real-time and subsequently use the immediate feedback of the classroom to improve the learning experience. With the intention of adding intelligent components to paper-based educational material, for example, we propose to employ the paper-based AMR sensor as the core of an educational clicker that can be naturally embedded in a textbook. We envision a simple, tactile clicker that especially young primary school students can easily operate. When answering a question, a student can choose between three answers ‘A’, ‘B’ and ‘C’ that correspond to the distinct angular positions ‘R sensor a,b.As an attempt to provide beginners to the braille system with teaching material that could help them improve their reading skills, we propose an educational game based on interactive braille flashcards as another application of the sensor c. A flasWhile designing both applications, we consulted with education researchers who recommended the use of motor cognition such as the turning of the clicker or the flashcard. Here, the principle of AMR naturally fulfills this requirement.To understand the response of the paper-based sensor, we first considered the qualitative AMR response of a 10 mm × 1 mm—strip of a Niubstrate . In 16]81Fe19 thAccording to the characterization method presented in gated in . FurtherEmploying the electro-magnetic computational model presented in Now that we know the existence of the t, and hence t, and hence decreasing We also propose that the angular shift between t of 900 nm, to interpret the measurements shown in In the following, we particularly consider the case of We scrutinized the AMR performance of a set of five sensors, f ≈0.4 % , whereasH, and for the corresponding loading cycle We assessed the reproducibility of the AMR response for each system and for each angular configuration over consecutive magnetic loading periods. Sweeping from positive to negative magnetic fields and back, we investigate the magnitude of the AMR peak of the paper-based NiAdditionally, we measure the asymmetry of absolute peak location as follows:The scatter plots given in Increasing the base resistance with the sensor stack to ∼1 kBased on the set-up described in For the fabrication of paper-based AMR sensors, we used low power magnetron sputter deposition to coat the paper surfaces with a thin film of Niented in ,16. In p markers a prior t markers b,c.After coating, we separated the anisotropic magneto-resistors by paper cutting away from the magnetic thin film. Due to the low thickness of the Niperature e,f. The Imposed by the paper surface, we found that the fabrication technique and patterning resolution dictate the volume, and therefore the electrical resistance, of the Nin series g. As an To interpret the empirically observed differences in the AMR of paper-based Niting. In , we obseC, the electrical current flows along a possible fiber path A. Each axis of fiber segment is characterized by a length As for modeling the path of the electrical current across the NiC, A)In the presence of a magnetic field, the NiGiven the orientation angle of a fiber segment, t, the electrical current partially passes through direct trails across regions where the fibrous topography becomes buried  is to be distributed statistically within u). Based on the central limit theorem, n) that can in turn be represented by an exponential-like distribution (r). In summary, we considered four normalized statistical distributions, Without loss of generality, and since we are interested in the qualitative response of paper-based Ni90∘,90∘] . Furtheral model c, and ini, is characterized by Thus, we generated each electrical path one fiber segment at a time. A fiber segment, The results obtained with the presented computational model are referred to in We used an AC magnetic field produced by Helmholtz coils at a frequency of 50 Hz with a maximum field intensity of 14 esistors b. In theH is the density of the magnetic field and H, is measured through an induced voltage in a measurement coil placed in the proximity of the sensor. While the orientation of the external applied magnetic field is fixed, we rotate the AMR element within the field (V and the input voltages of the amplifier We apply a constant voltage, i.e., he field a. At theFor the second metrology circuit, the input voltage In the case of a balanced WB and in the absence of a magnetic field, i.e., In the case of the presence of a magnetic field, we obtain Depending on the type of the metrology circuit, the magneto-resistive element possesses the following resistance:We conducted the characterizations at 21 We prototyped both sensor applications using the open-source micro-controller hardware and software platform Arduino UNO. We fed the sensor analog signal to the Arduino platform using the single-supply non-inverting operational amplifier Texas Instruments LM324. We used a plug-in 5V power source external to the Arduino hardware and amplifier circuit, and hence, noise-free. As for other sources of high and low frequency noise, we employed capacitors and cable twisting. For prototyping purposes, we employed the same magnetic field and the Helmholtz coils used in the characterization of the sensor. We note, however, that the source of magnetic field needs to be replaced by a different source of small size and light weight such as a permanent magnet or an inductive charger for a practical applicability of the sensor. Furthermore, we ensured that the magnetic field does not interfere with the functionality of the operational amplifier circuit and the Arduino platform. To identify the angular position of the sensor, we analyzed the sensor digital data using a sketch implemented on the Arduino development environment. We used the Processing environment to handle multimedia tasks needed for the application, for instance the audible locator indications needed for the interactive braille flashcards. We used a single non-bridged sensor, and hence, we solely considered the AC component of the sensor signal by filtering the steady part of the signal by means of a voltage subtraction circuit element designed before amplification. We prompted the user through the serial monitor of the Arduino development environment. For precise handling, we mounted the paper-based sensor on a turnstile that can be rotated using an attached handling knob.In this work, we developed a paper-based AMR sensor that can be used, for instance, in educational applications. We achieved a maximum AMR sensitivity of For a single AMR sensor, we could not make use of the mechanical bendability of the paper substrate as it moves the path of the electrical current away from the magnetization plane, and therefore, deteriorates the AMR sensitivity. For future work, we plan to investigate the foldability of paper for multi-plane sensing. In particular, we will investigate the planar fabrication of AMR sensors on the faces of a polyhedra, at first as a sheet of paper that we will ultimately fold to the desired polyhedral shape. As an application for the paper-based multi-plane sensor, we will consider a paper-based robotic building block.In this work, we fabricated hybrid prototypes of two educational applications using the paper-based AMR sensor. The lack of off-the shelf paper-based circuitry prevented the natural integration of the paper-based sensor in the application platforms, a book, and a flashcard, and hence, demolished the benefit of the low thickness of the paper-based sensor. As an outlook to the future of all-paper devices, it remains crucial to develop technologies, and make them widely accessible, to power and connect these devices in a way that is as mobile, thin, lightweight, and mechanically bendable as paper itself.Finally, the paper-based AMR sensor may represent an alternative to potentiometer sensors. For instance, rotary potentiometers rely on the mechanical force between a wiper and a resistive strip to change resistance, which need to be precisely controlled. In comparison, the functional paper-based Ni


The underlying mechanism for the giant AMR is an indispensable combination of atomic scale giant-MR-like effect and magnetocrystalline anisotropy energy, which was not accessed earlier. Furthermore, we demonstrate the bistable nonvolatile memory states that can be switched in-situ without the inconvenient heat-assisted procedure, and robustly preserved even at zero magnetic field, due to the modified interlayer coupling by 1% Ga-doping in Sr2IrO4. These findings represent a straightforward step toward the AFM spintronic devices.Antiferromagnets have been generating intense interest in the spintronics community, owing to their intrinsic appealing properties like zero stray field and ultrafast spin dynamics. While the control of antiferromagnetic (AFM) orders has been realized by various means, applicably appreciated functionalities on the readout side of AFM-based devices are urgently desired. Here, we report the remarkably enhanced anisotropic magnetoresistance (AMR) as giant as ~160% in a simple resistor structure made of AFM Sr 2IrO4 due to the combination of atomic scale giant-MR-like effect and magnetocrystalline anisotropy energy.The determination of the antiferromagnetic (AFM) orders by the anisotropic magnetoresistance (AMR) is one of the key components to the AFM-spintronics. Here the authors report enhanced AMR ~160% in Sr Although the antiferromagnetic (AFM) order serves as the second basic type of magnetic order, and has been discovered for nearly a century since the 1930s, it has so far been used as passive elements, such as pinning of the ferromagnetic (FM) layer in modern spintronics technology5. The main obstacle that keeps the AFM materials away from even more extensive applications is the great challenge in detection and manipulation of AFM orders because of their imperviousness to external magnetic field. Recently, this perception has been largely modified, and the emerging concept of AFM-spintronics has been garnering considerable interest9.Antiferromagnets represent the overwhelming majority of magnetic materials in nature, and exhibit fascinating physical properties, such as diverse spin textures and topologically protected states of matter12. The control of AFM orders, which was thought to be precisely difficult, has been experimentally realized by various means, including electrical switching16, optical excitation11, and heat-assisted magnetic recording18. On the detection side, anisotropic magnetoresistance (AMR), which is the magneto-transport counterpart of magnetic anisotropy energy, has been generally and successfully utilized, in analog to the traditional FM-based spintronics25. However, the readout signal, i.e., the AFM-based AMR (AFM–AMR), is commonly found to be small at a level of ~1% 22. This is incompatible with the scalability of the readout time and cell size in modern spintronics devices, and conceptual breakthrough on the readout side of AFM spintronics is required to obtain significantly larger signals.The AFM-spintronics, where magneto-transport is governed by an antiferromagnet instead of a ferromagnet, opens perspectives for both fundamental research and device technology, since the AFM orders offer some unique and irreplaceable advantages compared with ferromagnets. One of the major appealing features is the promise of ultrafast writing speed , enabled by the THz scale AFM resonance which is three orders of magnitude higher than the ferromagnets with GHz resonance frequency24. Although calculations predicted large density of states (DOS) anisotropy in antiferromagnets with strong SOC, experimentally observed AMR ratio is unfortunately small overall26. The substantial gap between theories and experiments based on MAE solely indicates that additional ingredients should be involved to enhance the AFM-AMR. Regarding this, AFM junction may be an alternative, and indeed giant AMR exceeding 100% at low temperature (T) was reported in an AFM IrMn-based tunnel junction25. However, spintronics effects in AFM heterostructures are strongly sensitive to disorder and perfect epitaxy, which hindered their experimental realization28.Magnetocrystalline anisotropy energy (MAE) determined by spin-orbit coupling (SOC) has been utilized as a generic principle to realize the AFM–AMR in previous studies. For instance, when the AFM spin axis is aligned along different directions with respect to the crystal axes, various resistive states are expected because of the induced anisotropy of electronic structure29 and anomalous Hall effect31 which were assumed to only happen in ferromagnets, were revealed in bulk AFM materials. This provides an excellent opportunity to combine the typical spintronics phenomena, i.e., giant or tunneling magnetoresistance (GMR or TMR) with AFM–AMR without expense of structural complexity. Note that AMR is also a bulk effect. Such a scheme may harvest two advantages. First, significantly enhanced AFM–AMR is expected because the typical spintronics effects are usually remarkable. Second, the synergy of different types of magneto-transports may lead to unconventional AFM-based functionalities.Recently, a number of exotic phenomena, such as spin polarized currentT in a simple resistor plate of spin-orbit coupled AFM Sr2IrO4 single crystal. Furthermore, by tiny Ga-substitution at Ir-site, nonvolatile resistive memory can be achieved, and the bistable states can be manipulated in-situ simply by varying the magnetic field (H) direction. Collaborative action of an atomic scale GMR-like effect and MAE is responsible for these super AFM-spintronics functionalities in this Jeff = 1/2 antiferromagnet. In the first part of the article, we illustrate the physical descriptions of anisotropic magneto-transport in Sr2IrO4. In the second part, we present remarkably enhanced AMR and its reversal behavior. In the third part, we demonstrate the AFM nonvolatile memory effect in the tiny Ga-doped Sr2IrO4.In the present work, we demonstrate the giant AMR reaching ~160% at low-2IrO4. The Jeff = 1/2 magnetic moments, entangling both spin and orbital momenta due to the strong SOC (~0.5 eV) at Ir site, develop a canted AFM order with uniform in-plane canting angle ϕ ~12o below TN ~240 K34. Neutron scattering demonstrated that the AFM state is in a twinned manner with equal domain populations33. Because of the canting, net magnetic moments appear alternatively in each IrO2 planes, and are coupled antiferromagnetically along the c-axis. Therefore, Sr2IrO4 is fully compensated at the ground state without macroscopic magnetization (M). A magnetic field H larger than the flop critical field Hflop drives the Jeff = 1/2 moments flop transition into a weak FM phase in which the net moments of the IrO2 layers are ferromagnetically aligned, accompanied concurrently with a sharp drop in resistance (R) at Hflop38. As revealed by microscopic investigations in Sr2IrO4, the basal-plane first nearest-neighboring exchange constant is about 60 meV39, and the exchange interaction along the c-axis is only about 1 μeV40. Such large anisotropic exchange interaction in Sr2IrO4 makes the flop transition possible. The AFM to weak-FM transition in Sr2IrO4 resembles the GMR effect in traditional FM-based spin valves, and we call it the GMR-like effect. More details of the GMR-like effect can be found in the 2CuO441, and then identified in double layered manganites42. This is an atomic scale effect and appears in a Jeff = 1/2 AFM state, which is unusual. While the previous studies of magnetotransport in Sr2IrO4 have illustrated some interesting features38, the AMR phenomenon related to the Jeff = 1/2 AFM lattice remains elusive. One possible reason is related to the crystal quality, as revealed by Kim et al.43. For instance, evident in-plane magnetic anisotropy was identified very recently when the Sr2IrO4 crystal quality was improved44.We first briefly recall some fundamentals of SrR(H) / R(0) − 1] data over a broad H (upto 5 T) and temperature T (35 K < T < 240 K) range, with the measuring geometry shown in the inset of Fig. I is always applied along the [001] direction (the c-axis), and H is rotated within the basal plane with an angle Φ relative to the [100] direction. The magnetic easy axis is [100] with Φ = 0o and the in-plane hard axis is [110] with Φ = 45o. Crystal quality is an important ingredient for observing evident anisotropy in Sr2IrO443. Therefore, X-ray diffraction (XRD) and energy dispersive spectroscopy (EDS) measurements were performed, which suggest that the samples are pure phase and high quality  curves at different Φ inter-cross at several H, as shown in Fig. Φ = 0o and 45o at three temperatures , relatively low Zeeman energy gain is required to overcome the MAE, and thus to trigger the Jeff = 1/2 moments flop transition and thereby the atomic-scale GMR-like effect. This is confirmed by the M(H) data at various T, as shown in Fig. Jeff = 1/2 moments flop transition is accompanied by a drastic enhancement in M in the low field range for both Φ = 0o and Φ = 45o, marking the conversion from the fully compensated state to the weak FM phase. In particular, it is true to see that the transition develops with a smaller critical field Hflop at Φ = 0o (easy axis) than at Φ = 45o (hard axis), in consistent with the MR data. An advantage is a very small Hflop ~0.2 T, favorable for practical AFM devices with Sr2IrO4.This phase diagram reflects the abnormal anisotropic magneto-transport behavior in SrM at Φ = 0o is overall larger than that at Φ = 45o upto H = 5 T (the maximum field used for M(H) measurements in the present work). This can be seen upto TN, demonstrating the unchanged magnetic easy axis after the flop transition45. By plotting ΔM (=M(Φ = 0o)–M(Φ = 45o)) as a function of H  to the [110] direction (hard axis)24. This is physically anticipated considering the essential role of the strong SOC in build up the electronic structure in Sr2IrO4. In Fig. Hc1 < H < Hc2 in the MR curves at Φ = 45o, after which the [110] direction is getting to be relatively more conductive than the [100] direction. This is indicative of the onset of the reduced bandgap dominating the transport. Complementary magneto-transport data measured under pulsed high magnetic field upto 50 T are shown in the Supplementary Fig. Furthermore, it is seen that H < Hflop, domain wall scattering may be qualitatively relevant based on three considerations. First, in region-I with H < Hflop, H is insufficient to trigger the flop transition, but may tilt the magnetic moments evidenced as gradual increase in M. However, the positive value of the finite MR in region-I excludes a possible origin arising from H-suppressed magnetic scattering effect, but indicates an enhancement of scattering effect in the system. Second, intensive domain wall motion has been demonstrated as H < Hflop in SIO43. For instance, with increasing H//[100], the domain with Jeff = 1/2 moments along [100] grows, but the domain with Jeff = 1/2 moments along [010] shrinks. The domain repopulation involves complex domain wall motions reflected as deviations from linear behavior and hysteresis in the magnetization measurements, as shown in Supplementary Fig. H < Hflop, coinciding with the hysteresis effect in M(H). This close relationship among the MR(H), M(H), and domain wall motion leads us to propose a domain wall scattering scenario responsible for the observed MR-bumps. However, with H//[110], the domains remain populated as H < Hflop, since the field has no preference to the domains43. As shown in Fig. H//[110], the MR-bumps are largely suppressed indeed, and instead continuous decrease can be seen in the MR curves. Simultaneously, the hysteresis in M(H) curves are also suppressed. These phenomena are consistent with the proposed domain wall scattering scenario. The remained weak MR-bumps may due to slight misalignment of H from the [110] direction, since any tilt of H leads to an imbalance in the domain population. Third, significant domain wall resistance has been theoretically revealed in SIO very recently by Lee et al37., further supporting the proposed domain wall scattering mechanism responsible for the MR-bumps in region-I. With increasing T, the MR bumps and its hysteresis are evidently suppressed at T > 50 K, indicating that H-suppressed magnetic scattering gets to dominate the magnetotransport. Surely, further comprehensive investigations are desired to clarify the low-field MR in region-I.Regarding the MR bumps at asing H//00, the d2IrO4, we now are in a position to track the AMR effects in our simple AFM resistor. In Fig. R as a function of Φ measured at T = 35 K and T = 90 K. Complementary AMR data can be seen in Supplementary Figs H-driven AMR reversal and large R-variation at intermediate H region.Having established the physical descriptions of the abnormal anisotropic magneto-transport in SrR(Φ)/Rmin−1) as a function of H obtained at T = 35 K and 90 K, respectively. Here, Rmin means the minimal R in the AMR traces. The AMR(Φ) curves exhibit pronounced peak around H~ 0.2 T. This is even remarkable at T = 35 K, and the maximum AMR ratio is found to be as large as 160% which is the largest value compared with those reported so far in AFM materials. AMR phenomenon was studied using different experimental setup in Sr2IrO4 previously, and a detailed comparison with the present work can be seen in the Hc1 < H < Hc2). In addition, inhomogeneities  within the sample resulting in regions with slightly different transition fields might also contribute a little to the AMR.Figure T = 35 K and 90 K, although a fourfold rotation symmetry is in principle anticipated because of the square lattice of Sr2IrO4. As revealed by several recent theoretical works, the in-plane anisotropy in Sr2IrO4 can be accurately described by a magnetic-lattice coupling model45. Importantly, it was found that the magnetic-lattice coupling effectively acts like a uniaxial anisotropy, once the magnetic moments are aligned along a certain direction, such as the Jeff = 1/2 moments flopping. Therefore, it is physically reasonable to expect a twofold AMR symmetry at H~Hflop, such as the present case, according to the proposed magnetic-lattice coupling model. In addition, weak R-tips can still be seen in the basin of the AMR trace, indicating existence of retained biaxial anisotropy.Here we note that the AMR symmetry in region II is more like twofold at both H//[110] are not expected to cause domain repopulation43. Therefore, the AMR hysteresis appears at both easy-axes and hard-axes. In Fig. H = 0.1 T is twofold with peaks at Φ~45o and ~225o. First, the application of H = 0.1 T is insufficient to trigger the flop transition at T = 35 K. Second, the domain wall motion becomes more impetuous when applying H along the magnetic easy axes  than along the hard axes . Therefore, rotating H = 0.1 T from hard-axis to easy-axis would significantly promote the domain wall motion, giving rise to the increase in R. If taking a closer look at the AMR trace, step-like anomalies with hysteresis can be identified (indicated by arrows), marking the booming of domain wall motion. Such domain wall motion process will be continued as further rotating H from Φ = 0o to 45o, since only the cases of H along the hard axes do not change the domain population. This gives rise to the ongoing increase in R till Φ = 45o. From Φ = 45o to 135o, the H direction is partly reversed, and thus the domain walls are gradually removed. As a consequence, R decreases with Φ from 45o to 135o. This process will be repeated when subsequently rotating H = 0.1 T from Φ = 135o to 315o, leading to the twofold AMR symmetry. In addition, such tunneling AMR is not observable at T = 90 K  follow H rotating within the basal plane of Sr2IrO4. For instance, the Ir moments can factually reach both the [100] direction and the [110] direction when rotating H within the ab-plane. In this sense, the anisotropic magneto-transport dominated by bandgap engineering emerges, for example it is relatively more conductive as Ir moments pointing along the [110] direction  compared with the [100] direction (with larger bandgap)24. As a consequence, a fourfold AMR symmetry with minima appearing right at the in-plane hard axes is obtained. More details of giant AMR phenomenon and its reversal can be found in Supplementary Fig. Regarding the fourfold AMR symmetry at  and the 0 directiJeff = 1/2 Sr2IrO4. Along this line, a natural proposal is if the various magneto-transport behaviors can be preserved after removing H. By this, we should be able to observe the interesting AFM-based spintronics functionalities at H = 0 T, i.e., the AFM memory effect. A key step is to retain the flopped magnetic state from recovery after the H-writing. It is found that the non-doped Sr2IrO4 is not proper to realize this purpose, since the pristine state can be recovered after different H sweeping  curves taken at T = 10 K. Importantly, Mr at Φ = 45o is found to be much larger than that at Φ = 0o. The reason includes that first the larger Mr means the stronger suppression of magnetic scattering. Second, more Ir moments remaining at the [110] direction would lead to relatively smaller bandgap in the resistor. Both effects are all pointing to a higher conduction along the [110] direction at H = 0 T, as compared with the [100] direction in the tiny Ga-doped Sr2IrO4.The above data have shown a highly efficient scheme, which is the combination of various types of magneto-transports dominated by either spin polarized current or MAE energy, to enhance the AFM-AMR effect in ing Fig. . We thenT = 10 K, and then measured the MR by performing successive H-cycles either at Φ = 0o or Φ = 45o. As shown in Fig. H-cycle, two reversible resistive states can be obtained by further H writing procedures, demonstrating an AFM memory effect. The two memory states can be switched by in-situ H-writing without heat-assisted procedure, and the resistive ratio of the two states is as large as ~4.5%. This is a major point deserved for high appreciation and it is different from the operation utilized in AFM MnTe17 and FeRh18. The drift effect seen in the resistance over time  data can be seen in the Supplementary Fig. H applied initially either at Φ = 45o or Φ = 0o, and the same results were obtained. In our devices, the memory states are stable against a field upto ~1 kOe. Although this is smaller than that in compensated AFM materials showing very high rigidity, it is robust against electromagnetic disturbances, and the relatively small switching field would facilitate the operation in devices.This is confirmed by further transport characterizations. We first zero field cooled the resistor to ime Fig.  may due 2IrO4, we then go to some details of the physical properties of the resistor. First, both the high and low resistances (RH and RL) are smaller than the pristine state. This can be understood directly by the different Mr for these cases. For instance, the initial state after zero field cooling has zero net magnetization46. Second, M at Φ = 45o is larger than at Φ = 0o, different from the case in the non-doped Sr2IrO4. This should be ascribed to the modification of interlayer coupling by Ga-doping. As revealed by recent calculations, the interlayer coupling can effectively change the anisotropic magnetization in Sr2IrO447. If considering bare effect of interlayer coupling in Sr2IrO4, the [100] direction is easier than the [110] direction as AFM interaction dominates. However, this situation is reversed, i.e., the [100] direction behaves even harder than the [110] direction, when the interlayer coupling becomes FM-like . The significant role of interlayer coupling in determining anisotropic magnetism looks to be general in iridates48. As shown in Fig. M(H) hysteresis evidences the appearance of FM coupling of the IrO2 layers, in analogous to the Rh-doping effect49. Therefore, it is physically reasonable to expect different anisotropic magnetization in the tiny Ga-doped Sr2IrO4 compared with the non-doped one.Having demonstrated the AFM-based nonvolatile memory in the tiny Ga-doped SrJeff = 1/2 antiferromagnets without auxiliary reference layer. Note that coupling to FM layer would lose the unique merits of antiferromagnets in AFM spintronics devices. The AMR ratio is found to reach ~160% at T = 35 K in the present work, which is much larger than previously available values37. It is noted that very large tunneling AMR exceeding 100% at T = 4.2 K was identified in AFM IrMn-based tunnel junctions, while additional FM NiFe layer was used for inducing exchange spring effect25, different from the present case. Regarding the AFM-based nonvolatile memory, it has been rarely reported before. In the previous works, to obtained different memory states, the sample has to be heated above TN, and then cooled below TN with magnetic field18. Here we show an in-situ manipulation of the bistable states, which may have advantages in practical devices.We have demonstrated giant AMR and nonvolatile memory in simple AFM resistors made of Jeff = 1/2 antiferromagnets. The crucial part of our scheme is to combine various types of magneto-transport behaviors, i.e., the atomic scale GMR-like effect due to spin polarized current, and crystal AMR due to the MAE energy, in a single system. Importantly, the scheme proposed in the present work is applicable to a broad class of AFM materials. As a fundamental piece of the two major findings, the spin polarized current was theoretically predicted to generally exist in most antiferromagnets except those with simple collinear spin orders very recently29. In addition, the scheme could also be extended to some recently discovered AFM alloys where exotic anomalous Hall effect was identified, and distinctive AFM spintronic functionalities would be expected50.Our work has shown an efficient mean to achieve significantly large AMR and nonvolatile memory in the T = 35 K is revealed in a simple resistor made of AFM Sr2IrO4 hosting Jeff = 1/2 moment due to strong spin-orbit coupling, owing to a combination of an atomic scale GMR-like effect and the magnetocrystalline anisotropy. The enhanced AMR can be observed at higher-T, although its magnitude decreases gradually with increasing T. Further experiments demonstrated that the plural magneto-transport behaviors can be preserved by only 1% Ga-doping in Sr2IrO4 without the assist of external magnetic field. Importantly, in the tiny doped resistor, nonvolatile AFM memory effect is identified, and the bistable memory states can be operated in-situ. The modification of interlayer coupling by Ga-doping is essential for realizing the nonvolatile memory. Our work has illustrated a very efficient scheme to significantly improve the spintronics functionalities in antiferromagnets.In summary, significantly enhanced AMR reaching ~160% at 2IrO4 single crystals (2 × 1 × 0.5 mm3) were synthesized from off-stoichiometric quantities of SrCl2, Sr2CO3, and IrO2 using the self-flux techniques. The thoroughly mixed powders were placed in a platinum crucible covered with a lid, and then melted at 1250 °C in a programmable furnace in air. After this, the crucible was cooled to 800 °C at a rate of 6 °C per hour and then furnace-cooled to room temperature. The molar ratio of SrCl2:IrO2 was set at ~8:1, which was found to be critical for obtaining high quality crystals. For a comparison, 1% Ga-doped Sr2IrO4 single crystals were also synthesized through the same method. The stoichiometry of the resulting crystals was confirmed using energy dispersive spectroscopy measurements. The pure phase of the crystals was examined by performing room-temperature powder X-ray diffraction measurements on thoroughly crashed crystals. The crystals were also checked using Rigaku XtaLAB miniTM diffractometer at room temperature.The SrI flowing through the sample, the electrodes of current source were made as large as possible (>1 mm2). With regard to the magneto-transport measurements, exciting current I was applied along the [001] direction, and the magnetic field H was always applied within the basal plane of the crystals. Therefore, the AMR refers to the  behaviors. Magnetization as function of T and H were measured using a QD superconducting quantum interference device. All the M(H) curves were measured after the zero-field cooled (ZFC) sequence. For the high field transport measurements, the same device structure was used, and the pulsed magnetic field upto ~50 T with a duration time of ~50 ms was generated by using a nondestructive long-pulse magnet energized by a 1 MJ capacitor bank.Electric transport measurements for the crystals were carried out using a four-probe method in a Quantum Design (QD) physical property measurement system equipped with a rotator module. Silver paste was used to make the electrodes. In order to have homogeneous electric current Supplementary Information


Liver disorders may be associated with normal pulmonary hemodynamic, hepatopulmonary syndrome (HPS), or portopulmonary hypertension (POPH). In this study, we aimed to investigate the effect of the severity of liver dysfunctions on blood-borne variables, and pulmonary hemodynamic during repeated ventilation with hyperoxic and hypoxic gases.n = 7), portal vein ligation , common bile duct ligation , and combination of them . Twenty-eight days later, right ventricular systolic pressure (RVSP) and systemic blood pressure were recorded in anesthetized animals subjected to repeated maneuvers of hyperoxia (O2 50%) and hypoxia (O2 10%). Besides, we assessed blood parameters and liver histology.Female Sprague Dawley rats were assigned into four groups of Sham  was not detected in both CBDL+PPVL and CBDL groups, whereas, it retained in the PPVL group.Severe liver damage increases RVSP in the CBDL+PPVL group linked to the high level of ROS, low levels of serum estradiol and platelets or a combination of them. Furthermore, the high RVSP at the noted group could present a reliable animal model for POPH in female rats. Pulmonary artery pressure decreases in HPS as a result of pulmonary vasodilation and vascularization. In addition, the alveolar-arterial Omitation , 2. On tmitation –5. Furthmitation , 7.The mechanisms of POPH and HPS have not been fully understood yet. It has been proposed that some vasoconstrictive and proliferative substances may escape the liver through porto-systemic shunt, and influence directly the pulmonary smooth muscle cells and capillary endothelium. Also, a prolonged increase in cardiac output may harm the pulmonary capillary endothelium. All aforementioned may pave the way for vascular remodeling and induction of POPH , 8, 9. IIt has been reported that the prevalence of pulmonary artery hypertension in women is higher than men . Some scThere are a few controversial investigations concerning the relationship between the severity of liver disease and pulmonary dysfunctions –32. HoweUnlike the systemic circulation, alveolar hypoxia, constricts the vessels in the affected region of the lung, thereby moves the blood from the area with low oxygen pressure to the well- ventilated ones. This physiologic phenomenon is called hypoxic pulmonary vasoconstriction (HPV). The limited studies have reported that HPV decreases or disappears in patients with liver disease and animal model of cirrhosis , 35. NevWith the above background, in this study, we established three graded models of liver dysfunctions including mild (PPVL), moderate (CBDL), and for the first time, severe (CBDL+ PPVL), based on liver histology and blood-borne variables. We assessed pulmonary and systemic hemodynamic, and the sensitivity of pulmonary vessels to hypoxia during repeated ventilation with hyperoxic and hypoxic gases. This study was performed in female rats, because the relationship between the estradiol level and the prevalence of pulmonary hypertension with liver dysfunction has not been reported in female animals yet.n = 7 in each group.Twenty eight female Sprague-Dawley rats (200–250 g) were purchased from the Laboratory Animal Breeding Center of Shiraz University of Medical Sciences, Shiraz, Iran. The animals were housed in standard cages under controlled laboratory temperature, humidity, and 12:12 h’s light/dark cycles. They had free access to water and standard food, and were fasted 2 h before starting experiments. Animals were divided randomly into 4 groups of Sham, partial portal vein ligation (PPVL), common bile duct ligation (CBDL), and combinations of them (CBDL+PPVL). In order to rule out effects of diurnal variations on our results, all experiments were performed during 11 am-16 pm. Only animals in diestrus cycle were entered to the study to exclude the effect of estrus cycle and different concentrations of estradiol on the experiments. This was performed by analysis the cell types of the vaginal lavages according to the previous studies . Briefly2 balanced with N2 (OX), and (iii) hypoxic gas: 10% O2 balanced with N2 (HOX) [Three different gas mixtures were employed in this study, (i) air, (ii) hyperoxic gas: 50% ON2 (HOX) .The experiments were designed in two phases. At the first phase, animals were anesthetized by intraperitoneal injection of 60 mg/kg Ketamine hydrochloride and 10 mg/kg Xylazine . In addi2) for 10 min, followed by 5 min ventilation with hypoxic gas (10% O2). Next, 10 min ventilation with hyperoxic gas and 5 min ventilation with hypoxic gas was repeated. The method of hypoxic challenges was optimized from our previous studies and others [The second phase of experiments was performed 28 days later. Animals were anesthetized by intraperitoneal injection of 60 mg/kg sodium thiopental , 42. It d others , 45, 46.Plasma was analyzed for AST, ALT and ALP spectrophotometrically using an automated analyzer system . Blood gas variables were measured by Easylyte blood gas analyzer . Also, WBC and platelet count were measured by autoanalzing method . Serum estradiol was measured by ELISA kit using a micro plate reader . All noted measurements were performed in a blinded manner in the hospital.At the end of the experiments, the abdomen was opened by a midline incision, liver removed and prepared for histological analyses in the department of pathology. Briefly, livers were fixed using 10% formalin for a few days. Then, the samples were dehydrated by different concentrations of ethanol, and embedded in paraffin. Next, 5 μm of sections were mounted on glass slides and stained with hematoxylin and eosin. All slides of histology were evaluated in a blinded manner by a pathologist that used Ishak histology scoring system for the evaluation of liver histological score in terms of liver necrosis, apoptosis, and inflammation and ductular reaction .Plasma concentration of MDA was determined using a TBARS assay. Briefly, plasma samples and standards  were mixed with 0.25 N, HCl (Sigma), 20% tricholoro acetic acid (Sigma) and 0.8% tribarbituric acid (Sigma) incubated at 90 °C for 60 min, cold in ice, and centrifuged at 4000 rpm for 10 min. Then, 200 μl of prepared solutions was added to each well, and the absorbance of well-plate was read at 532 nm using a microplate reader  .Griess method was used to measure plasma concentration of NO metabolites as described previously . BrieflyP < 0.05 and the confidence limits used were the 95% intervals.Data are given as mean ± SE. Analysis of variance (ANOVA) with the Tukey’s post hoc test was used for multiple comparisons. We also used the paired T-Test for comparing the data of one group before and after hypoxia maneuvers. Furthermore, we compared data of histology by non-parametric Mann-Whitney test. All analyses were performed using a software of SPSS 18. Significance was assumed when P < 0.01). Also, ALT in the CBDL+PPVL group was higher than the ones in the Sham and PPVL groups (P < 0.01), and in the CBDL group was higher than that in the Sham group (P < 0.05). Although, AST, ALP and ALT in the CBDL+PPVL seem to be more than those in the CBDL group, these differences were not statistically significant. In addition, AST, ALP and ALT in the PPVL were similar to those in the Sham group . There was no difference in PaO2 values among the CBDL, PPVL, and Sham groups. PaO2/FIO2 ratio in the CBDL+PPVL group was lower than the ones in the CBDL, PPVL and Sham groups (P < 0.05). Although, PaO2/FIO2 in the CBDL group seems to be lower than those in the PPVL and Sham groups, these differences were not significant. There was no alteration in PaCO2 values among the CBDL+PPVL, PPVL, and Sham groups. Nevertheless, PaCO2 in the CBDL group was lower than that in the Sham group (P < 0.05). Also, pH in the CBDL group was higher than those in the Sham and PPVL group (P < 0.05). pH in other group were almost similar. HCO3− in the CBDL+PPVL group was higher than the ones in the other groups (P < 0.05) , PPVL and Sham (P < 0.01) groups. Also, in the CBDL group, it was higher than the ones in the Sham and PPVL groups (p < 0.01). However, there was no difference in WBC between the PPVL and Sham groups. The plasma platelet level in the CBDL+PPVL group was lower than those in the other groups (P < 0.01), whereas, there was no difference in platelet level among the CBDL, PPVL and Sham groups (Table WBC in the CBDL+PPVL group was higher than those in the CBDL (m P < 0.0 groups. P < 0.001). Also, in the CBDL group, it was higher than those in the PPVL and Sham groups (P < 0.01). There was no difference in the liver histological scores between the CBDL and CBDL+PPVL groups, or between the PPVL and Sham groups  and CBDL+PPVL (p < 0.001) groups were higher than the one in the Sham group. Also, RVSP in the CBDL+PPVL group was higher than that in the PPVL group (p < 0.01). However, there was no significant variation in RVSP between the CBDL and PPVL groups, or between the PPVL and Sham groups.RVSP during the first ventilation with hyperoxia gas (OX1) in the CBDL (The first ventilation with hypoxic gas (HOX1) increased RVSP in the Sham and PPVL groups insignificantly with no change in the CBDL and CBDL+PPVL groups. There was no difference in RVSP between the PPVL and Sham groups, or between the CBDL+PPVL and CBDL groups during ventilation with hypoxic gas. Also, there was no difference in RVSP among all groups of Sham, PPVL, CBDL and CBDL+PPVL during ventilation with hypoxic gas.p < 0.05) and CBDL+PPVL (p < 0.01) groups were still higher than that in the Sham group. Also, RVSP in the CBDL+PPVL group was more than that in the PPVL group (p < 0.05). However, no alteration in RVSP was detected between the PPVL and Sham groups.During ventilation with hyperoxic gas for the second time (OX2), RVSP in the CBDL (p < 0.05), whereas, RVSP tended to decrease in the CBDL+PPVL group insignificantly. Furthermore, there was no difference in RVSP among all groups of Sham, PPVL, CBDL and CBDL+PPVL  increased RVSP in both groups of Sham and PPVL significantly  during OX1 conditions. There was no difference in mBP between the PPVL and Sham groups, or between the CBDL and CBDL+PPVL groups. Ventilation of animals with the first and second hypoxia maneuvers decreased mBP in all groups. No alteration was detected between the values of mBP during OX2 conditions , RVSP and RVDP have been shown in Fig. P < 0.001). There was no significant difference in the values of MDA between the PPVL and sham groups, or between the CBDL and CBDL+PPVL groups . There was no significant difference between the values of NO metabolites between the PPVL and sham groups, or between the CBDL and CBDL+PPVL groups , and CBDL+PPVL (p < 0.01) groups. Although estradiol in the CBDL+PPVL group tended to increase, it was not significantly different as compared with the Sham or PPVL groups. Also, estradiol in the CBDL+PPVL group was lower than that in the CBDL group (p < 0.01). There was no significant difference in the values of estradiol between the PPVL and sham groups  at the beginning of hypoxic maneuver linked to a reduction in depolarization rate of cardiac pacemaker cells . It was 2 in the CBDL and Sham groups, while PaCO2 and pH in the CBDL group were less than those in the Sham group. This could be caused by cirrhosis-induced hyperventilation [2 in the CBDL+ PPVL group may be linked to the dominant effect of diffusion impairment compared with the hyperventilation [2/FIO2 ratio in the CBDL+PPVL group is verifying the injury of the blood gas barrier in the severe liver dysfunction. In both HPS and POPH, low PaO2 and low saturation of hemoglobin with oxygen have been reported [2 may lead to pulmonary vasoconstriction and explain partly increased RVSP in the CBDL+PPVL group (Table There was not a difference between the values of PaOtilation . On the tilation . Furtherreported , 68–70. The plasma concentration of MDA in the CBDL group was more than those in the sham and PPVL groups. Other investigators also have expressed that oxidants increase and antioxidants decrease in liver cirrhosis , 71. ROSThe platelet level and RVSP in the CBDL+PPVL group was lower than those in the other groups. It has been indicated that platelet level is linked to pulmonary hypertension and the rate of survival , 79. On Together, POPH occurs following liver cirrhosis with portal hypertension, and is associated with a mild hypoxemia, thrombocytopenia and inflammation , 81, 83.In this study, we developed three levels of mild, moderate and severe liver dysfunctions in terms of liver histology and biochemical substances in the blood. We found that the ligations of CBDL together with PPVL in female rats, can be used as an animal model for induction of POPH. Also, the hypoxic response may change RVSP based on the severity of liver dysfunction. However, more studies are needed to clarify whether or not this model is applicable in male rats and other species. Furthermore, further studies are needed to compare the mechanisms of high RVSP in the noted model and POPH in human.