There is mixed evidence whether reflecting on an existential threat increases negative affect and thereby elicits subjective arousal and physiological activation. Additionally, it is debated whether different existential and non-existential threats elicit different arousal responses, although systematic comparisons are lacking. The current study explored affective, subjective, and physiological arousal responses while comparing several existential threats with a non-existential threat and with a control condition. One-hundred-and-seventy-one undergraduate students were randomly allocated to one of four existential threat conditions: mortality salience (MS), freedom restriction, uncontrollability, and uncertainty; or to the non-existential threat condition: social-evaluative threat (SET); or to a control condition . Self-reported positive/negative affect was measured before and after reflection, while subjective arousal and physiological activation  were measured on a high time-scale during baseline and reflection. Results showed larger increases in self-reported negative affect, as compared to the control condition, for all existential threat conditions, while there were no differences between the control condition and threat conditions regarding positive affect, subjective arousal, skin conductance, respiratory rate, and respiratory sinus arrythmia. There were subtle differences between existential and non-existential threat conditions, most notably in affective responses. Correlations showed positive associations between negative affect and subjective arousal and between trait avoidance and subjective arousal. This study is the first to systematically compare affective, subjective, and physiological changes in arousal due to reflecting on different existential threats, as well as one non-existential threat. We showed that, as compared to a control condition, reflecting on threats has a large impact on negative affect, but no significant impact on positive affect, subjective arousal, and physiological activation. A downside of the advanced human ability to think beyond the here and now is that we can anticipate threatening scenarios that may occur . Imaginea priori meaning  , that we are ultimately alone in the world , that we are responsible for everything we do , and that life has no meaning) . There ameaning) . The empmeaning) , whereasmeaning) , while omeaning)  or incremeaning) . Additiomeaning) , while ameaning) . Second,meaning)  as well meaning) ; while mmeaning) . In contmeaning) 1, althoue affect . Fourth,e affect , but it e affect . Experime affect . Similare affect . To our The main goal of the current study was to compare affective/subjective arousal/physiological responses elicited by reflecting on different existential threats. Despite the variety in existential threats and the debate about whether certain existential threats elicit unique responses over others e.g., , researcImportantly, we took a more fine-grained approach to investigating arousal than previous studies by measuring arousal on a high time-scale over the whole course of threat reflection. This is a novel approach, as previous existential threat research only measured affect before and after threat reflection  or physiMoreover, we measured cardiac output (CO) and total peripheral resistance (TPR), which, according to the biopsychosocial (BPS) model of arousal regulation  can diffFinally, since certain self-reported personality traits  have been proposed to offer anxiety/arousal-buffering effects when reflecting on threats , we alsoOne-hundred-and-eighty-five young adults  participated in the experiment. Participants were recruited via social media and locally in the university area, with the requirement that they were between 18 and 35 years of age and spoke fluent German.post-hoc combined into one threat condition (n = 115).In total, 14 participants were excluded, either due to technical difficulties  or other reasons . Thus, the final sample contained 171 participants , with 30 participants in the MS condition, 28 participants in the freedom restriction condition, 28 participants in the uncontrollability condition, 29 participants in the uncertainty condition, 28 participants in the SET  condition, and 28 participants in the control condition . To test for general effects of threat with increased statistical power, all existential threat conditions were also Participants were compensated with course credits or €7 in cash. The experiment was approved by the ethical committee of the University of Salzburg.Participants were semi-randomly allocated to the different conditions, based on the order that the participants were tested (by repeatedly cycling through a list of six conditions). Participants read a short instruction on a computer screen, asking them to think about a certain situation, as well as about the emotions their thoughts evoked and what else they thought would happen in the situation. The instructions were based on the traditional mortality salience (MS) manipulation , althougThus, in the MS condition, participants were asked to think about their own death. In the freedom restriction condition, participants were asked to think about a situation in their life where they had not been free . In the uncontrollability condition, participants were asked to think about the aspects of their life that make them feel powerless and that implied lacking control to influence important things in life. In the uncertainty condition, participants were asked to think about the aspects of their life that made them feel uncertain. In the SET condition, participants were asked to imagine that they were about to give an improvised socially-evaluated speech about their personality traits. Finally, in the TV salience condition (the control condition), participants were asked to think about watching television, which is a commonly-used control condition in MS research . The comAn overview of the experimental procedure is displayed in “How well did you manage to imagine the situation?” with a scale ranging from 1 (completely not) to 5 (completely). On average, participants responded with 3.5 (between “moderate” and “well”). The second question was: “Out of the 3 min that you had to think about the situation, how much percent of the time did you actually think about the situation?” ranging from 0 to 100%. On average, participants responded with 69.2%. The third and final question was an open-ended question: “Please describe shortly about what you thought about.” These responses were used to analyze the emotional content of the thoughts during the reflection period (see section “Written Affect-Related Words”).To check whether participants actually reflected on the instructed situation during the 3-min reflection period, three questions were asked. The first question was: enthusiastic, elated), pleasant activation , activation , unpleasant activation , activated displeasure , and displeasure . The adjective format (translated to German) was used, with scales ranging from not at all (1) to extremely (5). Since we were interested in valence more generally and in order to reduce the number of variables, we calculated a positive affect scale by averaging the positively valenced subscales  with a good internal consistency , and a negative affect scale by averaging the negatively valenced subscales  with a good to excellent internal consistency .To measure positive/negative affect, six subscales of the 12-point core affect circumplex  were usePlease describe shortly about what you thought about”). The German 2001 dictionary (SD = 23.0), consisting on average of 62% dictionary-recognized words (SD = 24.2). Since, ideally, these analyses would be performed with at least 50 words2, the results should be interpreted with caution. It should also be kept in mind that negations of emotional words – e.g., not happy – would also count as emotional words – in this case a positive affect-related word.As an exploratory additional measure of positive/negative affect, we analyzed the written responses to the open-ended attention check question  and negative emotion , as well as three specific negative emotions: anger , fear/anxiety , and sadness .We analyzed positive and negative affect-related words by using all available emotional categories in the dictionary, which have been shown to be sensitive to written emotions  and are 100  to 100 (very aroused), was shown on the right side of a black screen with a fixation cross. Participants were instructed to indicate their current arousal level  just before the baseline and reflection period, and then to reassess this at least once every 15 s or whenever they felt that their arousal level had changed. The average subjective arousal was exported for every 10 s and averaged into 1-min bins.To record subjective arousal on a high timescale during both baseline and reflection, we used “CARMA”: software for Continuous Affect Rating and Media Annotation . The scaSkin conductance, cardiovascular responses (electrocardiography and impedance cardiography), and respiration were recorded continuously using a 64-channel amplifier  and Polybench 1.22  with a sampling rate of 1024 Hz. The ground electrode was situated on the non-dominant wrist.Two software programs were used to analyze the physiological measures (except for BP): first, the ANSLAB toolbox V2.6;  was usedTwo Ag/AgCl electrodes  were attached with Velcro bands to the inside of the medial phalanges of the index and middle fingers of the participants’ non-dominant hand. The hand rested on a pillow with the palm upwards. The area bounded by the phasic signal and abscissa, divided by the epoch duration , was calculated automatically .Systolic and diastolic BP were measured from the non-dominant upper-arm using an automatic blood pressure monitor , which was operated by the experimenter after the baseline period and before and after the reflection period. BP data preprocessing was performed in SPSS 24 . Mean arECG was recorded using a two-lead unipolar modified chest configuration with electrodes on the right collar bone and on the lowest left rib. R-waves in the ECG were automatically detected and manually checked, and heart rate  was exported .Respiratory sinus arrhythmia (RSA) was analyzed by spectral analysis as the high frequency component of variation in inter-beat intervals  within the 0.14–0.5 Hz frequency band using fast Fourier transform with the Welch algorithm . RSA valRespiratory rate  was assessed to account for its potential confounding influence on RSA in within-subject reactivity analyses . RespiraICG signals were recorded using an eight-spot pairwise electrode configuration. Pre-gelled adhesive electrodes were placed at the neck and abdomen following the guidelines by The ICG signal was ensemble-averaged in synchrony with the ECG R-wave . The R- –5) was computed by dividing MAP by CO and multiplying those values by 80 , mean amplitude of baseline impedance , the amplitude of the C- and B-points, and left ventricular ejection time  values were exported. ICG data preprocessing was performed in SPSS 24 . Mean Z0es by 80 .“When I’m faced with a decision, I am afraid to make a mistake.”) and low trait approach  would increase the impact of threats. Both the trait avoidance (α = 0.87) and trait approach (α = 0.88) scales had good internal consistency.The generalized approach- and avoidance-motivated personality scales  were use“On the whole, I am satisfied with myself.”), an 11th general self-esteem item was added: “I have high self-esteem.” The scale had acceptable consistency overall (α = 0.74).The Rosenberg self-esteem scale  was usedStatistical analyses were performed in RStudio version 1.1.456  using R Reactivity  was calculated using reflection minus baseline . Specifimice R package  were used. To assess differences between conditions, two-sample t-tests (based on linear regressions) were used. Additionally, analyses of RSA reactivity were repeated with linear regressions and RR as a covariate, as recommended by U tests to assess condition differences.Before looking at reactivity, we checked whether there were any between-condition differences at baseline, using univariate ANOVAs with condition as a fixed factor. To assess whether the threats induced significant reactivity, one-sample d is reported (except for the sign tests for significant word counts). Additionally, Bayes factors (with default uninformed priors) using the BayesFactor R package (BF < 0.3125). Multiple comparison correction was applied for all analyses using false-discovery rate  for individual conditions and small effect sizes (d = 0.23) for the existential threat composite. Additionally, the final sample size offered 80% power to detect differences with the control condition with medium-large effect sizes (between d = 0.75 and d = 0.77) for individual conditions and with medium effect sizes (d = 0.60) for the existential threat composite. Finally, the complete sample size offered 80% power to detect correlations with small effect sizes (d = 0.19). Additional use of Bayesian model comparison offered the distinction between non-significant results due to lack of power or due to support for the null hypothesis.A  G∗Power  showed tp’s > 0.096, FDR-corrected p’s > 0.961.ANOVAs indicated no significant effect of condition or combined existential threat conditions on any of the baseline values of the dependent variables, uncorrected Plots for the three aggregate conditions  can be found in Self-reported positive affect decreased from before to after the manipulation in all conditions except for the SET condition, which did not change. This decrease was not more pronounced in the threat conditions than in the TV salience condition: Only the freedom restriction condition did not differ from the TV salience condition, while all other conditions had inconclusive results. All separate existential threat conditions  showed larger decreases in positive affect than the SET condition.Self-reported negative affect increased in the freedom restriction, uncontrollability, and uncertainty conditions, as well as for the existential threat composite, and these increases exceeded those seen in the TV salience condition. In the TV salience condition itself, negative affect did not change, while the MS and SET conditions had inconclusive results. The uncontrollability condition showed larger increases in negative affect than the SET condition, while the MS condition did not differ from the SET condition.An overview of the written affect-related word results can be found in Results showed that participants in all conditions reported positive and negative affect-related thoughts, which significantly differed from zero, though only the MS condition and combined existential threat conditions reported more negative affect-related thoughts than the control condition or the SET condition.For anger-related thoughts, only the combined existential threat conditions significantly reported anger, although this could not be compared to the control or SET conditions due to a lack of observations.For fear/anxiety-related thoughts, the MS and uncertainty conditions and the existential threat composite significantly reported fear/anxiety, though none reported more fear/anxiety than the control or SET conditions.For sadness-related thoughts, the MS and uncontrollability conditions and the existential threat composite significantly reported sadness, though only the MS condition and the existential threat composite reported significantly more sadness than the SET condition, and only the MS condition also reported more sadness than the control condition.An overview of the subjective arousal results can be found in Subjective arousal increased in all conditions for each minute of the reflection. However, the magnitude of these increases was not significantly higher for the threatening conditions than for the TV salience condition. There was substantial Bayesian evidence for no differences between the SET condition and freedom condition during minute two and between the SET condition and the uncontrollability condition and all combined existential threat conditions during minute three.An overview of the physiological activation results can be found in Results showed significant increases in SC  in the existential threat composite during the first minute of reflection, although there was inconclusive evidence for larger increases in SC compared to the control or SET condition. Additionally, all combined existential threat conditions showed significant increases in RR  during the first and last minute of reflection, as well as for the uncertainty condition in the last minute and for the SET condition during the second minute, though again there was either inconclusive evidence or substantial evidence for no differences compared to the control or SET condition. Finally, RSA  showed significant decreases during the first minute , second minute , and the third minute of reflection ; which did not change when correcting for RR reactivity for the first and second minute, although the effect disappeared for the freedom restriction and uncertainty conditions for the third minute; again there was either inconclusive evidence or substantial evidence for no differences in RSA reactivity compared to the control or SET condition.All other physiological measures  largely showed substantial evidence for no changes and no differences between individual conditions compared to the control condition or the SET condition, with some inconclusive results.An overview of the correlation results between reactivity of self-reported affect, subjective arousal, physiological activation, and personality traits can be found in Results showed interesting medium-strength positive associations between negative affect reactivity and subjective arousal reactivity (for minutes two and three), as well as between trait avoidance and subjective arousal reactivity (for minutes two and three). Additionally, as could be expected, there were associations with large effect sizes between the three different minutes of subjective arousal, and between the trait self-esteem and traits avoidance and approach (though not between traits avoidance and approach itself).Notably, there was either inconclusive evidence or substantial evidence for no associations between physiological activity and affect/subjective arousal/traits.The aim of the present study was to investigate whether reflecting on  threats elicits changes in self-reported affect, subjective arousal, and physiological activation, and whether these changes differ from a control condition . As hypothesized, results indicated that reflection elicited increases in negative affect, subjective arousal, (partly) sympathetic activation  and decreases in positive affect and parasympathetic activation (RSA). However, while the existential threat conditions evoked larger increases in negative affect than the control condition did, the threat and control conditions did not differ in terms of changes in positive affect, subjective arousal, or physiological activation. Therefore, we conclude that reflecting on threats in particular has a large impact on negative affect, but no significant impact on positive affect, subjective arousal, or physiological activation.Our arousal results are in line with previous research showing that reflecting on existential threats evokes large increases in negative affect , as wellThe current study extends the literature on affect and physiological activation by also measuring subjective arousal during reflection on a high time-scale. The subjective arousal responses showed large increases during threat reflection, although these did not differ from the control condition. These results demonstrate an absence of arousal suppression due to proximal defenses, as would be predicted by the dual defense model of terror management . InteresThe MS condition differed from the other threat conditions in terms of its sensitivity to the two measures of self-reported affect. Participants in the MS condition showed inconclusive changes in negative affect after reflection, with no significantly-larger increases in negative affect than in the control condition. This lack of affective responses has also been found in previous MS studies and forms the basis of the “affect-free claim” . HoweverConsidering associations between changes in affect, subjective arousal, physiological activation, and personality traits, we found no associations with physiological reactivity. Our results did show medium-strength associations between higher trait avoidance and larger increases in subjective arousal, which in turn were related to increased negative affect. This is consistent with several studies showing that those who use more avoidance coping tend to feel more stressed . TherefoTo answer the main question of the study – whether reflecting on  threat evokes negative affect, subjective arousal, and physiological activation – our results indicated that brief episodes of reflecting on existential givens do elicit large increases in negative affect, even when compared to a control condition. Threat reflection also evoked small decreases in positive affect, increases in subjective arousal, and changes in physiological activation, but these changes were not higher than those seen in a non-threatening control condition.Another aim of the current study was to compare the arousal responses elicited by reflecting on four different existential threats: mortality salience (MS), freedom restriction, uncontrollability, and uncertainty; and one non-existential threat: social-evaluative threat (SET). Although all threat conditions showed similar patterns overall, there were subtle differences between the existential threat conditions and the non-existential threat condition, most notably in terms of affect. Specifically, regarding negative affect: whereas all existential threats (except for MS) showed increases in negative affect and the MS condition reported more negative affect- and sadness-related thoughts, SET showed inconclusive changes in negative affect and specific affect-related words; with the uncontrollability condition even showing larger increases in negative affect as compared to the SET condition and the MS condition reporting more negative affect- and sadness-related thoughts than the SET condition. Regarding positive affect: whereas all existential threats showed decreases in positive affect, SET showed no change in positive affect, with all existential threats showing larger decreases in positive affect as compared to SET. Overall, we posit that the theory that all threats  cause similar arousal responses  was partpost-hoc power analysis showed that we only had sufficient statistical power to detect arousal changes with medium effect sizes and condition differences with medium-large effect sizes, which might not be sufficient for the typically-small affective changes caused by MS , restricting our statistical power and thus our confidence in the results. Specifically, a MS e.g., . This waMS e.g., . Indeed,MS e.g., , allowinMS e.g., , which wIn conclusion, the current study was the first to systematically compare affective, subjective, and physiological changes in arousal due to reflecting on different existential threats, as well as one non-existential threat. We showed that, as compared to a control condition, reflecting on threats has a large impact on negative affect, but no significant impact on positive affect, subjective arousal, and physiological activation. All threats caused similar responses overall, with the only notable differences between existential and non-existential threats regarding affective responses.All datasets generated for this study are included in The studies involving human participants were reviewed and approved by Ethics Committee of the University of Salzburg. The participants provided their written informed consent to participate in this study.EP: methodology, software, formal analysis, data curation, writing – original draft, writing – review and editing, visualization, and project administration. JK and EJ: conceptualization, methodology, writing – review and editing, supervision, and funding acquisition. DS: software, resources, writing – review and editing, and supervision. CM: methodology, writing – review and editing, and project administration.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The conducted studies have proven the possibility of the directed control of operational properties of epoxy composites, due to the addition of finely-ground ocher into their composition, and the use of microwave modification of the epoxy composition. The rational content of ocher as a modifying additive (0.5 parts by mass) and a filler (75 parts by mass) of the epoxy composition has been selected, which ensures the improvement of the studied complex of physical-mechanical properties. It has been proven that ocher affects the structure formation processes and the structure of the epoxy composite, thus increasing its thermal, heat and fire resistance. During the research, the application efficiency has been proven, and the optimal parameters of the microwave modification  of epoxy compositions filled with ocher, which increase physical-mechanical characteristics of composites, have been selected. One of the promising branches of chemical industry is the production of polymer materials . At presOne of the main directions of the further development of epoxy composites with enhanced operational properties is the addition of various fillers  into their composition, which can significantly decrease the cost of finished products by reducing the cost of expensive binders, as well as give them various functional properties ,10,11,12Technogenic waste from industrial enterprises is often used as dispersed fillers of epoxy resins. The authors of ,14 propoIn , marble The effectiveness of using brick dust as a cheap, active filler of an epoxy polymer, which provides an increase in both physicochemical and mechanical properties, was proved in ,17. It wIn recent decades, composites reinforced with natural fibers have aroused wide research and engineering interest, due to their low density, high specific strength, low cost, light weight, processability and biodegradability. In the article , wood duAs nanofillers, graphen, carbon nanotubes, fullerenes, astralenes, as well as titanium and silicon dioxide, diamond batch, white carbon black, zinc borate nanoparticles, etc., are widely used ,25,26,272 nanoparticles with the epoxy oligomer, their uniform distribution in the composition, which provides an increase in the physicomechanical characteristics of polymer composite materials.The authors ,24 propoIn Ref , zinc boDespite the enormous number of works devoted to the study of the effects of various fillers, there are still insufficiently studied issues related to the influence of fillers on the structure formation processes, the structure and performance characteristics of polymer composite materials, which predetermines the direction of the research of this work.Currently, to intensify the processes of modification of polymer materials, electro-physical methods are widely used, such as elastic vibrations of sound and ultrasonic frequency ranges, vibration processing, high-frequency currents, laser, electronic and ultraviolet radiation. The need for alternative technologies for the modification of polymers is connected with the multistage nature of traditional processes, high energy and labor costs, and environmental tensions in production ,29,30.Studies on the use of electro-physical methods of processing materials and products have shown the efficiency of using the microwave energy for this purpose. Microwave technologies, in contrast to traditional modification methods, have several advantages: they make it possible to reduce the duration of technological processes, to simplify the production installation, to lower energy consumption, to improve the environmental condition and cleanliness of production, to obtain products of a new, better quality. They also provide volumetric and inertia-free heating, the possibility of forming and maintaining the required distribution of the temperature field in any finite region of space, etc. ,29,30. IThe aim of this work is to improve physicochemical and deformation-strength properties of epoxy-based composites by adding a polyfunctional modifier of oligo(resorcinophenyl phosphate) with terminal phenyl groups Fyrolflex (ORPP) and a dispersed mineral filler—ocher.In this article has studied the effect of adding the mineral filler on the mechanical properties, the curing process, physicochemical properties of epoxy composites and the effects of using microwave technology on the mechanical properties of ocher/epoxy composites. This work shows an important reference value for modification, optimizing and designing of epoxy compositions for the production of high-performance ocher/epoxy composites.As a polymer matrix, epoxy resin ED-20 (GOST 10587-93) was used, which is characterized by a low viscosity—13–20 Pa·s; a narrow limit of the epoxy groups content—20.0–22.5%; stability of physico-chemical properties, epoxy equivalent—195–216 g/mol, manufactured by CHIMEX Limited . As a hardener of an epoxy oligomer, an amine type hardener was used—polyethylene polyamine (PEPA) (TS 6-02-594-85), manufactured by CHIMEX Limited . It is capable of forming a three-dimensional network structure without heating, its molecular mass is 230–250 g/mol, its amine number is 1250 mg KOH/g and its viscosity is 0.6–0.9 Pa·s.To plasticize epoxy composites, we used oligo(resorcinophenyl phosphate) with terminal phenyl groups (ORPP), with a purity of 99%, manufactured by ICL Industrial Products America Inc. . The choice of ORPP is due to the presence of combustion inhibitors—phosphorus (10.7%). When the composite thermally decomposes, the presence of phosphorus ensures an increase in the yield of carbonized structures. These structures are a physical barrier for the inter-diffusion of the oxidant and combustible gases to the combustion zone, which, in general, reduces the flammability of epoxy composite ,20.There are wide possibilities for improving the characteristics of composite materials by using both plasticizers and cheap and effective fillers ,10,11,12A previously developed composition, consisting of 100 parts by mass of epoxy resin brand ED-20, 40 parts by mass of ORPP and 15 parts by mass of a PEPA hardener was used as a polymer matrix ,12.Ocher was introduced into ORPP-modified epoxy compound as a modifying additive (0.1–1.0 wt. part per 100 wt. parts of the compound) or filler (10–100 wt. parts). To ensure more uniform distribution of ocher and to activate its surface and the binder, the formulation was subjected to ultrasonic treatment at 22 ± 2 kHz for 60 min. The mixture was degassed at 25 ± 5 °C for 30 min under vacuum, before curing.The preparation process of ocher/epoxy composites is shown in α radiation, λ = 0.15412 nm, angle range 2θ 5°–60°); the diffraction patterns were interpreted using Powder Diffraction File-2 (PDF-2) database of the International Center for Diffraction Data (ICDD) and the Crystallographic Search-Match program, version 3.1.0.2.B; determination of the particle-size distribution in the interval 0.01–1000 μm by laser diffraction with a Fritsch Analysette-22 Nanotech analyzer , using water as a dispersion medium; determination of the specific surface area of the samples with a Quantachrome Nova 2200 surface area and porosity analyzer  from the low-temperature nitrogen adsorption.The research was carried out using the following methods: the study of the surface morphology of ocher was carried out using a Tescan VEGA 3 SBH scanning electron microscope ; X-ray phase analysis was performed using ARL X’TRA X-ray diffractometer  at a 20 mm/min loading rate. The testing accuracy was 1%. The bending stress and flexural modulus was determined according to [ISO 178: 2010], the tests were carried out on samples in the form of blocks with 4 mm thickness, 10 mm width and a working part length of 80 mm. The strength and modulus of tensile elasticity was determined according to [ISO 527-2: 2012], the tests were carried out on samples in the form of spatulas with 4 mm thickness, 10 mm width and a working part length of 50 mm. The compressive strength was determined according to [ISO 604: 2002], the tests were carried out on samples in the form of cube with rib length 30 mm. The impact strength was determined according to [ISO 179-1: 2010], using an impact testing machine LCT-50D . The heat resistance, according to Vicat, was determined according to [ISO 306: 2004], method B50-load 50 N; the rate of temperature increase was 50 °C/h. The change in mass, rate of change in mass and magnitude of thermal effects during the heating of the samples was studied using the method of thermogravimetric analysis, with the help of a derivator of the “Paulik–Paulik–Erdei” system of the MOM brand Q-1500D , under the experimental conditions: weight—100 mg, medium—air, heating interval—up to 800 °C, heating rate—10 °C/min, relative error does not exceed 1%. The study of the surface morphology of the samples was carried out using a Tescan VEGA 3 SBH scanning electron microscope . We have studied the process of the composition curing with the construction of the dependence G = f , where τ is the duration of the process in minutes; T—temperature, °C. In this analysis, the thermal insulation of objects was provided. It was possible to study the effect of heat dissipation on the curing process. The temperature rise curve consists of three characteristic sections .The first section characterizes the viability of the composition before the start of temperature rise; the second section of the rapid increase in temperature up to the inflection point characterizes the self-accelerating curing reaction; in the third section of the curve, the chain growth rate decreases after the inflection point. Then, the sample cooling begins. The inflection point on the curve of the curing temperature versus time, which characterizes the maximum curing rate, can most accurately be determined as the maximum value of the derivative of the function of temperature change in time in sections I and II, There is a great potential for improving the characteristics of composite materials, which is due to the use of both plasticizers and inexpensive and effective fillers, which include dispersed mineral fillers, in particular ground ocher, the chemical composition of which is presented in As a result of the research, it has been found that ocher mainly consists of iron oxides, aluminum oxide, chromium and nickel, and it also contains small impurities of Ti, Cu, Ca oxides.The fractional composition of ocher is characterized by a bimodal distribution and is represented by particles from 0.1 to 100 μm, with average particle sizes of 2–3 μm and 30–40 μm , which i2O3) and magnetite (Fe3O4) ), hematite (Fe (Fe3O4) .Goethite has needle-shaped crystals, hematite crystals are flattened, from tabular to scaly or lamellar, magnetite is represented by cubic crystals. In addition, magnetite has strong magnetic properties, which imparts magnetic properties to composite materials, and thereby expands the possible areas of their application.Due to the fact that ocher particles have a scaly and needle-shaped form, we can attribute ocher to active reinforcing fillers. The presence of needle-shaped particles must provide the effect of micro-reinforcement, which will lead to the improvement of physico-mechanical properties of composites based on it.2/g.The specific surface area of chromite particles, determined on the specific surface area and porosity analyzer Quantachrome Nova 2200 using a low-temperature nitrogen adsorption method, is equal to 7.2 mThus, the analysis of the structure, chemical composition and specific surface of finely ground ocher has shown that it can be used as a structuring additive and a filler for epoxy composites, which should improve their operational properties. In this case, preliminary drying of the filler is required, since the moisture content in ocher amounts to 27%. Drying was carried out at 105 °C for 3 h to obtain constant mass.The conducted studies have shown that the most rational addition of ocher as a modifying additive is 0.5 parts by mass, since this ensures higher values of the studied physical and mechanical properties: bending stress increases by 30% and flexural modulus increases by 58%, strength increases by 75% and tensile modulus increases by 20%, impact strength increases by 83% .The structuring effect of ocher is observed in the effect of small additives. All known polymers are microheterogeneous, therefore, they contain both tightly packed (ordered areas) and loose (more defective zones), in which small modifier additives are concentrated. They play an essential structural-modifying role, contribute to kinetically stimulated polymer ordering, and increase the mobility of the loop chains, ensuring their denser packing ,8,12.In terms of energy concept, the hardening of ocher-filled epoxy compositions occurs due to the increase in the energy required to fracture the material, which is associated with the elongation of the crack front, due to the flow of particles around the crack, In terms of reducing the cost of production, the addition of ocher as a filler of the epoxy composite (50–100 parts by mass) is effective, while the addition of 75 parts by mass is the most rational, since the physico-mechanical characteristics are improved: bending stress increases by 27% and modulus of elasticity in bending increases 4.5 times; strength increases by 50% and the tensile modulus increases two times; resistance to impact loads increases by 50%; and we also observe that breaking stress in compression increases by 56%, compared to an unfilled plasticized epoxy composite .According to published data ,12, at hIn addition, under the action of ultrasound, it is possible to evenly distribute the filler in the epoxy composition, and to avoid its aggregation.When estimating the effect of the modifying additive on network polymers, we should take into account the fact that the curing process takes place in the presence of a developed surface of the solid material (ocher), thus affecting the kinetic characteristics of the polymerization reaction during curing, as well as the formation of the phase structure of the material ,8,12. WeThe analysis of the curing kinetics of epoxy compositions has shown that the addition of ocher affects the structure formation processes , which cDue to the fact that ocher itself is a heat-resistant material, its addition to an epoxy composite leads to an increase in Vicat heat resistance from 132 °C to 148–210 °C, The addition of ocher into an epoxy composite provides an increase in the composite heat resistance, which can be seen in a shift in the initial temperature of the main stage of destruction to higher temperatures (from 230 °C to 240–245 °C), while the yield of carbonized structures also increases from 54% to 58–76%, providing a decrease in the emission of volatile pyrolysis products into the gas phase, which reduces flammability of the epoxy composite. With the addition of ocher, an increase in the flammability indicator oxygen index from 28 to 32% by volume is observed .Microwave modification was used to improve deformation-strength properties of epoxy composites. The uncured hardener-free epoxy composition was subjected to microwave modifications after ultrasonic dispersion of the components, then a hardener was added, and the curing process was carried out under normal conditions at room temperature. The studies made it possible to determine the most rational mode of microwave processing: power—350 W, duration—30 s , which eThus, the studies have shown the effectiveness of applying microwave modifications of epoxy compositions filled with ocher, which ensures the improvement of physico-mechanical characteristics of composites, which is explained by additional structuring of the material as a result of microwave processing. In As a result of these studies, the effectiveness of using ocher as a cheap, active filler of an epoxy polymer has been proven, which provides the improvement of both physicochemical and mechanical properties of epoxy composites. The rational content of ocher as a modifying additive (0.5 parts by mass) and filler (75 parts by mass) of the epoxy composition has been selected, which ensures the improvement of the studied complex of physic-mechanical properties. It has been proven that ocher affects the structure formation processes of the epoxy composition, which can be seen in the reduced duration of the gelation process from 27 min to 17–21 min, and the duration of the curing process from 38 min to 29–30 min, with an increase in the maximum curing temperature from 88 °C to 96–99 °C. It has been proven that the addition of ocher into the epoxy composite provides an increase in the thermal stability of the composite, which can be seen in a shift in the initial temperature of the main stage of destruction to higher temperatures (from 230 °C to 240–245 °C). We can also see an increase in the yield of carbonized structures from 54% to 58–76%, providing a decrease in the emission of volatile pyrolysis products into the gas phase, which ensures a decrease in the flammability of the epoxy composite.The efficiency of the application has been proven, and the optimal parameters of the microwave modification of epoxy compositions filled with ocher have been selected, which increase the physico-mechanical characteristics of composites.


Alzheimer’s disease (AD) is a neurodegenerative disease that leads to progressive loss of memory and dementia. The pathological hallmarks of AD include extracellular accumulation of amyloid-β peptides forming senile plaques and intracellular accumulation of Tau oligomers and filamentous species. Tau is a microtubule-binding protein that stabilizes tubulin to form microtubules under physiological condition. In AD/ pathological condition, Tau detaches from microtubules and aggregates to form oligomers of different sizes and filamentous species such as paired helical filaments. Microglia are the resident brain macrophages that are involved in the phagocytosis of microbes, cellular debris, misfolded and aggregated proteins. Chemokine receptor, CX3CR1 is mostly expressed on microglia and is involved in maintaining the microglia in a quiescent state by binding to its ligand, fractalkine (CX3CL1), which is expressed in neurons as both soluble or membrane-bound state. Hence, under physiological conditions, the CX3CR1/CX3CL1 axis plays a significant role in maintaining the central nervous system (CNS) homeostasis. Further, CX3CR1/CX3CL1 signalling is involved in the synthesis of anti-inflammatory cytokines and also has a significant role in cytoskeletal rearrangement, migration, apoptosis and proliferation. In AD brain, the expression level of fractalkine is reduced, and hence Tau competes to interact with its receptor, CX3CR1. In microglia, phagocytosis and internalization of extracellular Tau species occurs in the presence of a chemokine receptor, CX3CR1 which binds directly to Tau and promotes its internalization. In this review, the pathophysiological roles of CX3CR1/fractalkine signalling in microglia and neurons at different stages of Alzheimer’s disease and the possible role of CX3CR1/Tau signalling has been widely discussed. Alzheim., . Among t., , 14. Cur., –23.GPCRs belong to the largest class of membrane proteins that are involved in cell-to-cell communications, signal transduction pathways and hormonal regulation , 25. Thei.e. phagocytosis and clearance of excessive neuronal cells and synapse leading to proper neuronal function and synaptic plasticity in developing CNS [.,) [Microglia are the resident macrophages that act as innate immune cells of the brain and play a significant role in regulating brain development , 42. Micping CNS . In healCNS [.,) . SeveralCNS [.,) , 50. MicCNS [.,) –53. The CNS [.,) , 52–55. CNS [.,) , 57. MicCNS [.,) . Genome-CNS [.,) , 60. TRECNS [.,) –63. MutaCNS [.,) . In micrCNS [.,) , 65, 66.CNS [.,) –69. In TCNS [.,) , 71. ExtCNS [.,) . The genCNS [.,) . Though CNS [.,) .i protein-bound GPCR that on fractalkine binding activates several signalling molecules and transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and cAMP response element-binding protein (CREB) [CX3CR1 is a chemokine receptor that belongs to the class A family of G-protein coupled receptors. In humans, CX3CR1 is abundantly expressed in white blood cells such as lymphocytes and monocytes for their migration . In the n (CREB) , 86. Then (CREB) , 85, 86.. demonstrated that fractalkine treatment activates nuclear transcription factor such as nuclear factor erythroid 2-related factor 2 (NRF2) mediated by PI3K and Akt activation, GSK-3β inactivation in microglial cells [heme oxygenase 1 and attenuate the pro-inflammatory phenotype in microglia [., mediated by MSK-1 and NFκB [Fractalkine is involved in the inhibition of microglial activation through the CX3CR1 receptor by activating PI3K and Akt signals and maintains microglia in a quiescent state . In agedal cells . These nicroglia . In 2018and NFκB . CX3CR1 and NFκB . In addiand NFκB  Apart from the indirect effects of fractalkine on neuronal cells through microglial signalling, there are several direct roles of fractalkine in neuronal cells. In the CNS, fractalkine is involved in anti-inflammatory effects and protects neuronal cells against neuroinflammation and tissue damage. Fractalkine treatment to neuronal cells led to the activation of ERK and Akt kinases upon transient phosphorylation . Fractal−/− mice models, microglial activation by lipopolysaccharides promoted p38 MAPK-mediated Tau hyperphosphorylation and behavioural impairments. Further, it is proved that microglial activation led to secretion of pro-inflammatory cytokine IL-1 that promotes Tau hyperphosphorylation and aggregation by TLR4-mediated pathway in neurons [Microglial CX3CR1/CX3CL1 axis plays a significant role in the progression of Alzheimer’s disease with controversy in Aβ and Tau pathology . CX3CR1  neurons . In hAPP neurons , whereas neurons . Further neurons .. demonstrated that extracellular Tau is capable of binding to N-terminal peptides of CX3CR1 and promotes its internalization in microglial cells [In AD brain, neurons undergo severe inflammation and tissue damage that spreads aggregated Tau species such as oligomers and filaments around the microglial environment. Bolos et alal cells . In AD bal cells . Pro-infal cells . SimilarMicroglia plays a critical role in the progression of Alzheimer’s disease. Microglia are capable of internalizing and degrading both Aβ deposits and Tau aggregates , 35, 40.


The transdermal delivery of therapeutic agents amplifying a local concentration of active molecules have received considerable attention in wide biomedical applications, especially in vaccine development and medical beauty. Unlike oral or subcutaneous injections, this approach can not only avoid the loss of efficacy of oral drugs due to the liver’s first-pass effect but also reduce the risk of infection by subcutaneous injection. In this study, a magneto-responsive transdermal composite microneedle (MNs) with a mesoporous iron oxide nanoraspberry (MIO), that can improve the drug delivery efficiency, was fabricated by using a 3D printing-molding method. With loading of Minoxidil , MNs can break the barrier of the stratum corneum through the puncture ability, and control the delivery dose for treating androgenetic alopecia (AGA). By 3D printing process, the sizes and morphologies of MNs is able to be, easily, architected. The MIOs were embedded into the tip of MNs which can deliver Mx as well as generate mild heating for hair growth, which is potentially attributed by the expansion of hair follicle and drug penetration. Compared to the mice without any treatments, the hair density of mice exhibited an 800% improvement after being treated by MNs with MF at 10-days post-treatment. For male baldness, this genetic disease occurs at age 30–60, which is estimated that over 50% of the general population suffer from hair loss . TraditiAs a new type of painless administration, microneedles (MNs) with the advantages of convenient use, minimally invasive procedure, and relatively inexpensive cost, are easy to overcome stratum corneum to facilitate pharmaceuticals entering epidermal as well as dermal layers . MNs areMagnetic mesoporous nanoparticles consisted of silica as well as iron oxide, and are broadly employed in many fields such as catalyst, cancer therapy, antibacterial composites, energy storage, and drug delivery system ,17,18,19In this study, the concept of a physical promotion method for patching increases the efficiency of percutaneous absorption and reduces the chance of inducing side effects. A highly biocompatible polyvinyl alcohol was used to make a dissolvable microneedle patch, reaching the smart device in biomedical applications. Digital light processing (DLP) 3D printing technology was used to fabricate the MNs master with high resolution, inexpensive cost, flexible manufacturing, customization, and fast forming prototype compared with conventional process . A mesop3·6H2O, ethylene glycol, sodium acetate (NaAc), oleylamine, Mx, and phosphate buffered saline were purchased from Sigma-Aldrich, St. Louis, Missouri, USA. CdSe/ZnS core/shell Quantum Dot Solid (QDs) were purchased form Ocean Nano Tech, San Diego, California, USA. 3--2,5-diphenyltetrazolium bromide (MTT reagent) were bought from Amresco, Solon, Ohio, USA. Ham’s F-12 medium, fetal bovine serum (FBS) and penicillin/streptomycin were purchased from Gibco, Thermo Fisher Scientific, Waltham, Massachusetts, USA. Trypsin (2.21 mM EDTA Solution) was purchased from Corning, Steuben County, New York, USA. C57BL/6 mice obtained from National Laboratory Animal Center, NLAC, Taiwan.FeCl3·6H2O were dissolved in 40 mL of ethylene glycol with vigorous stirring till the color of the solution changed to a clear yellow. Then, anhydrous NaAc (3.29 g) was added to the mixture in gentle stirring thereafter to the extent of homogeneity overnight. After the color of the mixtures changed to black, 0.6 mL of oleylamine was added under ultrasonication for effective mixing. Subsequently, 20 mL of the solution was transferred into a teflon-lined stainless steel autoclave (25 mL capacity) for hydrothermal reactions at 220 °C for 5, 15, and 25 h, respectively. After the Teflon-lined stainless steel autoclave was allowed to cool down to room temperature, the precipitate was washed by ethanol, three times, and stored in 4 °C, this was called MIOs. MIOs were dried under vacuum at room temperature before characterization and applications later. For Mx encapsulation, Mx was loaded to MIOs-5h by mixing 1% Mx with MIOs in dimethyl sulfoxide (DMSO) for 12 h. Then, the mixture was placed into vacuum at 50 °C for 24 h to evaporate DMSO. The drug concentration was determined by ultraviolet–visible (UV-vis) spectroscopy .The synthesis process of MIOs follows the hydrothermal method of our previous studies . BrieflyWe used 3D printing technologies to prepare MNs master so that we can freely adjust the specification of MNs including height, width, and length of MNs. Each needle was 300 µm in a round base diameter and 600 µm in height. Needles were arranged with 600 µm tip-tip spacing. Polydimethylsiloxane (PDMS) was placed over the 3D printed MNs master to make female mold, followed by curing in the oven at 60 °C for 8 h, and the female mold was finally finished by carefully peeling the 3D printed MNs. For preparation polyvinyl alcohol (PVA)-MNs patch, the mixture, PVA and Mx-MIOs, were loaded onto PDMS female mold, and placed in a centrifuge at 4500 rpm for 1 h, so that the mixed solution would fill the pyramidal cavity of the mold. The back of MNs was filled with pure PVA solution, and centrifuged at 4500 rpm and 25 °C for 1 h. Subsequently, the device was allowed to dry at room temperature for 12 h, and then the patch was carefully detached from PDMS mold.The morphology of MIOs are analyzed by field emission scanning electron microscope , and MIOs were dried up on silicon wafers. The wafers were anchored to SEM specimen mounts using double-sided carbon tape, and sputter deposited with platinum in 10 mA for 120 s. An X-ray diffractometer  was used for identification of crystal dimensions. A thermogravimetric analyzer  provided a proportion of each compositions based on differential melting temperature with physical and chemical properties. Dynamics laser scattering (DLS) analysis, by using a particle sizer , determined the average size and size distribution of MIOs diluted with deionized water. Field-dependent magnetization curves were evaluated by a superconducting quantum interference device  from −10,000 to 10,000 Oe.For heat generation studies, MIOs-5h, MIOs-15h, and MIOs-25h were inserted to the center of the coils, and MIOs were sequentially conducted with a MF  at a power of 3.2 kW and frequency with 1 MHz. The temperature of solution increased and was detected at various times.Mx was used to evaluate the drug loading capacity and release properties of MIOs. Then, 1% Mx were mixed with MIOs in DMSO for 12 h, and then the mixture was placed into vacuum at 50 °C for 24 h to evaporate the DMSO. After the organic solvent was evaporated, the mixture was washed by DI water through being centrifuged twice. Mx was quantified by a UV–vis spectrometer with the wavelength in 230 nm. The loading capacity of Mx in MIOs were calculated by the equation: EE% = (A − B)/A × 100, where A is the total amount of Mx, and B is the amount of Mx remaining in the supernatant. To estimate the drug release profile, Mx containing MIOs were dispersed in phosphate buffered saline (PBS). The solution was centrifuged at 4000 rpm and taken at various times for detection. For magnetically triggered release, MF was applied to activate and induce heat of MIOs at a power of 3.2 kW and frequency with 1 MHz for 1 min at the beginning. Mx-MIOs were dispersed in water and placed into tubes for detection at various times.v/v) FBS and 1% (v/v) penicillin-streptomycin at 37 °C and in 5% CO2. The culture medium was replaced every three days with a fresh one. For biocompatibility, we followed “Biological evaluation of medical devices—Part 5: Tests for in vitro cytotoxicity” (ISO 10993-5) to investigate the MNs. Briefly, we extracted the substance released from MNs in culture medium with serum following ISO 10993-12. After seeding HIG-82 cells in 96-well  with 100 μL of medium for 24 h, we added the extraction into each well for another 24 h incubation. Finally, each well was added with 100 μL of MTT agent (1 mg/mL) for 4 h, and then dissolved in DMSO to make purple color liquid. The absorbance value was read with a microplate reader  with 570 nm in wavelength and 650 nm as reference. Cell viability was calculated by comparison with untreated cells and calculated according to the following: Cell viability (%) = absorbance of experimental group/absorbance of control group. HIG-82 was obtained from the American Type Culture Collection (ATCC), and were maintained in F12 medium containing with 10% , National Tsing Hua University, Hsinchu, Taiwan . Mice with 8 weeks of age were shaved and divided into 4 groups, including drug-containing control group (PBS), Mx-loaded MNs (Mx@MNs), Mx-MIOs@MNs, and Mx-MIOs@MNs+MF. Mice was treated with patches at day one after shaving. For control group, the shaved back of mice was covered with PBS solution. For Mx@MNs, Mx-MIOs@MNs, and Mx-MIOs@MNs+MF, the patch was pressed firmly for the first 30 s to penetrate through the epidermis and pressed softly for additional 2 min. The patch base was peeled at 10 min postinsertion into the skin, leaving the MNs settled in the skin for further sustained drug release. For Mx-MIOs@MNs+MF group, the mice were further treated under MF  at a power of 3.2 kW and frequency with 1 MHz. Photos of the mice back were recorded for the quantitation of the hair density by Zen Desk software. As an analysis of the variance, both one- and two-way ANOVA were used, and statistical divergences were assessed by ANOVA with Tukey’s multiple comparison test. The Graph Pad-Prism was used with a significance level of alpha 0.05 to evaluate the statistical significance.The synthesized process of MIOs was illustrated in 2) at 77 K. The particles were treated at 80 °C under vacuum to remove the surface adsorption and were degassed at 180 °C for 4 h before BET analysis. The results revealed that each MIO-5h and MIO-10h had a surface area of ~265 and ~78 m2g–1, respectively  as shown in ectively . Compare3O4 crystal planes [In l planes . OA withl planes . MIOs wil planes . While 10 μg/mL of MIOs were subjected to a high frequency MF at a strength of 3.2 kW with a frequency of 1 MHz, an obvious temperature increase could be monitored a. WithinConsidering the porosity and mild heating rate, MIOs-5h was used in the further studies. The Mx release from MIOs was monitored in PBS at 37 °C for 120 min b. WithouTo prepare the MNs, PDMS served as the negative mold was reprinted according to the microneedle template printed in advance by 3D printing a. Due toTo form the composite MNs, a two step filling process was applied. First, the Mx-loaded MIOs (Mx-MIOs) were filled to PDMS modes. Followed by centrifugation and drying, the similar processes of PVA MNs were used to construct the MNs in the second step. The resulting composite MNs was shown in Have demonstrated the structures of composite MNs, the mechanical property of composite MNs was estimated to confirm the ability to break through the stratum corneum barrier. The setup of the experiment was illustrated in In addition, we performed an in vitro microneedle swelling test to simulate the in vivo condition. PVA MNs swelled quickly within a minute d,e. ThisThe MNs were applied to a pork skin to investigate the insertion . With 104 cells/mL. Then, the culture medium was changed, and cells were exposed to serial dilutions of tested dissolved MNs. Cell viability was assessed after 72 h by means of MTT assay by measuring absorbance at 570 nm wavelength using ELISA Reader. In Having exhibited the insertion of MNs, the toxicity of PVA and MIOs@MNs were evaluated in 2. The hair was applied to the back of the hairless mouse and peeled off after 10 min of attachment. The same dosage of Mx was used in the four groups. After photographing the back of the mouse, a fixed range was tracked for 16 days and taken to quantify the percentage of the selected range of hair by the computer software ZEN zeiss at various times , Mx-MIOs@MNs, and Mx-MIOs@MNs+MF a. A micrus times . The resus times . The resIn summary, magneto-responsive transdermal composite microneedles with a mesoporous iron oxide nanoraspberry were developed to improve androgenetic alopecia (AGA) treatment. Unlike traditional administration, this approach can reduce side effect from treating on the undesired local with inaccurate use. MIOs with porous structure and hydrophobic surface can capture hydrophobic pharmaceuticals, which also are the most important nutrition avoiding hair loss in human body. Besides, under the non-contact trigger, MF, MIOs, would generate wild heating for aiding increases of cutaneous blood flow as well as vasodilation. Minoxidil is a drug for hair regrowth with high efficiency. By using 3D printed technology, it can build various morphologies microneedle molds for further uses according to the geometry of tissue anatomies. Through filling Mx-loaded MIOs and PVA subsequently to mold to MNs, the layer-by-layer composite MNs is constructed with high mechanical property for overcoming the barrier of the stratum corneum via the punctuation, and dissolved, later, after administration. The successful delivering the Mx-loaded MIOs to skin and integrating the magneto–thermal drug release achieved eight-fold greater improvements of hair growth with low toxicity. This composite MNs provides a new synergistic delivery strategy for transdermal drug delivery and potential for wide clinical applications.


Cervical cancer is a common and fatal malignancy of the female reproductive system. Human papillomavirus (HPV) is the primary causal agent for cervical cancer, but HPV infection alone is insufficient to cause the disease. Actually, most HPV infections are sub-clinical and cleared spontaneously by the host immune system; very few persist and eventually develop into cervical cancer. Therefore, other host or environmental alterations could also contribute to the malignant phenotype. One of the candidate co-factors is the β-catenin protein, a pivotal component of the Wnt/β-catenin signaling pathway. β-Catenin mainly implicates two major cellular activities: cell–cell adhesion and signal transduction. Recent studies have indicated that an imbalance in the structural and signaling properties of β-catenin leads to various cancers, such as cervical cancer. In this review, we will systematically summarize the role of β-catenin in cervical cancer and provide new insights into therapeutic strategies. Cervical cancer is among the most common female malignant tumors. In 2018, cervical cancer was the fourth diagnosed malignancy and the fourth leading cause of cancer death in women worldwide. With the development of precancerous screening methods and popularization of Human papillomavirus (HPV) vaccination programs, the morbidity and mortality of cervical cancer in high-income countries have declined. However, in low- and middle-income countries, cervical cancer continues to be a heavy burden and threatens female health [HPV has been identified as a necessary cause of cervical cancer. Based on epidemiological studies, the viral infection rate might amount to 80% in sexually active women . A vitalCTNNB1 gene in humans [β-Catenin, the vertebrate homolog of Drosophila Armadillo, is a multifunction protein encoded by the n humans . As a men humans . In normn humans , gastricn humans , bone can humans , colorecn humans , and hepn humans , the cytn humans . Yet, moβ-Catenin is a 781-amino-acid protein and belongs to the armadillo protein families. It was initially discovered in the late 1980s as an E-cadherin-associated protein  and charCellular β-catenin exists in three different pools: membranous, cytoplasmic, and nuclear . Freshlyβ-Catenin executes two main tasks: structural role in the adherens junctions and signaling activity in the gene transcription. These two functions are orchestrated by mechanisms, which regulate the spatial separation, retention, or stability of β-catenin.Cell–cell junctions are requisite for maintaining cell and tissue polarity and integrity. One of the cancer characteristics is defective cell–cell and cell–matrix adhesion . Vertebrβ-Catenin is a pivotal component of the canonical Wnt signaling pathway, regulating embryonic development, tissue regeneration, stem cell maintenance, and adult tissue homeostasis . In the Interestingly, accumulated evidence has verified that the disruption of the E-cadherin/β-catenin complex affects not only the intracellular adhesion but also the canonical Wnt pathway. Many target genes of Wnt canonical cascade, such as Twist and Slug, could also influence cadherin adhesion . Therefoβ-Catenin executes two main functions in epithelial cells. The degree to which β-catenin participates in both roles is regulated through phosphorylation by various kinases Table . This phPhosphorylation of β-catenin at the membrane often leads to a weakening of the E-cadherin/β-catenin complex . Two tyrThe significance of phosphorylation at Serine45(S45), Serine33(S33), Serine37(S37), and Threonine41(T41) sites is underscored for maintaining normal cytoplasmic β-catenin concentration. Without Wnt stimulation, β-catenin is recruited by the destruction complex. It is first phosphorylated at S45 by CK1 and then at S33, S37, and T41 by GSK3β . S33 andβ-Catenin does not possess any DNA-binding domain, so it functions by interacting with other DNA binding transcription co-factors. Previous findings demonstrated that phosphorylation of β-catenin might modulate the recruitment of these factors. β-Catenin Y142 phosphorylation by c-Met promotes Bcl9-2 binding, which acts as co-activators in Wnt signaling . ProteinUnlike other cancers, persistent infection of HPV plays a unique role in cervical carcinogenesis. There are three events during HPV infection as cancer promoters: viral DNA integrates to host genome, viral oncoproteins (E6 and E7) express in the epithelial cells, and viral oncoproteins interact with cellular proteins . The welGSK3β gene, which in turn modulates cellular β-catenin [Lichtig et al. demonstrated for the first time that HPV 16 E6 enhances β-catenin/TCF transcription in an E6 associated protein(E6AP)-dependent manner, providing a possible mechanistic link between HPV and the β-catenin signaling in cervical cancer cell lines . Sominsk-catenin . The imp-catenin . Protein-catenin . Other f-catenin .With the previous evidence, HPV oncoproteins directly or indirectly interact with β-catenin, subsequently activate β-catenin signaling, and finally promote cervical carcinogenesis. Thus, HPV may be the initial hit in the multistep tumorigenesis, alterations of β-catenin and hyperactivation of the Wnt/β-catenin pathway in cervical cancer cells serve as a second hit to accomplish the development of cervical cancer.APC gene, dysfunction of GSK3β, or mutations of β-catenin itself [CTNNB1, have rarely been detected [+/H+ exchanger regulating factor 1 (NHERF1) is reduced significantly in cervical cancer tissues. NHERF1 regulates β-catenin protein levels in HeLa and CaSki cells. It may attenuate β-catenin expression via suppression of α-actinin-4 (ACTN4) expression and inhibit cervical cancer cell proliferation via the NHERF1-ACTN4-β-catenin axis [In various types of cancer, deregulation of the Wnt/β-catenin signaling pathway occurs almost invariably via mutations in n itself . Howeverdetected , 62. We detected . Li et adetected . The Dicdetected . Leucinedetected . Li et adetected . Wang etnin axis .The roles of non-coding RNAs should also be valued. MicroRNAs (miRs) are a class of non-coding RNAs with ~ 20 to 22 nucleotides in length and negatively regulate the expression of various cancer-related genes by binding to 3′-untranslated regions (UTRs) . Recent As critical epithelial markers, the lack of β-catenin at the membrane promotes epithelial cells to convert to mesenchymal cells, which have been recognized as an essential process during carcinogenesis. Frequent cytoplasmic localization of β-catenin observed in cervical cancer tissue, and nuclear β-catenin expression was faint . These rPrimary or secondary resistance to chemotherapy or radiotherapy results in treatment failure. The molecular mechanisms involved in chemo-radiotherapy resistance are complex. Accumulating evidence has found that β-catenin may participate in these molecular pathways. Zhang et al. observed that the nuclear localization of β-catenin is a poor prognostic marker and correlated with chemo-/radio-resistance in cervical squamous cell cancer . Zhou’s In addition to being considered a potential prognostic biomarker, β-catenin is also a vital molecular-target in cervical cancer therapy. Imura et al. assessed the prognostic influence of β-catenin by immunohistochemistry in cervical cancer patients. In this multivariate analysis, the low pathologic stage (stages I and II) and preservation of β-catenin expression is independently favorable prognostic factors . Liang eSeveral approaches for targeting β-catenin, which include enzyme inhibitors, β-catenin/TCF antagonists, and transcriptional regulators, have been developed. For example, a small-molecule MSAB directly targets β-catenin at Armadillo repeat region 2 and inactivates oncogenic β-catenin signaling . TankyraCTNNB1. In epithelial, β-catenin regulates epithelial cell growth and intracellular adhesion. In the Wnt signaling pathway, it is a crucial effector controlled by Wnt proteins and modulates transcription of genes. The Wnt signaling and phosphorylation systems regulate the switch between β-catenin’s adhesive and nuclear translocation functions. Different forms (phosphorylated vs. non-phosphorylated) have different effects on carcinogenesis and tumor progression. It has become definite that β-catenin contributes to cervical cancer through accumulating experimental evidence. It has effects on promoting cell proliferation, mediating EMT, enhancing cell resistance to chemo-/radio- therapy. The alterations of β-catenin itself, disruption of E-cadherin/β-catenin complex, and molecules directly or indirectly impacting the abnormal expression of β-catenin may contribute to this progression. A more accurate perception of the β-catenin precise regulatory mechanism in cervical cancer carcinogenesis is still needed to conduct in the future. For instance, further studies could focus on the genetic mutations and epigenetic alterations of CTNNB1 in cervical cancer, the relationship between other HR-HPV oncoproteins or different HPV subtypes, and β-catenin, the precise biomolecules-β-catenin binding mechanisms. β-Catenin is a potential prognosis biomarker and a druggable target for cancer therapy. More profound research of β-catenin useful for diagnosis, treatment, and prognosis of cervical cancer in larger samples and multicenter settings is worth exploring.To sum up, β-catenin is a kind of multifunctional protein-encoding by