Entrepreneurship education is increasingly becoming a focal strategy for promoting entrepreneurship, particularly to foster entrepreneurial intentions and startups. However, learning and support are equally important after startup for novice entrepreneurs to gain a good level of confidence to manage their business and achieve the desired outcomes. Using a sample of 189 young self-employed individuals in Uganda, this study examines the differential impact of mentoring and self-efficacy on the achievement of intangible outcomes of entrepreneurship including satisfaction of need for autonomy, work satisfaction and the intention to stay in self-employment. We found self-efficacy to mediate the effects of mentoring on these intangible outcomes. In addition, the results showed substantial gender differences. Whereas women’s satisfaction of the need for autonomy and intention to stay in self-employment were strongly associated with the direct effects of mentoring, their male counterparts seemed to benefit more if mentoring resulted in increased self-efficacy. Overall, our findings suggest that whereas mentoring improves the competence of small business owners and consequently achievement of superior outcomes, mentoring should also focus on boosting self-efficacy which in turn is essential for the application of the entrepreneurial competencies. The need to foster entrepreneurship to boost innovation, self-employment, and economic growth has sparked greater efforts in reviving entrepreneurship education and training . The assEntrepreneurial mentoring involves an experienced entrepreneur supporting a prospecting or novice entrepreneur in acquiring the necessary competency for establishing and managing his or her business venture . The supIn work contexts, mentoring is associated with career clarity, superior performance, adaptability in career and work, job satisfaction, higher income, and professional commitment, . This deIn the present study, we highlight the importance of self-efficacy as a mediating mechanism through which entrepreneurial mentoring asserts its influence on satisfaction of need for autonomy, intrinsic and extrinsic work satisfaction, and the desire to stay in self-employment. The study of In the present study, we posit that self-efficacy is a mediating mechanism through which entrepreneurial learning accruing from mentoring impacts on entrepreneurial outcomes. Self-efficacy reflects an individual’s belief in his/her abilities and skills to perform a given task and is a precedence for exerting effort, performance, persistence, and success in the task , 2010. ROne of the central ideas in the self-efficacy theory is that engagement and persistence in a given activity is a function of judgment about one’s skills and capabilities to accomplish the activity but also the ability to cope with the environmental demands in which the activity is conducted . FollowiIndividuals go into entrepreneurship for different reasons. Therefore, success does not necessarily have a uniform meaning among all entrepreneurs. To some, it is about creating wealth or financial gain . To otheThe Self-Determination Theory suggests that the autonomous motivation to engage in behavior or activity, which is mostly intrinsic in nature, represents the desire for psychological growth and flourishing , 2017. PThe Industrial and Organizational psychology literature is not devoid of work or job satisfaction research, most of this research is concerned with the intrinsic and extrinsic job satisfaction of employees in organizations though, while rarely job satisfaction of own-account workers or entrepreneurs is taken into account. In the present study, satisfaction denotes the conceptualization of work satisfaction as a state of emotional pleasure accruing from the appraisal of an individual’s work as facilitating the achievement of one’s work values . This inThe willingness to continue with work in the entrepreneurship field could be an important proxy indicator of the positive evaluation of their work and outcomes. Extant research has investigated the related constructs of entrepreneurial success, failure, exit, and re-entry. However, literature is silent on entrepreneurs’ intention to stay in their roles for a long time. Scholars and practitioners alike are increasingly focusing attention on entrepreneurship education. The assumption is that entrepreneurial learning has the potential to stimulate successful innovations and entrepreneurial startups through the acquisition of entrepreneurial competencies, development of positive entrepreneurial attitudes, and fostering innovative ideas . WhereasAt the general level, entrepreneurial mentoring is a learning process in which the experienced entrepreneur supports the development of a prospecting or novice entrepreneur . EntreprLike formal mentoring, informal mentoring facilitates skills acquisition and change in attitudes among prospecting and novice entrepreneurs , hence iThe immediate outcomes of entrepreneurship education and learning include the acquisition of entrepreneurial skills and knowledge. Beyond professional skills such as business planning and financial management, mentoring does support the development of soft and affective skills that are related to the core functions of an entrepreneur. Soft skills such as self-efficacy or boost in confidence are important  which fuHypothesis 1: Entrepreneurial mentoring is positively related to the self-efficacy of entrepreneurs.Hypothesis 2: Entrepreneurial mentoring positively predicts (a) satisfaction of the need for autonomy (b) intrinsic work satisfaction, (c) extrinsic work satisfaction, and the (d) intention to stay in self-employment.It has been suggested that prospecting entrepreneurs should be supported to develop their self-efficacy given their limited experience and knowledge of the entrepreneurial process . MentoriSelf-efficacy, also referred to as confidence  is the sAlthough some researchers have demonstrated that high levels of entrepreneurial self-efficacy harms business success , entreprSelf-efficacy also enhances entrepreneurial outcomes through its usefulness in resolving conflicts with stakeholders to the business , businesHypothesis 3: Self-efficacy mediates the relationship between entrepreneurial mentoring and (a) satisfaction of the need for autonomy (b) intrinsic work satisfaction, (c) extrinsic work satisfaction, and (d) intention to stay in self-employment.There is a big gender gap in entrepreneurship . This isThe business environment is certainly gendered, both culturally and socially , with maIt has been observed that low self-efficacy is one of the barriers to women’s engagement in more lucrative business industries . HoweverHypothesis 4: The direct effects of entrepreneurial mentoring on (a) satisfaction of the need for autonomy (b) intrinsic work satisfaction, (c) extrinsic work satisfaction, and (d) intention to stay in self-employment are stronger for men than for women.Hypothesis 5: The indirect effects of entrepreneurial mentoring on (a) satisfaction of the need for autonomy (b) intrinsic work satisfaction, (c) extrinsic work satisfaction, and (d) intention to stay in self-employment via self-efficacy are stronger for men than for women.M = 24.72, SD = 7.99). Given that participants were young and recently graduated from school, their businesses were nascent. The average time participants had spent in business was 2.58 years (SD = 0.99) with only 3.19% reporting that they have been in business for 5 or more years. Most of the participants were graduates of universities or technical colleges, with 51.6% being degree holders and 22.34% having ordinary and advanced certificates in technical or vocational studies. It was also observed that 40.43% had studied business related courses.The sample comprised of 188  young business owners in Uganda’s capital, Kampala. These were young people who had recently graduated from high school, technical/vocational colleges, and universities; and are engaged in self-employment. Participants were recruited through youths’ business forums, while others were approached at their business premises and requested to participate in the survey. The survey questionnaires were administered through the paper and pencil method. Participants were aged 17 to 30 years  of the six (6) items from the career commitment scale . In addition, the control variable (age) was positively related to self-efficacy  but not with the intangible entrepreneurial outcomes. The moderator variable (gender) had substantial effects on all three outcomes: satisfaction of the need for autonomy , intrinsic work satisfaction , extrinsic work satisfaction  and the intention to stay in self-employment . The negative association between gender and work satisfaction implies that women were more satisfied with their work than their male counterparts.Correlations among study variables and descriptive statistics are presented in B = 0.40, p < 001) and intention to stay in self-employment . Whereas mentoring had insubstantial effects on intrinsic work satisfaction, it was negatively associated with extrinsic work satisfaction . The insignificant association of mentoring and intrinsic work satisfaction suggests that this relationship was fully mediated by self-efficacy; or what is also known as indirect-only mediation , extrinsic work satisfaction , and intention to stay in self-employment . In support of Hypothesis 3, our results show that self-efficacy mediated the association between mentoring and the three intangible outcomes as reflected in the indices of the moderated mediation: satisfaction of need for autonomy , intrinsic work satisfaction , extrinsic work satisfaction , and intention to stay in self-employment .We further proposed in Hypothesis 2 that mentoring predicts intangible entrepreneurial outcomes including (a) satisfaction of need for autonomy, (b) work satisfaction, and the (c) intention to stay in self-employment. The findings revealed significant positive associations of mentoring with satisfaction of need for autonomy , intrinsic work satisfaction , extrinsic work satisfaction , and intention to stay in self-employment . These interaction effects are reflected in the regression plots in We proposed that the direct effects (Hypothesis 4) of mentoring on the three intangible outcomes are moderated by gender. The findings in B = 0.50, p < 001), intrinsic work satisfaction , extrinsic work satisfaction  and intention to stay in self-employment . The moderations are confirmed in the regression plots in In hypothesis 5, we proposed that indirect effects of mentoring on intangible entrepreneurial outcomes are moderated by gender. The interactive effects of self-efficacy and gender were significant for all the intangible entrepreneurial outcomes: satisfaction of the need for autonomy  and not for females. On the other hand, the indirect effects on intrinsic work satisfaction were significant for both females  males , although stronger for females. A similar trend is observed for extrinsic work satisfaction. Finally, the indirect effects on intention to stay in self-employment were significant for both males  and females , but stronger for males.The conditional indirect effects and indices of moderated mediation in The present study highlights the role of entrepreneurial mentoring and self-efficacy in the attainment of intangible entrepreneurial outcomes. We argue that besides the development of entrepreneurial skills that lead to objective success, mentoring nascent entrepreneurs is directly and indirectly associated with their level of satisfaction of the need for autonomy, their work satisfaction (both intrinsic and extrinsic), and consequently the desire to stay in self-employment. Individuals seek different goals by engaging in entrepreneurial activities; hence success indicators are not uniform among entrepreneurs. The subjective aspects of success could be as important as the objective aspects given that they present what the entrepreneurs themselves value . MoreoveEntrepreneurial mentoring plays an important role in enterprise growth and success through problem identification, providing solutions, information and emotional support, persuasion, and many other functions . Our resThe findings of the present study further extend our theoretical understanding of how mentoring results in entrepreneurial success and persistence. First, our results build on the entrepreneurial socialization approaches  which hiOur findings further contribute to the literature on the role of gender in entrepreneurship and entrepreneurial socialization. Extant literature shows that there are gender differences in involvement and persistence in entrepreneurial activities . In the R2 are quite low for most of our interaction effects, our findings suggest that men and women benefit from entrepreneurial mentoring differently. In relation to both intrinsic and extrinsic work satisfaction, women benefit more from mentoring if the mentoring process improves their self-efficacy. This is consistent with earlier findings suggesting that women could benefit more than men in entrepreneurial terms from self-efficacy (Second, and contrary to the above finding, the moderation effects of gender on the association between mentoring and intangible entrepreneurial outcomes reveal that the effect of mentoring on the satisfaction of the need for autonomy and intention to stay in self-employment is stronger for women. Hence, mentoring has the potential to enabling women entrepreneurs to gain independence in their work as well as increasing their likelihoods to persisting in entrepreneurial activities for a longer time. Nonetheless, when considering self-efficacy, men still reported a higher level of satisfaction of the need for autonomy and intention to stay in self-employment. A similar pattern of findings is observed regarding the moderation effects of gender on the indirect effects of mentoring through self-efficacy. Although the changes in efficacy . Whereasefficacy .One possible explanation for the weak mediation effects of self-efficacy in the association between mentoring for women and particularly the satisfaction of the need for autonomy could be the overall low number of female entrepreneurial role models and mentors as well as the cultural aspect of patriarchy that may deny women the desired level of autonomy even when they have access to good entrepreneurship mentoring. However, having female role models and mentors does not necessary imply that females will benefit much more than when they have male role models and mentors . Future R2 are quite small for most of the moderation effects. However, overall, our results are in line with previous studies that associated entrepreneurship education and training to the development of entrepreneurial self-efficacy and entrepreneurial outcomes (Despite the theoretical and practical contributions discussed above, our study is not without limitations. First, we used cross-sectional data to test our hypotheses. Caused by the fact that mentoring, self-efficacy and the three intangible outcomes of entrepreneurship were measured at the same time, we cannot firmly claim that the intangible outcomes accrue from mentoring and self-efficacy. Moreover, our sample may not be representative of young entrepreneurs in less developed countries given that the study was conducted in one major city in Uganda. It should also be noted that changes in outcomes . We recoAnother potential limitation of the study relates to the use of self-report measures. This is in addition to our focus on only the subjective intangible outcomes of entrepreneurship. Subjective outcomes of entrepreneurial activities, specifically satisfaction, are linked to or affected by the performance level of the business . The shoThe present research has demonstrated the differential impact of mentoring on intangible outcomes of entrepreneurship among men and women. The study has also validated self-efficacy as an underlying mechanism for the realization of the impact of entrepreneurial mentoring. Consequently, this study contributes to the understanding of the effectiveness of entrepreneurship education and learning interventions among women and men in the context of a less developed country as well as in the cultural context of collectivism and patriarchy. In doing so, we were able to discover the gaps in the effectiveness of entrepreneurship mentoring and learning and make a call for interventions that strengthen the entrepreneurial self-efficacy and autonomy of novice entrepreneurs but particularly of novice women entrepreneurs which can be achieved by using successful women entrepreneurs and mentors.The datasets generated for this study are available on request to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.MB is the main author and was in charge of developing the manuscript and data collection. LM participated in the data collection and analysis as well as editing of the manuscript. KO participated in conceptualizing the data, data analysis, and editing of the manuscript. All authors contributed to the article and approved the submitted version.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.


In addition to the standard scaling rules relating critical exponents at second order transitions, hyperscaling rules involve the dimension of the model. It is well known that in canonical Ising models hyperscaling rules are modified above the upper critical dimension. It was shown by M. Schwartz in 1991 that hyperscaling can also break down in Ising systems with quenched random interactions; Random Field Ising models, which are in this class, have been intensively studied. Here, numerical Ising Spin Glass data relating the scaling of the normalized Binder cumulant to that of the reduced correlation length are presented for dimensions 3, 4, 5, and 7. Hyperscaling is clearly violated in dimensions 3 and 4, as well as above the upper critical dimension  D are known as hyperscaling relations.” [It has been tacitly or explicitly assumed that Edwards–Anderson Ising Spin Glasses (ISGs), where the quenched interactions are random, follow the same basic scaling and Universality rules as in the canonical Ising models, whose properties are understood in great detail through Renormalization Group Theory (RGT). Here we will present numerical evidence for hyperscaling violation in ISGs. A textbook definition of hyperscaling is: “Identities obtained from the generalised homogeneity assumption involving the space dimension ations.” . The hype energy . The twoHyperscaling “collapses” in Ising models in dimensions above the upper critical dimension ractions ,6,7,8. Txponent”  with θ∼1 3D RFIM ,10. LogiThough not conventionally written this way, in the standard Ising models above Ising spin glasses (ISGs) are also systems with quenched randomness in which hyperscaling might be expected to break down, from a generalization of Schwartz’s argument. The exponent As usual the Hamiltonian is A and B indicate two spin systems on the same interaction realizations (samples). The susceptibility is then The magnetisation L definition for the second-moment correlation length kth spin coordinate so we let D directions. For ISGs we then also take the sample average of F in Equation χ(τ)=perature . (The WeAt infinite temperature on terms ).L and so are the same as those of the infinite-L model. A standard rule of thumb for the approximate onset of the ThL regime is t is used.For ISG models with symmetric interaction distributions an appropriate thermal scaling variable is pression ,15,19,20Q than To apply the Wegner formalism to other observables The reduced second-moment correlation length is defined as G models . Note thial case ). From eial case .The temperature-dependent effective exponent is then defined as K is the kurtosis of the interaction distribution.The temperature-dependent effective exponents L throughThe second field derivative of the bulk susceptibility see Ref.  EquationFor Ising models in the ThL (bulk or χ4(β) is (8)γ4=γ+L value of L Ising The standard “dimensionless renormalized coupling constant” can be defined aslso used  the infiG4(β)=χ4(From the hyperscaling rule, the critical exponents for see Ref.  for detaFor the 5D Ising model, in an equivalent ThL plot covering the entire paramagnetic temperature regime the breakdown of standard hyperscaling leads to a critical exponent for the normalized Binder cumulant which is not /2 but 2 , i.e., (D for ISGs can be displayed in just the same way as for the Ising model data in The normalized Binder cumulant against reduced correlation length to the power In each case the ThL data can be seen to have a critical limit constant slope with corrections coming into play at high temperatures. The value of the limit slope is in each case distinctly stronger than the standard hyperscaling value Data for the bimodal and Gaussian 4D models, Finally, in the bimodal 7D ISG (above the ISG critical dimension D, For the canonical simple cubic Ising model, from data presented in the form of the normalized Binder cumulant


Acute myeloid leukemia (AML) is a common leukemia subtype and has a poor prognosis. The risk of AML is highly related to age. In the context of population aging, a comprehensive report presenting epidemiological trends of AML is evaluable for policy-marker to allocate healthy resources.This study was based on the Global Burden of Disease 2017 database. We analyzed the change trends of incidence rate, death rate, and disability-adjusted life year (DALY) rate by calculating the corresponding estimated annual percentage change (EAPC) values. Besides, we investigated the influence of social development degree on AML’s epidemiological trends and potential risk factors for AML-related mortality.From 1990 to 2017, the incidence of AML gradually increased in the globe. Males and elder people had a higher possibility to develop AML. Developed countries tended to have higher age-standardized incidence rate and death rate than developing regions. Smoking, high body mass index, occupational exposure to benzene, and formaldehyde were the main risk factors for AML-related mortality. Notably, the contribution ratio of exposure to carcinogens was significantly increased in the low social-demographic index (SDI) region than in the high SDI region.Generally, the burden of AML became heavier during the past 28 years which might need more health resources to resolve this population aging-associated problem. In the present stage, developed countries with high SDI had the most AML incidences and deaths. At the same time, developing countries with middle- or low-middle SDI also need to take actions to relieve rapidly increased AML burden. FLT3, IDH1, IDH2, TET2, ASXL1, and DNMT3A could be found in the bone marrow or peripheral blood of patients without overt AML [TP53 mutation endow preleukemic hemopoietic stem cells with enhanced resistance to chemotherapy which further elevates the competitive advantage over normal hemopoietic stem cells [Acute myeloid leukemia (AML) is a malignant disease of hemopoietic stem cells or progenitors which is characterized as the differentiation arrest and aberrant proliferation of myeloid lineages . In 2017vert AML –12. Thisvert AML . For patvert AML . It is nvert AML . For patvert AML . Some soem cells , 17.According to SEER database, over ten thousand people died from AML which accounted for 62% of all leukemia-related deaths in the USA . In the http://ghdx.healthdata.org/gbd-results-tool). The background information such as social demographic index (SDI) was also downloaded for the following correlation analysis. SDI values range between 0 and 1 which reflect the degree of social development.The Global Burden of Disease (GBD) database contains the statistical data of 354 diseases in 195 countries or territories , 32. They = α + βx, y means log10 (ASR) value while x refers to the calendar year. EAPC values were calculated based on the formula EAPC = 100* (10^β -1). For EAPC value and its 95% confidence interval (CI) above zero, the corresponding ASR was in an upward trend and vice versa. To investigate the correlation between ASR change trends and social development degrees, we calculated Pearson’s correlation coefficient between EAPCs and SDI values. Lastly, we searched the GBD database for potential risk factors contributing to AML-related mortality and visualized corresponding results.Annual incidence cases, deaths, DALYs, and corresponding age-standardized rates (ASRs) were used to describe the burden to AML. ASRs could exclude the interference from changes in age distribution and population quantity. DALY was the summation of the years lived with disability and the years of life lost. Moreover, EAPC based on ASRs including age-standardized incidence/death rate (ASIR/ASDR) and age-standardized DALY rate per 100,000 persons were employed to reflect the change trends of AML’s burden. In the formula All data analysis was based on the open-source software R (version 3.6.0). The data visualization was performed with packages including maps, ggplot2, and RcolorBrewer. Data cleaning was conducted with package dplyr. Histograms were used to demonstrate the quantities and change trends of AML’s incidence cases, deaths, and DALYs from 1990 to 2017. Maps were adopted for the visual presentation of AML’s burden and corresponding ASRs in the 195 countries and territories. Scatter diagrams and regression curves were employed to analyze the correlation between ASRs and SDI values. Area under the curve was used to present the dynamic distribution of the age composition of AML patients.3 in 1990 to 119.57 × 103 cases in 2017, increasing by 87.3%, EAPC = 0.56, 95% CI 0.49~0.62) (Table 3 in 1990 and 43.42 × 103 cases in 2017). In the meanwhile, middle SDI had the most rapid increase during the 28 years . Subgroup analysis by geographical zone showed Western Europe and South Asia had the most incidence cases . Andean Latin America and East Asia had the most mushrooming rise . In the country or territory level, India, China, and the USA had the most incidence cases   . Subgroup analysis by a socio-demographic factor indicated that the high SDI region had the most death cases (21.87 × 103 death cases in 1990 and 40.91 × 103 death cases in 2017). At the same time, the middle SDI and low-middle SDI regions had a relatively huge rise in ASDR . As for a specific geographical zone, Western Europe, South Asia, and high-income North America zones were the top 3 regions with the most AML-related deaths . Andean Latin America had the fastest rise in ASDR . Subgroup analysis by country or territory showed that the USA, India, and China were the top 3 countries with the most death cases  , the age-standardized DALY rate in the high SDI region was modestly decreased in the past 28 years. In the contrast, the age-standardized DALY rate in the middle SDI and low-middle SDI regions were gradually increased . In subgroup analysis by geographical zone, we found that South Asia had the highest DALY until 2017 (369.72 × 103 in 1990 and 705.85 × 103 in 2017). Andean Latin America had the most sharply increase in age-standardized DALY rate . In the level of country or territory, India, China, and the USA had the most DALY   which indicated that the incidence might be underestimated in regions with a low incidence rate   Fig. a–c.Fig.We analyzed the incidence and its rate in five different age groups: under 5 years, 5~14 years, 15~49 years, 50~69 years, and above 70 years in the globe and different regions. The results demonstrated that most incidences were aged 50 years or older in the globe. Besides, in the high SDI region, patients aged 50 years or older accounted for approximately 80% AML’s incidence cases in 2017. In the low SDI regions, this ratio of patients aged 50 years or older in total incidences was about 35% (Fig. We searched the GBD database for the potential AML-related mortality attributable risk factors. Eventually, we found four risk factors contributing to AML-related death and DALY: high body mass index, occupational exposure to benzene, occupational exposure to formaldehyde, and smoking. Among all risk factors, smoking was the greatest contributor to AML-related death and DALY from 1990 to 2017 in the globe (Fig. TET2, JAK2, and ASXL1 [In this study, we reported the incidence, death, and DALY data of AML based on GBD database. Besides, we analyzed the epidemiological trends of AML by calculating the EAPC values during the past 28 years. Generally, the AML’s incidence and related death were gradually increased in the globe. We found the incidence rate of AML was significantly higher in high SDI countries such as the UK which could be attributed to better cancer diagnosis and registry system, as well as population aging in these countries. Actually, aging is an important factor contributing to leukemogenesis. Accompanied by aging, multiple cancer-associated events occur including genomic alterations, protein homeostasis dysregulation, and mitochondrial dysfunction . As an end ASXL1 –36. As and ASXL1 . Moreovend ASXL1 . With thIn addition to age, sociodemographic factors are also important variables in AML’s epidemiology especially for AML-related mortality. Consistent with the data of solid tumors, marital status is closely associated to the risk of AML-related death. Compared with unmarried AML patients, married or cohabitating counterparts had a lower risk of death , 39. In Apart from the epidemiological trend of AML, we also investigated the potential risk factors contributing to AML-related mortality. In this study, we found smoking was the primary risk factor for AML-related death and DALY. In multiple previous case-control studies, smoking was closely related with the increased risk of AML , 43. A mDuring the last few decades, the standard induction treatment for AML has always been based on 7 + 3 chemotherapy regimen. Generally, the complete remission rate is approximately 60–80% in younger patients and 40–60% in elder patients . Post-reGlobally, the incidence rate and mortality rate of AML were gradually increased. Males and elder people had a higher risk to develop AML. The incidence rate of AML was positively correlated to SDI values which meant the incidence rate in the developed region was significantly higher than in the developing region. In the meanwhile, the incidence rate in some developing areas such as the middle SDI and low-middle SDI countries increased rapidly. Smoking, high body mass index, occupational exposure to benzene, and formaldehyde were mainly risk factors contributing to AML-related mortality. There is plenty of room to control occupational exposure to carcinogens especially in developing countries. Generally, considering the accelerated aging trend in the globe, the incidence rate and mortality rate of AML might further increase. Therefore, the policy-marker should rationally allocate public health resources to relieve the mushrooming burden of AML.Additional file 1: Table S1. Top 20 countries or territories with most incidence cases in 1990. Table S2. Top 20 countries or territories with most death cases in 1990. Table S3. Top 20 countries or territories with highest DALY in 1990. Table S4. Top 20 countries or territories with highest ASIR in 1990. Table S5. Top 20 countries or territories with highest ASDR in 1990. Table S6. Top 20 countries or territories with highest age-standardized DALY rate in 1990. Table S7. Top 20 countries or territories with most incidence cases in 2017. Table S8. Top 20 countries or territories with most death cases in 2017. Table S9. Top 20 countries or territories with highest DALY in 2017. Table S10. Top 20 countries or territories with highest ASIR in 2017. Table S11. Top 20 countries or territories with highest ASDR in 2017. Table S12. Top 20 countries or territories with highest age-standardized DALY rate in 2017. Table S13. Top 10 countries or territories with the most rapid increase in ASIR. Table S14. Top 10 countries or territories with the most rapid increase in ASDR. Table S15. Top 10 countries or territories with the most rapid increase in age-standardized DALY rate. Figure S1. The contribution ratio of four risk factor for AML-related death from 1990 to 2017 in the globe and different regions. Figure S2. The contribution ratio of four risk factor for AML-related DALY from 1990 to 2017 in the globe and different regions.


Reduction of intracellular or extracellular Ca2+ levels strongly inhibited Rg3-induced activation of mitochondrial respiration and biogenesis. Taken together, Rg3 enhances capabilities of mitochondrial and antioxidant functions mainly through a Ca2+-dependent pathway, which improves the proliferation and differentiation potentials and prevents the senescence of human mesenchymal stem cells.Although mitochondrial functions are essential for cell survival, their critical roles in stem cell fate, including proliferation, differentiation, and senescence, remain elusive. Ginsenoside Rg3 exhibits various biological activities and reportedly increases mitochondrial biogenesis and respiration. Herein, we observed that Rg3 increased proliferation and suppressed senescence of human bone marrow-derived mesenchymal stem cells. Osteogenic, but not adipogenic, differentiation was facilitated by Rg3 treatment. Rg3 suppressed reactive oxygen species production and upregulated mitochondrial biogenesis and antioxidant enzymes, including superoxide dismutase. Consistently, Rg3 strongly augmented basal and ATP synthesis-linked respiration with high spare respiratory capacity. Rg3 treatment elevated cytosolic Ca Mitochondria are essential for energy metabolism, calcium homeostasis, cell survival, and apoptosis; however, their role in stem cell proliferation, differentiation, and senescence has not been fully elucidated. In a stem cell niche, quiescent cells have a low mitochondrial mass in a low oxygen environment . These cPanax ginseng has various pharmacological actions, including antioxidant i) in BMSCs loaded with Fura-2  Transcriptional regulations of main regulator of mitochondrial biogenesis (PGC1α) and antioxidant enzymes  by Rg3 were measured by quantitative PCR.  Effects of acute  and chronic  exposure of Rg3 on AMP-activated protein kinase (AMPK) and cAMP response element-binding protein (CREB) activation. Data are presented as means ± SEMs, * P < 0.05 and ** P < 0.01. Supplementary Fig. S2. Ca2+ increase by Rg3 activates mitochondrial respiration. (A) Increased cytosolic Ca2+ concentration ([Ca2+]i) under extracellular Ca2+ free condition. [Ca2+]i measurement using fluorescence imaging system after Fura-2-AM dye loading. Rg3-induced [Ca2+]i elevations under Ca2+ free and normal Ca2+ conditions were compared by the area under the curve (AUC) above the baseline. (B) Role of intracellular Ca2+ increase on acute Rg3-induced mitochondrial activation. BAPTA-AM (10 or 20 μM) were pretreated for chelating intracellular Ca2+. Effects of intracellular Ca2+ reduction on mitochondrial oxygen consumption rate (OCR) changes by 1 h exposure of Rg3 were evaluated. (C) Rg3-induced augmentation of biological health index. Based on oxygen consumption rate (OCR) data in Fig. 10[(ATP synthesis-linked) × (Spare Respiratory capacity) / (Proton leak) × ]. Data are presented as means ± SEMs, * P < 0.05, ** P < 0.01, *** P < 0.001 and **** P < 0.0001. Supplementary Fig. S3. Role of sustained Ca2+ elevation by Rg3 on stem cell fates. (DOCX 3166 kb)


Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of glucose-lowering agents that significantly improve the prognosis of patients with type 2 diabetes (T2D) and heart failure. SGLT2i has recently been implicated in the treatment of atrial fibrillation (AF) with clinical data demonstrating that these agents decrease the incidence of AF events in patients with T2D. Fundamental findings have suggested that SGLT2i may alleviate atrial electrical and structural remodeling. The underlying mechanisms of SGLT2i are likely associated with balancing the sodium and calcium handling disorders and mitigating the mitochondrial dysfunction in atrial myocytes. This review illustrates the advances in understanding the underlying mechanisms of SGLT2i as an evolving treatment modality for AF. Atrial fibrillation (AF) is a prominent public health and economic issue globally. It is estimated that about 33.5 million people worldwide suffered from AF in 2010, and the number of affected patients is predicted to reach 12.1 and 14–17 million by the year 2030 in the United States and Europe, respectively, exerting tremendous pressure on the global economy . In clin+ and Ca2+ handling are critical pathophysiological hallmarks  are novel glucose-lowering agents used in the treatment of T2D. SGLT2 is a low-affinity, high-capacity glucose transporter located in the proximal tubule in the kidneys and is responsible for glucose reabsorption into the body from urine . The Em. In the nt of AF .+ and Ca2+ fluxes between the intracellular and extracellular spaces in cardiac myocytes is pivotal to ensure normal contractile function and cardiac rhythm. During the plateau phase of the cardiac action potential, a small amount of Ca2+ enters the cardiac myocytes through L-type Ca2+ channels, causing a large Ca2+ release into the cytosol via the RyR2 channel. This channel is located in the membrane of the sarcoplasmic reticulum (SR), which is called Ca2+-induced Ca2+ release (CICR)  (2+ is mainly extruded into the extracellular fluid via a forward-mode Na+/Ca2+ exchanger (NCX).The delicate balance of Nae (CICR) . The cytpparatus . This prSERCA2a) . The rem+ hemostasis in cardiac myocytes is regulated by the Na+ channels and transporters that couple the Na+ influx to either co- or countertransport of other ions, such as NCX, Na+/H+ exchange (NHE), and Na+/K+-ATPase (NKA). Na+ channels and NCX are the dominant Na+ influx and efflux pathways in the atrium, respectively. There is a tight coupling between Na+ and Ca2+ homeostasis via the NCX in the microdomain beneath the T-tube. The NCX may operate in both forward and reverse directions, depending on the electrochemical gradients and membrane potential. Elevated intracellular Ca2+ levels activate the forward mode of NCX, extruding the Ca2+ in exchange for Na+ with a stoichiometry of 1:3 that generates a net inward current. The transient inward current results in delayed after-depolarizations (DADs) during the diastolic period and triggers activity once it reaches the threshold of the Na+ channel  complex is activated and phosphorylates several Ca2+-handling proteins, such as RyR2 and phospholamban (PLN) in atrial myocytes. This enhances the Ca2+ leak from the SR, resulting in the triggered activity that serves as the initiation of AF  production and impairment of energetic metabolism, resulting in the oxidation of the calcium-handling proteins, such as RyR2 and exacerbation of the Ca2+ leak, subsequently promoting the initiation and maintenance of AF.A growing body of evidence has shown that the development and maintenance of AF are associated with dysregulation of the Camodeling . The laton of AF . Elevateammasome . NLRP3 e+ overload underlies the development of AF. The late Na+ current (INa–L) is enhanced in AF, driving NCX in the reverse mode and increasing the cytosolic Ca2+ levels  is another example that barely regulates glucose uptake under physiological conditions. However, it activates NADPH oxidase 2 (NOX2) and causes Na+ overload when it is overexpressed  and increased protein expression of SERCA2a were responsible for the action of empagliflozin. In the ventricular myocytes isolated from patients with HF, 2+ handling in the failing ventricular myocytes were reversed. It is notable that acute (30 min) empagliflozin exposure did not alter CaMKII activity and did not improve Ca2+ handling disorder in failing ventricular myocytes, whereas the elevated cytosolic Na+ levels were attenuated. + overload.Several studies have shown that acute administration of SGLT2i promptly improves cardiac function in patients with HF. 2+ regulation may play an essential role in the atrial remodeling of AF  anchored on the inner mitochondrial membrane mainly takes charge of Ca2+ uptake from the cytoplasm during diastole. The mitochondrial membrane potential generated by proton-ATPase drives Ca2+ across the inner membrane via MCU. The free energy of ATP hydrolysis (ΔGATP) supports the proton pump to maintain the electrochemical proton gradients and transport of Ca2+, which can be disordered when ΔGATP is decreased due to mitochondrial dysfunction , increasing mitochondrial fragility  .In mitochondria, acetyl-CoA derived from glucose initiates the tricarboxylic acid cycle (TAC), which produces the ATP used for cellular activities. At the same time, ROS that causes an imbalance in ion handling and deterioration of cellular function is also generated through oxidative phosphorylation. Cafunction . Hyperacragility . In the rogenase . Thus, Cse (SOD) . Ca2+ ef2+ signaling-dependent pathway in atrial myocytes , which are dependent on GTPases. Second, optic atrophy 1 (OPA1) promotes the fusion of inner membranes. Thus, the exchange of material becomes easier, and mitochondria can continue to sustain their function, including metabolism and ATP production. Mitochondrial membranes are linked to the SR via Mfn2 in AF and when under oxidative stress, forming a construction called mitochondria-associated membrane (MAM), where Caevention .2+-dependent  upregulation and mitochondrial network fragmentation. Partial blocking or downregulation of MCU may attenuate atrial remodeling by preventing increased mitochondrial Ca2+ influx  is recruited to the surface of mitochondria to initiate this process . If mitoependent . The mov+ influx .2+ overload following acute ischemic reperfusion injury (Improvement of mitochondrial metabolism has been recognized as a therapeutic mechanism of SGLT2i. In a high-fat diet mouse model, canagliflozin protected against obesity-related metabolic disorders by improving mitochondrial function and fatty acid oxidation in adipose tissue . Sa-Nguan injury . Mfn2 ann injury .More recently, 2+-induced MPTP opening and reduces the release of ROS in ventricular myocytes in patients with HF. As mentioned above, mitochondrial function is tightly influenced by Na+ and Ca2+ levels in the mitochondria. SGLT2i are novel NHE blockers and are likely involved in the improvement of mitochondrial function in AF by modulating the mitochondrial Na+ and Ca2+ flux.To date, the underlying mechanisms of improved mitochondrial function by SGLT2i have not been completely investigated. NHE1 is expressed in the membrane of cardiac mitochondria. Downregulation of NHE1 inhibits CaSGLT2i are a new class of diabetic medications used for the treatment of T2D. In the last few years, compelling clinical evidence showed that SGLT2i reduces the incidence of AF in patients with T2D and HF. The potential role of SGLT2i in the treatment of AF is emerging. Based on the current knowledge of AF pathophysiology and the pharmacological actions of SGLT2i, it is speculated that SGLT2i potentially prevents AF by ameliorating ion handling and mitochondrial dysfunction. Understanding the therapeutic mechanisms of SGLT2i in AF has gained considerable interest and has developed rapidly. It is expected that a collaborative effort between clinical and basic science researchers will continue to enable the development of a promising treatment for AF.XP wrote the manuscript. LL, MZ, QZ, KW, RB, and YR took part in preparing the manuscript. NL prepared and reviewed the manuscript before publication. All authors confirmed that they have read and approved the manuscript and they have met the criteria for authorship.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 clonal evolution of acute myeloid leukemia (AML), an oligoclonal hematological malignancy, is driven by a plethora of cytogenetic abnormalities, gene mutations, abnormal epigenetic patterns, and aberrant gene expressions. These alterations in the leukemic blasts promote clinically diverse manifestations with common characteristics of high relapse and drug resistance. Defining and real-time monitoring of a personalized panel of these predictive genetic biomarkers is rapidly being adapted in clinical setting for diagnostic, prognostic, and therapeutic decision-making in AML. A major challenge remains the frequency of invasive biopsy procedures that can be routinely performed for monitoring of AML disease progression. Moreover, a single-site biopsy is not representative of the tumor heterogeneity as it is spatially and temporally constrained and necessitates the understanding of longitudinal and spatial subclonal dynamics in AML. Hematopoietic cells are a major contributor to plasma cell-free DNA, which also contain leukemia-specific aberrations as the circulating tumor-derived DNA (ctDNA) fraction. Plasma cell-free DNA analysis holds immense potential as a minimally invasive tool for genomic profiling at diagnosis as well as clonal evolution during AML disease progression. With the technological advances and increasing sensitivity for detection of ctDNA, both genetic and epigenetic aberrations can be qualitatively and quantitatively evaluated. However, challenges remain in validating the utility of liquid biopsy tools in clinics, and universal recommendations are still awaited towards reliable diagnostics and prognostics. Here, we provide an overview on the scope of ctDNA analyses for prognosis, assessment of response to treatment and measurable residual disease, prediction of disease relapse, development of acquired resistance and beyond in AML. The expanding knowledge of its genomics has revealed the molecular complexity of the abnormal leukemogenesis in AML, which has immensely contributed to the refinement of risk stratification and personalized therapeutic strategies for these patients (Acute myeloid leukemia (AML) is a rapidly progressing hematological malignancy that display varied clinicopathological features as well as treatment outcomes . With anpatients . Of the patients . Neverthpatients . A signipatients .In the current scenario with several options of standard chemotherapy, low-intensity regimens, combination chemoimmunotherapy, and clinical trials, AML patients may certainly benefit from the provision of concurrent real-time longitudinal monitoring of disease burden. The persistence of patient-specific genetic alterations in the due course of disease progression holds potential prognostic value. Monitoring these alterations may further guide strategies for maintenance of remission in the long term. Since liquid biopsy techniques are extensively being explored as non-invasive methods for tumor diagnosis and disease monitoring, these can provide early insights into treatment efficacy as well as predict recurrence of the disease. Here, we present an overview of the scope of molecular analysis of ctDNA in tracking relevant genetic markers for longitudinal monitoring of disease burden in AML.RUNX1, CBFB, RARA, and alterations in other transcription factors), it has become evident that more than 95% of AML patients carry known driver and co-occurring mutations that are implicated in the survival of the neoplastic clone or subclones  introduced a new classification system of AML based on recurrent cytogenetic abnormalities in 2001  and subsubclones . Somaticubclones . Hencefofication . The timTP53 gene. The updated European Leukemia Net (ELN) recommendation for risk stratification of AML patients into favorable, intermediate, and adverse groups is governed by a comprehensive integrated genomic profiling that includes recurrent chromosomal abnormalities, gene mutations, and FLT3-ITD allelic ratio , and PCR or NGS-based molecular analyses, primarily performed on the bone marrow sample, guides prognostication as well as therapeutic choices for individual patients. The current practice for the evaluation of both remission and MRD for response assessments rely on bone marrow sampling, whereas peripheral blood evaluation may be adequate for monitoring of relapse in most cases , the European Leukemia Net (ELN), and the National Comprehensive Cancer Network (NCCN) guidelines . The comst cases .Once complete clinical remission is achieved post-therapy, the frequency of follow-up bone marrow biopsies is not well defined. Moreover, the clinical utility of monitoring residual leukemic burden during initial induction therapy is currently not known . Most coFor assurance to a patient in clinical remission to sustain in a clinically disease-free state, several issues remain. These include (i) sampling error introduced from a single bone marrow specimen that represents only a very small fraction of the total bone marrow cellular population ; (ii) spRUNX1-RUNX1T1, CBFB-MYH11, and PML-RARα) or mutations  by quantitative PCR (qPCR) and more recently NGS are commonly used tools for MRD assessment  has emerged as an independent prognostic indicator in AML . The cursessment . The ELNFor MRD assessment, the sample of choice is bone marrow, although, peripheral blood is easy to obtain and lacks immature normal populations of cells that may interfere with analysis by multiparameteric flow cytometry. However, the sensitivity of MRD analysis of the peripheral blood circulating tumor cells (CTCs) is apparently lower than that of bone marrow and requires a lower MRD threshold to be prognostic. Numerous technical challenges remain regarding MRD monitoring in AML including (i) preferred source material (blood versus bone marrow); (ii) ideal sampling time; (iii) sampling interval; (iv) duration of screening for relapse; (v) identifiable and reliable molecular marker/s; and (vi) thorough validation and standardization of MRD assays for each individual marker.DNMT3A, TET2, and ASXL1) that are associated with age-related clonal hematopoiesis, rather than residual leukemic cells , plasma cell-free DNA (cfDNA), microRNAs (miRNA), and exosomes have emerged as biomarkers with immense potential . Plasma N-RAS point mutations in patients with AML and myelodysplastic syndrome (MDS)  .N-RAS mutations in plasma cfDNA than in DNA obtained from blood cells or bone marrow suggested that a bone marrow biopsy or aspiration may not necessarily contain all the malignant clones involved in the disease  mutation levels with clinical characteristics of AML patients, researchers quantitated the copies per milliliter of NPM1-A mutation in plasma cfDNA , defined as the total number of non-synonymous mutations in the coding regions of the genes. A significant correlation between TMB and efficacy of targeted therapy is emerging. The clinical utility of assessing TMB using plasma cfDNA, which contains ctDNA, as a surrogate specimen to biopsy has been proposed . To invema cfDNA . This grwith AML . During IDH1/2 genes and hotspot mutations in other genes).The technological advancement in the genomic profiling of ctDNA facilitated the tracking of driver mutations and karyotypic abnormalities in AML and MDS for disease monitoring and assessment of treatment response. Highlights of the co-evolution of important breakthroughs in AML genomics and utility of cfDNA analysis are shown in Sequencing of cfDNA may identify clinically relevant mutations not detected in the bone marrow and may play a role in the assessment of MRD and prediction of relapse as further corroborated in a recent study. Targeted NGS of plasma cfDNA and bone marrow at the time of diagnosis and after achieving remission was conducted in 22 patients with AML . Among 2The studies so far demonstrate a great potential for ctDNA in AML MRD assessment and thus may relieve patients from frequent risk-prone painful bone marrow punctures. Monitoring ctDNA enhances detection of relapse and defines molecular remission better. Early intervention at the stage of minimal tumor burden maybe possible by serial monitoring of ctDNA. Indeed, our experience with longitudinal molecular monitoring of plasma ctDNA during the course of AML disease progression supports these findings as described below.RUNX1-RUNX1T1 recurrent abnormality and KIT D816V mutation, we retrospectively determined the fractional abundance of KIT D816V mutation by droplet digital PCR. Paired samples of plasma cfDNA and bone marrow aspirates were collected at baseline, for MRD assessment, at CR after consolidation and relapse  and specificity . TechnolThe major technical revolution witnessed is the range of ultrasensitive NGS platforms available for optimized detection of multiple somatic alterations simultaneously using ctDNA. The choice of target regions to be identified governs the selection of the NGS platform . Ultra-DAmplification-based methods including PCR and NGS are limited by the need for specific primers to initiate the amplification process. In this scenario, the utility and flexibility of HPLC-based mass spectrometry methods for the analysis of short DNA sequences is promising . The shoThe applications of ctDNA analysis go beyond initial diagnosis, treatment stratification and monitoring, prognosis, assessment of MRD, and prediction of relapse . cfDNA iThe International Society of Liquid Biopsy (ISLB) has recently elaborated on the various challenges associated with cfDNA analysis such as technological, biological, reporting-related, socio-economic, and regulatory . It is eDNMT3A, TET2, and ASXL1) drive asymptomatic proliferation of blood cells arising from hematopoietic stem cells harboring them. These age-related CHIP mutations become a potential source of false positives in cfDNA in the absence of a hematological malignancy  and a regulatory body the International Liquid Biopsy Alliance (ILBA) that includes ISLB and regulatory agencies with a goal of increasing efficiency, minimizing duplication and expedition of the inclusion of liquid biopsy based assays into routine clinical practice. So far, the only FDA-approved liquid biopsy tests include Cobas EGFR mutation assay for non-small-cell lung carcinoma  and TherLiquid biopsy technologies for qualitative and quantitative analysis of cfDNA have immensely broadened our ability to assess cancer, specifically in its cryptic stage without the need for invasive sampling. A serial longitudinal monitoring of AML using cfDNA analysis from the peripheral blood may provide a series of screenshots that can potentially be coalesced together to generate a time-lapse movie of clonal evolution of leukemia. With an almost excellent concordance with matched bone marrow aspirates, cfDNA can quantify disease burden by providing mutational landscape as well as identify acquired drug resistance mechanisms which may guide clinical management in real time.As rapid diagnosis of genetic alterations is required to opt for appropriate induction therapy by the oncologists, therefore, a quick turnaround time for comprehensive cfDNA sequencing may provide actionable information to guide clinical management. In this regard, the convenience of sample acquisition and storage of cfDNA provides added procedural advantage over currently practiced protocols. So far, the small cohorts evaluated for cfDNA necessitates further validation with a certain sample size to examine the frequency of the gene mutations in AML patients that may facilitate significant statistical power for meaningful comparisons. Initiatives have been taken by researchers through multicentric studies, cooperative-group trials, and regulatory bodies are formulated to devise universal guidelines. Further investigations will have to define the role of cfDNA as a diagnostic tool by determining clinically relevant tumor thresholds relative to currently used routine parameters.The use of ultrasensitive sequencing technologies has facilitated the reliable detection of very low amounts of ctDNA that excellently complement the currently used methods. Therefore, an immediate clinical application of cfDNA genotyping in AML may be its incorporation in larger prospective clinical trials for the identification of patients carrying actionable mutations and their longitudinal genetic monitoring during targeted therapy administration. Monitoring of ctDNA may provide surrogate end-points for clinical outcomes. This can reduce the extended follow-up durations as well as become more cost-effective for clinical trials related to adjunct therapies. Moreover, ctDNA analyses based MRD estimation may aid the discovery of novel drugs targeted at elimination or control of residual tumor in high-risk AML patients prone to relapse .Plasma ctDNA may be used for the study of virtually all genomic abnormalities including both coding and non-coding regions, loss of heterozygosity, microsatellite loci, mutations, polymorphisms, methylation, and copy number variations. Deep sequencing as a standalone for ctDNA analyses may get a boost by additional assessment of epigenetic modifications, immune signatures, platelets, exosomes, and miRNA analyses. Moreover, a better understanding of the dynamics of ctDNA in AML disease progression may be necessary before blood can be routinely used as a source to monitor tumor burden. Nevertheless, longitudinal monitoring of AML patients by ctDNA analysis could complement bone marrow cells as a diagnostic marker without sampling bias.DT and RG designed and conducted the study, performed the data interpretation, statistical analysis, and wrote the manuscript. RKS is the medical oncologist who treated the patient included in the case study. PV performed the ddPCR experiments. IK performed NGS experiments. SV conducted RT-PCR and fragment analysis assays. All authors contributed to the article and approved the submitted version.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.


Acute myeloid leukemia (AML) cells modulate their metabolic state continuously as a result of bone marrow (BM) microenvironment stimuli and/or nutrient availability. Adipocytes are prevalent in the BM stroma and increase in number with age. AML in elderly patients induces remodeling and lipolysis of BM adipocytes, which may promote AML cell survival through metabolic activation of fatty acid oxidation (FAO). FAO reactions generate acetyl-CoA from fatty acids under aerobic conditions and, under certain conditions, it can cause uncoupling of mitochondrial oxidative phosphorylation. Recent experimental evidence indicates that FAO is associated with quiescence and drug-resistance in leukemia stem cells. In this review, we highlight recent progress in our understanding of fatty acid metabolism in AML cells in the adipocyte-rich BM microenvironment, and discuss the therapeutic potential of combinatorial regimens with various FAO inhibitors, which target metabolic vulnerabilities of BM-resident, chemoresistant leukemia cells. In the bone marrow (BM) microenvironment, AML cells modulate their metabolic state to respond to extracellular stimuli, like hypoxia and nutrient availability, and can therefore undergo cell kinetic quiescence, proliferation, or differentiation . GlucoseAcute myeloid leukemia (AML) is primarily a disease of the elderly, with 75% of AML patients greater being over 60 years old at diagnosis . In adulA recent study demonstrated that BM-resident adipocytes markedly impaired the antileukemia efficacy of various chemotherapeutic agents, and that the rate of relapse after chemotherapy was higher in obese mice compared to their normal-weight counterparts , 9, 10. Although reports are increasing regarding the roles of altered energy metabolism during tumor progression, including AML tumorigenesis, studies focusing on fatty acid metabolism in this process remain relatively rare, and the molecular mechanisms associated with fatty acid metabolism and the tumorigenic properties of AML progenitors or LSCs are poorly characterized .Interestingly, while it triggers various adaptive mechanisms that contribute to survival of AML cells, inhibition of FAO disrupts metabolic homeostasis, increases reactive oxygen species (ROS) production, and causes apoptosis in AML cells . Therefo2 that are oxidized in the electron transport chain to produce ATP  followed by ligation of PPARγ. Activated PPARγ then induces downstream target genes, including tic BCL2 . In facttic BCL2 , 26.In mitochondria, fatty acids that are consumed in FAO are imported in to the matrix by uncoupling protein 2 (UCP2), which can cause mitochondrial inner membrane uncoupling with the proton motive force dissipated as heat . Mitocho2+ influx via AdipoR1is necessary for the activation of AMPK  , which i of AMPK . BM adip of AMPK . HSPs th of AMPK , supportLSCs are a subpopulation of AML cells in the BM microenvironment that become resistant to drugs by entering a quiescent state, which is induced by growth factor signaling, epigenetic regulation, and altered metabolism , 39. FAOBM-resident LSCs exposed to adipocytes also exhibit a pro-inflammatory phenotype inducing lipolysis in vicinal adipocytes that further fuels FAO in the leukemic cells .Adipocytes support survival and growth of various types of tumor cells including prostate and breast cancers by stimulating mitochondrial metabolism in tumor cells due to high energy lipid transfer , 45. Niede novo from AML patients were dependent on amino acid metabolism for oxidative phosphorylation , a key therapeutic target, hydrolyzed plasma asparagine and glutamine to disrupt metabolic homeostasis. ASNase also induces a compensatory increase of FAO and cellular respiration to overcome metabolic stress, and the inhibition of FAO by etomoxir markedly increased the sensitivity of acute lymphocytic leukemia (ALL) cells to ASNase .in vitro and in vivo  cells. The fatty-acid derivative and FAO inhibitor AIC-47 reversed the TKI-induced upregulation of FAO and exhibited synergic cytotoxicity with imatinib , 64. In  in vivo . These fHere we have described recent evidence for the role of fatty acid metabolism and FAO in AML survival in the adipocyte-rich BM microenvironment. Metabolic alterations in leukemia cells have drawn increasing attention as an important therapeutic objective, and encouraging results with reagents that targeting fatty acid metabolism have been achieved in preclinical leukemia models. Leukemic cells may be critically dependent on certain metabolic pathways as their molecular heterogeneity suggest. Hence, the metabolism changes in leukemia cells vs. their normal hematopoietic counterparts can be used to generate a therapeutic window of selective sensitivity for the tumor cells. Nevertheless, tumor cells can adapt quickly to nutrient deprivation via activation of multiple metabolic bypass processes with support by their microenvironment. In this manner, FAO inhibition triggers various adaptive mechanisms that enhance AML survival in the BM, suggesting the inadequate usefulness of FAO inhibitors when used as alone . AlternaIn conclusion, recent studies have highlighted the importance of understanding AML cell metabolism in the BM microenvironment, and emphasize the potential of drug combinatorial strategies aiming at metabolic vulnerabilities of resistant AML cells and LSCs. The metabolic adaptation of AML cells and the variation of fatty acid metabolism signify an attractive therapeutic target for use against hematological malignancies. Emphasis should be placed on ROS as the executioners of cytotoxicity by metabolism-targeting therapeutics, and predictive biomarkers of response to these drugs should be explored, since both are critical to improving clinical outcomes. More comprehensive mechanistic findings from future studies may reveal that therapeutic targeting of fatty acid metabolism and FAO, especially in elderly patients with increased adiposity in the BM microenvironment, will hopefully increase the efficacy of related chemotherapeutic agents as well as reduce their toxicity.All authors have contributed to the preparation of the manuscript and reviewed/approved it in its final form.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.


Accumulated evidence indicates that the underlying mechanism for this is that abnormal intracellular Ca2+ levels stimulate the dysregulation of intracellular signaling, which subsequently induces neuronal cell death. We examined intracellular Ca2+ homeostasis in cortical (in vivo) and hippocampal (in vitro) neurons from young (3-months), middle-age (12-months), and aged (24-months) wild type C57BL6J mice. We found a progressive age-related elevation of intracellular resting calcium ([Ca2+]r) in cortical (in vivo) and hippocampal (in vitro) neurons associated with increased hippocampal neuronal calpain activity and reduced cell viability. In vitro, removal of extracellular Ca2+ or treatment with SAR7334 or dantrolene reduced [Ca2+]r in all age groups and dantrolene treatment lowered calpain activity and increased cell viability. In vivo, both middle-aged and aged mice showed cognitive deficits compared to young mice, which improved after dantrolene treatment. These findings support the hypothesis that intracellular Ca2+ dyshomeostasis is a major mechanism underlying the cognitive deficits seen in both normal aging and degenerative neurologic diseases.Neuronal intracellular Ca The three mice ages: young, middle age, and aged were selected to be the equivalent to approximately 10, 40, and 80 human years based on the fact that one human year is equivalent to nine mice days , and water was withheld for 1 h before anesthesia. Mice were anesthetized with ketamine/xylazine (100/5 mg/kg body weight) and then placed on a temperature-controlled pad. Its nose was inserted into an anesthesia mask  and all mice inhaled ultra-pure grade air  and were allowed to breathe spontaneously. The vital signs  were monitored throughout the procedure. Tail and/or toe pinches were used to ensure the animal was fully anesthetized throughout the investigative procedures. Body temperatures were maintained between 36.9 and 37.3°C using a Peltier thermostatic low noise temperature controller ATC2000  with feedback control from a rectal probe.For 2+]r (data not shown). After shaving and disinfection of the surgical site, the skin above the frontal-parietal temporal lobes was removed, and a mixture of lidocaine and epinephrine solution was injected into the periosteum to avoid bleeding and to reduce pain. A small circle of about 1 cm in diameter etched away with the aid of a pneumatic dental drill. The drilling was stopped when a very thin layer of bone was left. By pushing gently in the center of the draw circle, and the aid of small forceps, the remaining bone was removed from the skull. Gelfoam sponge was used in case of bleeding. Petrolatum was deposited around the craniotomy to create a “chamber,” which was filled and continuously perfused at a rate of 3–5 ml/min with warm sterile artificial cerebrospinal fluid (ACSF) equilibrated with a 95/5/% O2/CO2 mixture.Anesthetized mice were placed in a stereotaxic frame, and the head was firmly secured with the ear bars. Eye ointment was applied to prevent the animal’s eye from drying out. Dexamethasone (0.2 mg/Kg) was administered subcutaneously to prevent brain swelling. Pilot experiments show that dexamethasone at the dose used in the present study does not modify neuronal r but did not interfere with the ability of the mice to swim (unpublished observations).The Morris learning test was conducted in young, middle-aged and aged mice, which were divided randomly into two groups: Group 1: in vivo studies contained in (mM) 135 NaCl, 1.8 KCl, 26 NaHCO3, 1.25 NaH2PO4, 2 CaCl2, 1 MgCl2, and 5 glucose . Ringer-Locke’s solution used for in vitro studies contained the following (in mM): 135 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 5 glucose, tetrodotoxin (TTX 1.5 μM), 3.6 NaHCO3 (pH 7.4). Ca2+ free solution was prepared by omitting Ca2+ and adding 1 mM EGTA. In all experiments, ACSF and the Ringer-Locke’s solution were aerated with a mixture of 95% O2 and 5% CO2. Dantrolene solution was prepared by dissolving the dantrolene powder in dimethyl sulfoxide and then adding the appropriate amount of dissolved dantrolene to the Ringer-Locke’s solution to make the desired concentration (20 μM). SAR7334 solutions  were prepared by adding concentrated stocks of the drug to the Ringer-Locke’s solution to a final concentration of 0.1 or 1 μM. We added TTX  to the Ringer-Locke’s solution to suppress Ca2+ oscillations because spontaneous Ca2+ oscillations interfered with the measurement of [Ca2+]r. In previous experiments, we have demonstrated that TXX did not alter either the resting membrane potential or [Ca2+]r in hippocampal neurons that were not firing spontaneously  used for post hoc comparisons tests to determine significance. p < 0.05 was considered as statistically significant. Analysis of these data failed to show sex differences; therefore, the data from male and female mice were combined for analysis. micen: indicates the number of mice used and cellsn: represents the number of successful measurements.Values are expressed as mean ± SD. The data were subjected to analysis of variance (one-way ANOVA) followed by Tukey’s 2+ homeostasis is considered to be a key pathological factor leading to aging-related neuronal dysfunction , middle-aged (12-months), and aged (24-months) mice to determine if there were any changes associated with normal aging in mice. In young mice, cortical neuronal [Ca2+]r was 121 ± 2 nM. Interestingly in middle-aged WT mice neuronal [Ca2+]r, increased 1.9-fold to 226 ± 27 nM, and in aged mice, it rose 2.7-fold to 334 ± 43 nM  and aged mice have a 2.4-fold higher [Ca2+]r (286 ± 40 nM) than neurons from young mice . We found that [Na+]r was 1.3-fold higher (10.6 ± 0.9 mM) in middle-aged neurons), and 1.8-fold higher in aged neurons (14.4 ± 0.9 mM) than in young neurons  significantly reduced [Na+]r in neurons of all age groups, and like its effect on [Ca2+]r, the reduction was more prominent in middle-aged (20%) and aged neurons (31%), compared to young neurons (6%) (To determine how  is maintained in the range of 100–120 nM in resting cells against a large extracellular concentration gradient  than those which are usually considered aged (24 months or older). This has important clinical implications since it demonstrates that alterations of neuronal [Ca2+]r are progressive with age and begin at a much earlier age than has been previously assumed. Therefore, to be effective over the long term, therapies oriented to prevent cognitive decline might need to be initiated at a much earlier age. Our data showing an age-related increase in [Ca2+]r with age are in agreement with the findings reported by Tonkikh et al.  neurons compared to young animals. However, other reports  and TRPC channels to maintain the appropriate ER [Ca2+] that regulates neuronal functions  to reduce SR leak and maintain normal SR Ca2+ stores  glial cell alterations  the demonstration of dysregulation of [Ca2+]r in middle-aged as well as aged cortical and hippocampal neurons; (iii) the revelation that the elevation in [Ca2+]r in middle-aged and aged neurons can be decreased or normalized by either dantrolene or SAR7374; (iv) that disruption of normal neuronal intracellular Ca2+ homeostasis leads to increases in calpain activity and a decrease in neuronal viability; (v) neuronal [Ca2+]r dysregulation is associated with an age-related cognitive decline, as measured by MWM performance; and (vi) the reduction in [Ca2+]r associated with dantrolene treatment in middle-aged and aged animals was accompanied with an improvement of cognition as measured by MWM.In summary, the novel findings of the present study are: (i) the direct measurement of [Ca2+ dysregulation. Despite that alterations in ER-RyR Ca2+ leak and TRPC channels may not be the only pathogenic factors contributing to the pathogenesis of aging, the potential modification of those alterations is enough to enable expectations for new preventive or therapeutic strategies. Further research must be carried out to explore more in-depth the role of intracellular Ca2+ dysregulation and cognitive decline observed with aging.Based on the above findings, it appears there is an interaction between cognitive decline observed in middle-aged and elderly mice and chronic intracellular CaThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher.All protocols used in the study were performed following the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the IACUC of the Mount Sinai Medical Center.AU and VF: performed research and analyzed data. JA and PA: analyzed data and wrote the article. JL: designed research, performed research, analyzed data and wrote the article. All the authors contributed to manuscript revision, read and approved the submitted version.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.


Several important cellular functions are finely tuned by the physical and functional interactions between mitochondria and other organelles, such as lipid trafficking, mitochondrial dynamics, calcium flow and Endoplasmic Reticulum stress. These functions in turn impact on apoptosis, autophagy, cell proliferation and differentiation, playing an important role in the pathogenesis of various human diseases. Mitochondria are closely interconnected with several organelles, such as Endoplasmic Reticulum, lipid droplets, Golgi apparatus, lysosomes, melanosomes and peroxisomes, through physical contacts. Several findings demonstrated that these interaction sites are important to fulfill specific cellular functions. In this review, we will highlight the role of membrane contact sites with mitochondria in modulating mitochondrial metabolism and intracellular signaling in the context of cancer development and progression, with a special focus on calcium signaling. In particular, we will discuss on mitochondria–ER, mitochondria–lysosomes and mitochondria–peroxisomes contact sites.Mitochondria are organelles that are mainly involved in the generation of ATP by cellular respiration. In addition, they modulate several intracellular functions, ranging from cell proliferation and differentiation to cell death. Importantly, mitochondria are social and can interact with other organelles, such as the Endoplasmic Reticulum, lysosomes and peroxisomes. This symbiotic relationship gives advantages to both partners in regulating some of their functions related to several aspects of cell survival, metabolism, sensitivity to cell death and metastasis, which can all finally contribute to tumorigenesis. Moreover, growing evidence indicates that modulation of the length and/or numbers of these contacts, as well as of the distance between the two engaged organelles, impacts both on their function as well as on cellular signaling. In this review, we discuss recent advances in the field of contacts and communication between mitochondria and other intracellular organelles, focusing on how the tuning of mitochondrial function might impact on both the interaction with other organelles as well as on intracellular signaling in cancer development and progression, with a special focus on calcium signaling. Primordial mitochondria were symbiotic resident proteobacteria of the cell, providing an efficient energetic supply due to their ability to generate ATP using molecular oxygen as a final electron acceptor during respiration. As their counterpart, the host gives these ancient bacteria protection from the external environment and constant support in term of nutrients  . Primord2+) flow and ER stress. These functions in turn impact on apoptosis, autophagy  is constantly reduced to nM concentration (≈100 nM) by the continuous activity of Ca2+ ATPases, which move Ca2+ into stores  or the extracellular matrix (≈2 mM [Ca2+]). The cytosolic basal Ca2+ level can be rapidly altered upon activation of Ca2+ signaling. Indeed, it can almost instantly increase by up to 3 μM due to several selective Ca2+ channels located in the plasma membrane or on the ER surface  can be taken up by the mitochondrial calcium uniporter MCU [2+-dependent enzymes [2+] results in elevated generation of ATP [2+ signals have a dual effect: excessive and prolonged [Ca2+] within the mitochondrial matrix can induce apoptosis, for example by triggering permeability transition pore (PTP) opening [2+-dependent channel [0F1 ATP synthase [2+ imbalance also induces the oligomerization of Bcl-2-associated X protein (BAX), so as to increase the permeability of mitochondrial membranes [2+ release from the ER, and can thus modulate Ca2+ fluxes to the mitochondria, with consequent regulation of the induction of the intrinsic apoptotic pathway. Recently, it has been demonstrated that all three IP3R isoforms are required for maintaining MERCs [2+ transfer by dephosphorylating both IP3R3 and AKT and leading to cell death [2+ relocation and inhibits apoptosis in cancer cells [2+ release and apoptosis [2+ transfer and conferring resistance to cell death. In fact, Bcl-2 overexpression is a key event for cancer cell survival and chemoresistance, as observed for the cisplatin treatment in ovarian cancer [2+ fluxes and cell death by interacting with the glucose-regulated protein 75 (GRP75). GRP75 is one of the key proteins localized at MAMs, and is important for Ca2+ signaling, able to form a complex with IP3R and the voltage-dependent anion channel (VDAC). It has been demonstrated that GRP75 creates a molecular bridge between IP3R and VDAC1 at the MAMs, supporting Ca2+ transfer from ER to mitochondria [2+ movement from ER to mitochondria, and to a decreased number of MERCs controlling the interaction between IP3R and GRP75 at the MAMs [Several oncogenic pathways supporting tumor cell growth and survival depend on cellular metabolism and Caignaling . Emerginignaling ,34,35. Eunctions . Multiplrter MCU ,38, regurter MCU . The Kre enzymes , thus aln of ATP . However opening , a Ca2+- channel , proposesynthase . Mitochoembranes . This prembranes . Severalng MERCs , and thang MERCs . PTEN, oll death . On the er cells ,51,52. Spoptosis . Conversn cancer ,55. Recechondria . A lack the MAMs . TG2 ovethe MAMs .2+ fluxes from ER to mitochondria are also tuned by Sigma receptor 1 (SIG1R), a chaperone located in different districts within the cell and enriched at MAMs, where it can interact with GRP78  [2+-activated potassium (SKCa) channel and the Ca2+-release-activated Ca2+ modulator 1 (ORAI1), which favors cancer cells migration [2+ signaling [2+ signal and mitochondrial bioenergetics [2+ homeostasis may affect cancer progression. For example, superoxide anions can target IP3R thiol groups so as to affect MERCs and to modulate Ca2+ signaling by promoting Ca2+ transfer from the ER to mitochondria [Caled BIP) . SIGR1 iigration ,61. Whetigration  remains ignaling . Very reergetics . In addichondria . Such a 2+ modulates these structural changes both in normal and in cancer cells [2+ overload increases fragmentation. Ca2+ influx into the mitochondria has important consequences, not only in the context of apoptosis, but also concerning mitochondrial dynamics. For example, Ca2+ influx through VDAC and MCU induces rapid mitochondrial fission by phosphorylation of the dynamin-related protein 1 (DRP1) in neurons [Since mitochondria have several distinct functions, they can constantly change their shape to satisfy the cell requirements and modulate their functions. Thus, both the balance between oxidative and glycolytic metabolisms as well as the balance between fusion and fission, which is intimately linked to the bioenergetic efficiency of this organelle ,65, are er cells ,67—indee neurons .2+ channeling and ATP translocation to the ER Ca2+ ATPase (SERCA), generating an efficient synergistic cycle. Mitochondrial membrane depolarization triggered by high Ca2+ levels is followed by a decrease in ATP synthesis, leading to decreased SERCA function, and ultimately leading to cell death [2+ into the ER, leading to a catastrophic and cyclic impairment of cell functions  activity, which suppresses the conversion of pyruvate to acetyl CoA via inhibitory phosphorylation of the pyruvate dehydrogenase complex, dampens MAMs formation and improves insulin signaling by preventing MAM-induced mitochondrial Casistance . Importasistance . On the sistance . Reductisistance . In addisistance . Thus, dsistance .+/- (Transcription factor A mitochondria) heterozygous knock-out mice crossed with adenomatous polyposis coli multiple intestinal neoplasia (APCMin/+) mouse cancer models [Finally, MERCs dysfunction-linked ER stress impacts on several important cellular processes, including Wnt signaling ,100, whir models . Similarr models  . Moreovr models  , a protein kinase involved in several biological process, whose mutations can trigger carcinogenesis . mTOR is2+ plays a crucial role. While the concentration of Ca2+ within the cell in the cytosol is about 100 nM, in the lysosome lumen it is about 500 μM [2+ fluxes across lysosomal membranes are regulated by several ion channels, like those of the TRP family, namely TRPM2, TRPML1, TRPML2 and TRPML3, and those of the TPC family [2+ and other cations from the lumen of the lysosome into the cytosol. The increased cytosolic Ca2+ concentration leads to the dephosphorylation and activation of TFEB, the master regulator of lysosome biogenesis and autophagy-related genes, inducing the removal of damaged cellular components and re-establishing organelle homeostasis [2+ can activate the lysosomal big-conductance K+ (BK) channels, known to be implicated in cancer migration, proliferation and metastasis [2+ from lysosomes, which mediates lysosomal membrane trafficking. Improper conductance through these lysosomal ion channels has been associated with many diseases; in particular, BK and TPC have been linked to cancer cell proliferation and metastasis formation [To allow the proper performance of lysosomes, several ion channels finely adjust ion homeostasis within the organelle . The funt 500 μM . Ca2+ flC family . Upon aceostasis . Lysosomeostasis . Moreovetastasis . BK can ormation ,128.During carcinogenesis, mitochondria also adjust their ion homeostasis to favor cellular growth and metabolism . An incrConsidering the intertwined tasks between lysosomes and mitochondria, the question of how these two organelles can communicate with each other became an important issue. Nowadays, some rather limited information about the interactions between endosomes or lysosomes and mitochondria is available . LysosomThe contact sites between lysosomes and mitochondria seem to play a crucial role in calcium homeostasis as well. In particular, lysosomal calcium released by TRPML1 has been recently shown to promote calcium transfer to mitochondria, which was mediated by the tethering of mitochondria–lysosome contact sites . InteresPeroxisomes are single membrane-surrounded dynamic organelles that play important roles in biosynthetic processes and signal transduction, since they are involved in phospholipid biosynthesis, fatty acid α- and β-oxidation, bile acid and docosahexaenoic acid synthesis, glyoxylate metabolism, amino acid catabolism, polyamine oxidation, ROS and nitrogen species metabolism, inflammation and innate immunity ,142. PerIn mammalian cells, the contact sites among mitochondria and peroxisomes are mediated by a complex constituted by a splice variant of enoyl-CoA isomerase 2 (ECI2)  Figure . Mitocho2O2. The impairment of catalase activity will lead to mitochondrial oxidative stress response induction, which could trigger damages to the cell components [2O2, are important signaling molecules able to support cancer proliferation by, for example, activating the epidermal growth factor (EGF) of the platelet-derived growth factor (PDGF), or by regulating the PTEN activity of the phosphoinositide 3-kinase (PI3K) signaling pathway [Furthermore, peroxisomes are important organelles involved in the clearance of ROS, since they contain catalase to break Hmponents ,148. ROS pathway ,150. In  pathway . General pathway . Moreove pathway . WhetherIn summary, while the relevance of the targeting of mitochondrial metabolism by molecules able to specifically disrupt mitochondrial fitness and trigger cell death exclusively in cancer cells has been recognized by the scientific community as a promising strategy against cancer , the exp


Rabbits contain several parasites that can be harmful to their health as well as human being’s health due to the probability of causing parasitic zoonosis. The present research was designed to study ectoparasites and endoparasites of New Zealand White rabbits in North West of Iran and potential risks of parasitic zoonosis for researchers and owners.Totally, 50 rabbits were purchased from rabbit sellers and breeders in suburbs of Urmia and Tabriz between Jul and Dec 2016. The rabbits were assessed for ectoparasites by hair brushing, skin scraping, acetate tape preparation and othic swabs. They were euthanized and inspected for helminths and protozoa infection. Faecal sampling was carried out directly from recti and the oocysts or cysts were isolated using sedimentation and floatation techniques and the sporulated oocyst were identified based on morphological.Passalurus ambigus 54%, Trichostrongylus retortaeformis 42%, Nematodirus leporis 32%, Cestoda: Cysticercus pisiformis 26%, Protozoa: Eimeria steidae 44%, E. magna 30%, E. media 12% and Arthropoda: Sarcoptes scabiei 18% and Cheyletiella parasitivorax 38%. No significant difference was recorded in infection rate between male and female rabbits.The following parasites, with their respective prevalence; Nematoda: Both domestic and wild rabbits are a potential source of human parasitic zoonosis, and strict hygienic practices are recommended during and after handling rabbits or in case of exposure to their feces. Spreading worldwide, rabbits are the small mammals belongs to the family of Leporidae, order Lagomorpha. Until now, 28 races and 77 species of the rabbits have been identified . The mosThe rabbits are subjected to various diseases. Among the numerous pathogens that affect the rabbits, parasites play a major role in causing several diseases in rabbit with greater morbidity and mortality leading to economic losses. Some of the parasites are helminths like roundworms, tapeworms, flukes, and the others are ectoparasites like ticks, mites, lice, etc. Ectoparasites are considered as common and important cause of pruritic skin diseases and hypersensitivity disorders in rabbits, as well as some ectoparasites, which are vectors of a wide range of important zoonotic diseases worldwide, such as borreliosis, bartonellosis, ehrlichiosis, rickettsiosis, anaplasmosis, yersiniosis, tularemia .Several studies have been published on the distribution and prevalence of parasites on various breed of rabbits in different parts of the world –11. UnfoTherefore, this study, for the first time seeks to determine the species and prevalence of ectoparasites and gastrointestinal parasites in NWZRs of North West of Iran, for the first time.This study was reviewed and approved by the Ethics Committees of Tabriz University, Tabriz, Iran. The present study has been performed since Jul until Dec 2016 based on cross-sectional design. The samples including, 21 (42%) female and 29 (58%) male NZWRs were purchased from two counties where domestic rabbit keeping is common practice in there. These areas included: Urmia (40 from 7 rabbit breeders in Nazlu) and Tabriz (10 from 4 rabbit breeders in Sardroud and Basmenj). The majority of the farms had poor to very poor housing sanitation as characterized by dirty floors, soiled water and feed/feeding equipment, presence of fresh fecal pellets on cage floors. None of the rabbits had received anti-parasitic drugs.The animals were anesthetized by diethylether and euthanized by intra muscular injection of high doses of the Ketamine 10 % according to the protocol described by Arabali and Hooshyar with some modifications .The collected samples were preserved in glass containers with a 70% ethanol solution until identification. Fleas and mites were cleaned by water and immersed in a slightly warm 5% potassium hydroxide (KOH) for 10–15 min, and then samples were transferred to 30% acid alcohol for 5 min. The samples were dehydrated by using series of alcohol from 50% to 100% (absolute) and then cleared by xylene for 5 min. After mounting and drying, the fleas were identified using light microscopic examination, based on the guidelines .According to the protocol , to collEimeria species has been performed using some biological features such as oocyst size and morphology  using the keys previously described by Bowman . The identification of parasitic eggs was done by morphological characters . For dety Bowman .Chi-square test was used for analyzing statistical association between the data findings by using SPSS statistical software . Probability of <0.05 was regarded as significant with confidence interval of 95%.Passalurus ambigus (54%), Eimeria stiedae (44%) and Trichostrongylus retortaeformis (42%) were the most common parasites. There was no significant difference in infection rate between male and female NZWRs (P>0.05). However, infection rates with exception of Cheyletiella parasitivorax, in males was higher than that in females.Among 50 NZWRs used in study 29 (58%) of them were male and 21(42%) were female, forty-two (84%) were infected to at least one of the parasite. Ten species of endoparasite including helminthes and protozoa and two ectoparasites were detected in the rabbits under examination . There wIn Iran, NZWRs are mostly kept as pets for children and experimental lab animals due to their low cost, relative size, and perceived ease of care. Rabbits are important as the potential reservoir hosts of a variety of endoparasites and ectoparasites in medical and veterinary point of view and may include various parasites that are transmittable to human , 9.S. scabiei and C. parasitivorax found in this study are zoonotic and may cause important public health problems. Therefore, these parasites are potential threats to veterinaries, researchers and public health agencies. In the present study, the overall prevalence of parasitic infection  in NZWRs was 84%, exactly similar to what reported in previous studies which were 79.56% in slaughter rabbits in Poland . This is higher than the estimated prevalence previously found in laboratory animals including rabbits in Iran with 40% infection , (0.4%), (4.74%)  are the most common definitive hosts of T. pisiformis but dogs and jackals are also infected in Iran  , 18. The in Iran . The lowis found .In the present study, the prevalence of coccidiosis infection 28%) was consistent with the previous study in Urmia, Iran (67%) . However% was conE. magna (30%), E. steidae (44%) and E. media (12%). The prevalence of 30% for E. magna in NZWRs in this study is higher than that reported for wild rabbits from Fars province, Iran (16.9%)  . HoweverE. media %. The prE. media %. The pria, Iran . In the such as; (26.86%),such as; 3.33%). .33%. E. S. scabiei and C. parasitivorax, parasitic zoonoses, were identified in our investigation with prevalence rate of 18% and 38% respectively. The overall prevalence of S. scabiei infestation among rabbits was 18%. This finding was far lower than that reported among breeds of Soviet Chinchilla rabbits (57.14%) and NZWRs (28.57%) in previous studies (C. parasitivorax (38%) identified by in Frank, Kuhn ( studies . Our res rabbits 7.14% and studies . The othFindings of this study indicated a high prevalence of endo and ectoparasite infections in NZWRs in this particular Iranian context. Some of the identified parasites, known as agents of zoonotic diseases, most probably deteriorate the rabbit’ health, and the zoonotic character of some parasites found in this study must serve as an alert to public health agencies, veterinarians, researchers and pet owners.