Methanobrevibacter A smithii significantly decreased and was replaced by Methanobrevibacter A sp900769095 within 2 weeks after weaning. For the functional potential, the richness of KEGG KOs increased over time. LEfSe analysis identified 18 KOs, including for example, ko04623 (cytosolic DNA-sensing pathway), ko00500 (starch and sucrose metabolism), and so on, significantly enriched in the weaning pigs, suggesting the involvement of archaea in the piglets’ adaptation to the new diet after weaning. Correlation analysis based on Random Forest regression and Pearson correlation showed that archaeal species richness was significantly associated with pig bodyweight on both days 70 and 140. Methanobrevibacter A sp900769095  and Methanobrevibacter A smithii  were positively linked with pigs’ bodyweight on days 70 and 140, respectively. Our results revealed the dynamic changes of archaeal diversity and functions and demonstrated the effects of weaning on the gut archaea of pigs, suggesting archaea might play essential roles in swine nutrition, metabolism, and growth performance, especially during the critical weaning process.Archaea are considered a “keystone” of the gut microbiome and are linked with the host’s energy harvest and health. Although a few studies have investigated the gut archaea in pigs, especially piglets, little is known about the effects of weaning on archaeal structure and function. In this study, we explored the effects of weaning on the longitudinal changes of archaeal composition, diversity, and functional potential in pigs overtime by re-analyzing a recently published metagenomic dataset that included 176 fecal samples collected from commercial pigs on days 7, 14, 21, 28, 35, 70, and 140 after birth. Overall, the richness and diversity of archaeal species showed an increasing trend, and weaning significantly affected the richness of archaeal species.  Archaea are considered a kingdom independent from bacteria with unique energy sources and metabolic characteristics. Archaea are commonly detected in the digestive tract of humans and animals , where sMethanobrevibacter was reported as the dominant genus of archaea in the digestive tract, especially in the hindgut .Kraken2  taxonomiN50 = 1,571) were assembled. Gene prediction followed by removal of the redundant genes  were sequentially performed on assembled contigs using Prodigal  were measured using the QIIME2 platform . Kruskal ggplot2 .Regression analysis between the relative abundance of archaea and bodyweights was performed using Random Forest regression in the randomForest R package  and PearWe characterized the dynamics of archaea in the swine gut by re-analyzing 176 fecal samples sequenced using metagenomic technology . Seven sp = 0.003) and day 70 (p = 0.001) compared with the previous time point according to Kruskal–Wallis (pairwise) test.We first explored the changes in alpha and beta diversity with age. The overall observed species increased over time throughout all growth stages (from day 7 to day 140), especially throughout the first 28 days, where the observed species of each time point was significantly increased compared to the previous time points . Shannonp ≤ 0.05). However, changes in community membership between days 7, 14, and 21 were greater than the inter-group’s comparison of later neighboring time points according to the ANOSIM R value. The p-value (lower triangle) and R value (upper triangle) of the ANOSIM test based on Jaccard distance are shown in R = 0.039, p = 0.102). The p-value (lower triangle) and R value (upper triangle) of the ANOSIM test of Bray–Curtis distance are shown in A significant shift in archaeal community membership (Jaccard distance) between days 7, 14, 21, 28, 35, 70, and 140 were observed according to the PCoA plots . All timp = 0.032) pigs that were still nursing, as well as the numbers of observed species trend to be higher for W14 than W21 (p = 0.071). Additionally, the numbers of observed species of W14 and W21 pigs were significantly higher than those of the W28 group on day 28 . Interestingly, 7 days after weaning (day 35), the archaeal richness of W28 pigs was elevated to a level similar to those of the W14 and W21 groups, and no significant difference was detected between the three groups (p > 0.05) on day 35. No trend-specific change was observed for the Shannon index after weaning (p = 0.003).During this study, three weaning time points of W14 (Weaning on day 14), W21 (Weaning on day 21), and W28 (Weaning on day 28) were conducted. Therefore, we investigated the effect of weaning time on alpha diversity metrics between the different weaning groups at each time point. A significant difference in observed species was observed between the weaning group and non-weaning groups on days 21 and 28 . On day  weaning , and no Methanobrevibacter A, which is defined as a different genus than Methanobrevibacter in the GTDB database. The relative abundance of Methanobrevibacter A was 0.23% of the total gut microbiome. Methanobrevibacter (0.067%), Methanomethylophilus (0.062%), and Methanosphaera (0.023%) are ranked from second to fourth. Methanobrevibacter A is still the dominant genera from day 14 to 140, except for day 7, on which day Methanobrevibacter is the dominant genera with a relative abundance of 0.08%.The average relative abundance of total archaea in the gut microbiome (archaea/archaea + bacteria) was 0.62% (ranging from 0.07 to 2.15%). Throughout all growth stages, the lowest relative abundance of total archaea was detected on day 7 (mean = 0.16%). The highest relative abundance of total archaea occurred on day 35  was the most abundant species, followed by Methanobrevibacter ruminantium A (0.068%), Methanomethylophilus alvus (0.063%), and Methanobrevibacter A sp900769095  and others for both Jaccard . Meanwhile, we also found that weaning affects the absence/presence (Jaccard) of KEGG KOs, as weaning and nursing groups were significantly separated on day 21 and day 28 (R = 0.12) difference of archaeal KEGG KOs absence/presence (Jaccard) between groups  diversity of gut archaea . Observe Jaccard  and Bray Jaccard . Howeverd day 28 . Howeverd day 28 . Signifid day 28 . Addition groups . We furtn groups . A totaln groups . Of themMethanobrevibacter A. Two uncultured species of Methanobrevibacter A were listed as the most important predictor during different stages, Methanobrevibacter A sp900769095 (days 14 and 70) and Methanobrevibacter A sp900319535 (days 35 and 140). The number of observed species was listed as one of the top 30 predictors on both days 70 and 140. Furthermore, Pearson’s correlation coefficient analysis showed that observed species was significantly positively correlated with pig bodyweight on both day 70  and 140 , and no significant association was detected on days 14 and 35 (Methanobrevibacter A smithii (days 7 and 140), Methanobrevibacter A sp900769095 (days 35 and 70), and Methanobrevibacter ruminantium A , were the most abundant archaeal species at specific stages; therefore, we chose to focus on them for additional analyses. An association analysis revealed that the relative abundance of Methanobrevibacter ruminantium A did not associate with pigs’ bodyweight at any stage. However, a significant association was detected between pigs’ bodyweight on day 140 and the relative abundance of Methanobrevibacter A smithii . Interestingly, the relative abundance of Methanobrevibacter A sp900769095 was significantly correlated with bodyweight on day 70 , at which point its relative abundance increased and replaced Methanobrevibacter A smithii as the most abundant archaeal species. However, the correlation was no longer present on day 140 .According to previous publications, the archaeal metabolic activity may directly or indirectly contribute to gut fermentation and energy harvest in pigs, meaning that there is potential for archaea to be used as probiotics to improve growth performance. To detect the relation between archaea and bodyweight, regression-based random forest models were developed based on samples collected at days 14, 35, 70, and 140, representing the lactation, nursery, growing, and finishing. Given the relatively low abundance of archaea in the gut, a total number of 73 archaeal species with a relative abundance within the total gut microbiome, defined as total archaea plus total bacteria in this study, higher than 0.05% in at least one sample and both alpha diversity indices (Shannon index and Observed species) were selected for correlation analysis. The top 30 predictors of growth performance at different stages are presented in 4 and 35 . Three sMethanobrevibacter A sp900319535 and Methanobrevibacter A smithii were also identified as the top predictors of bodyweight gain by the new model based on dynamic data. Scatter plot shows that Methanobrevibacter A sp900319535 was significantly positively associated with bodyweight gain from day 70 to 140  significantly changed with age  replaced M. smithii to become the most abundant species in the growing stage. Except for a metagenomic genome assembly (RefSeq accession number: GCF_900769095.1), no information related to M. A sp900769095 is available to infer its potential biological function.Our study showed that ’s study  showed tsumption . InteresWe have previously shown that gut archaea have important and unique functional features and are valuable gut microbiome members . We founM. smithii was able to partially, but not entirely, explain the improvement in host energy harvest. Our result suggests that gut archaea potentially enhance the piglets’ ability to extract energy from plant-based carbohydrates.Samuel’s study  suggesteRandom forest regression was used to identify bodyweight-related archaeal species for each growth stage. The Observed species alpha diversity metric was listed as a top predictor for both the growing and finishing stages. Furthermore, Pearson correlation analysis between Observed species and bodyweight confirmed the positive association. Archaea are considered a “keystone” member of the complex microbiome, and their metabolic activity is beneficial for bacteria . Here, tM. A sp900769095 is positively associated with bodyweight on day 70. Interestingly, at the same time, the relative abundance of M. A sp900769095 increased after weaning and became the most abundant archaea species on day 35 and day 70, indicating M. A sp900769095 may play an important role in the growth performance of pigs during the growing stage. Unfortunately, except for the metagenomic genome assembly assembled from a human metagenomic dataset, there is no information over M. A sp900769095. It is necessary to culture and further characterize this archaeal species. Additionally, M. smithii was positively associated with bodyweight during the finishing stage (day 140). Several previous studies have revealed that M. smithii is involved in fat deposition by influencing SCFA production and calorie harvest. Additionally, it is associated with obesity in humans , Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding (2019B030301010), and Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes (2019KSYS011).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


A complete and prompt cardiac arrest using a cold cardioplegic solution is routinely used in heart transplantation to protect the graft function. However, warm ischemic time is still inevitable during the procedure to isolate donor hearts in the clinical setting. Our knowledge of the mechanism changes prevented by cold storage, and how warm ischemia damages donor hearts, is extremely poor. The potential consequences of this inevitable warm ischemic time to grafts, and the underlying potential protective mechanism of prompt graft cooling, have been studied in order to explore an advanced graft protection strategy. To this end, a surgical procedure, including 10–15 min warm ischemic time during procurement, was performed in mouse models to mimic the clinical situation (Group I), and compared to a group of mice that had the procurement performed with prompt cooling procedures (Group II). The myocardial morphologic changes (including ultrastructure) were then assessed by electron and optical microscopy after 6 h of cold preservation. Furthermore, syngeneic heart transplantation was performed after 6 h of cold preservation to measure the graft heart function. An electron microscopy showed extensive damage, including hypercontracted myofibers with contraction bands, and damaged mitochondria that released mitochondrial contents in Group I mice, while similar patterns of damage were not observed in the mice from Group II. The results from both the electron microscopy and immunoblotting verified that cardiac mitophagy  was present in the mice from Group II, but was absent in the mice from Group I. Moreover, the mice from Group II demonstrated faster rebeating times and higher beating scores, as compared to the mice from Group I. The pressure catheter system results indicated that the graft heart function was significantly more improved in the mice from Group II than in those from Group I, as demonstrated by the left ventricle systolic pressure (31.96 ± 6.54 vs. 26.12 ± 8.87 mmHg), the +dp/dt (815.6 ± 215.4 vs. 693.9 ± 153.8 mmHg/s), and the -dp/dt: (492.4 ± 92.98 vs. 418.5 ± 118.9 mmHg/s). In conclusion, the warm ischemic time during the procedure impaired the graft function and destroyed the activation of mitophagy. Thus, appropriate mitophagy activation has emerged as a promising therapeutic target that may be essential for graft protection and functional improvement during heart transplantation. During heart transplantation, the use of a cold cardioplegic solution for flushing and the storage of the donor heart is thought to protect the graft function by slowing metabolism. However, unlike mouse hearts (whose temperatures can be immediately dropped to 2 °C), large animal hearts usually take 10–15 min to reach 4 °C during the procedure, despite protocols that include a flush with cold preservation solution via the aorta root cannula, and immediate ice cooling [It is generally accepted that the metabolic rate is the difference between WI and cold ischemia (CI) and, increasingly, the evidence indicates that CI and WI can result in different histological characteristics in lung, liver, and kidney preservation ,3,4. IskAs the intracellular organ that continuously provides ATP to cells with high-energy requirements, mitochondria control the fate of cardiomyocytes by regulating the reactive oxygen species (ROS) levels, calcium storage, metabolic substrate utilization, etc. ,7. Thus,In the present study, we examined whether the inevitable WI time during procurement has any significant impact on graft function. Moreover, we explored the potential mechanism of the injuries caused by the WI time on graft cold storage. We found that WI time is a key player in causing damage to the graft structure and function during heart transplantation. Mitophagy is widely activated during cold storage, but the WI time destroys mitophagy activation. Identification of the underlying mechanism of injuries caused by the WI time during procurement may contribute to the understanding of graft protection, which could further provide more relevant methods for prolonging the isolated heart preservation time.Male and female C57BL/6 mice aged 8–12 weeks, and weighing from 20–30 g, were used in this study. The original generation of these mice was purchased from Jackson Laboratory , and they were maintained and bred in the Division of Laboratory Animal Resources at the University of Cincinnati Medical Center. All research protocols conformed to the Guidelines for the Care and Use of Laboratory Animals, published by the National Institutes of Health . All animal-use protocols and methods of euthanasia  used in this study were approved by the University of Cincinnati Animal Care and Use Committee.Histidine-tryptophan-ketoglutarate (HTK) solution, purchased from CUSTODIOL, was used as a cardiac preservation solution for this study. Heparin sodium injection  was used for the systemic heparinization of donors. An isoflurane vaporizer  was used for the recipient anesthesia. A microsurgical microscope  was used with 4, 10, 16, and 25× interchangeable magnifications. The 11-0 surgical sutures  were used for vascular anastomosis, and 6-0 sutures  were used for donor heart ligations and recipient vessel blockings during the surgery. We used 6-0 sutures  for the purse-string suture, and 4-0 sutures  were used for closing abdomens. Graft function was measured by Mikro-Tip pressure-catheter transducers  and analyzed with LabChart Reader . A mixed solution with 20% xylazine hydrochloride , and 80% ketamine hydrochloride , was diluted 10 times using 0.9% saline solution. Intraperitoneal injection was performed on both donor and recipient mice at a dose of 0.1 mL per 10 g body weight. Inhalation anesthesia  and 6–8 L/min oxygen were delivered to the recipient via a mask from the anesthesia device system for increased oxygen supply and to prevent awakening during the surgery.n = 22): in which we freed and ligated the superior vena cava (SVC), inferior vena cava (IVC), and azygos veins, cut off the IVC, SVC, azygos vein, aorta, and pulmonary artery, then ligated the pulmonary veins and removed the heart into 4 °C HTK solution, perfused the heart with cold HTK solution until there was no blood left, and kept the heart in 4 °C HTK solution for 6 h until transplant; and (b) Group II (n = 24): in which we cut off the aorta and pulmonary artery immediately, using 4 °C Bretschneider-HTK cardioplegic solution. The grafts were perfused until the heart completely stopped beating. Then, the superior vena cava (SVC), inferior vena cava (IVC), the azygos vein, and the pulmonary veins were ligated, followed by the removal of the heart into 4 °C HTK solution, and perfusion with cold HTK solution again until there was no blood left. The hearts were kept in 4 °C HTK solution for 6 h until transplantation. (0.3 mL of 100 Unit/mL heparin sodium was slowly injected into the donor mice at the inferior vena cava (IVC) using an insulin syringe. After waiting for 15 s for systemic heparinization, the chest was opened. Sterilized ice was then put into the chest, and the heart was wrapped with a 4 °C wet surgical gauze. The donor mice were randomly divided into two groups: (a) Group I . Tissue blocks were embedded in paraffin for sectioning, and the sections were stained with hematoxylin-eosin (H & E). Protein samples were collected from the two groups after 6 h of HTK preservation. A total of 25 micrograms of protein per sample was loaded on a precast protein gel , followed by semi-dry Western blotting before transfer onto polyvinylidene fluoride (PVDF) membranes. The membranes were then blocked with 5% milk in TBST for 1 h and incubated overnight with primary antibodies against LC3 I/II , SQSTM1/P62 , and GAPDH . Subsequently, the membranes were incubated with HRP-conjugated secondary antibodies  for 1 h at room temperature. Finally, the bands were visualized on immunoblots using ECL Chemiluminescent Substrate , and quantification of the band intensity was determined using Image J software .Grafts were preserved in 2 mL 4 °C HTK solution for 6 h, after which the HTK solution from the two groups was collected. Lactate dehydrogenase (LDH) activity in the HTK solution was measured using an LDH Activity Assay Kit . Creatine kinase (CK) activity in the HTK solution was measured using a CK Activity Assay Kit . All procedures followed the manufacturers’ technical instructions as indicated. The beating score of the heart grafts was assessed visually 10 min after restoring blood flow (before closing the abdomen), using the Stanford cardiac surgery laboratory graft scoring system  (0: No cLeft ventricle systolic pressure (LVSP), left ventricle end-diastolic pressure (LVEDP), the maximal rate of change of the left ventricular pressure (±dp/dt), and the heart rate were recorded after 10 min of restoring the sinus rhythm, using a Millar pressure–volume (PV) catheter, and were analyzed using LabChart reader, as previously described . BrieflyRapamycin  was dissolved according to the manufacturer’s instructions  B, contriAfter 6 h of preservation, the heart graft was collected for transmission electron microscopic examination. Isolated hearts procured without a prompt cardiac arrest (Group I) showed a disordered sarcomere and mitochondria arrangement, and the continuity of some sarcomeres was disturbed A.Moreover, contraction bands indicating myocardial injury were observed in this group (as shown by the yellow arrows), and the majority of the mitochondria were swollen with matrix clearance. Thus, while the mice in Group I showed damaged mitochondria with incomplete mitochondrial membranes and broken cristae, the grafts of the mice in Group II showed sarcomere and mitochondria orders that were smooth and that displayed a well-organized ultrastructure with intact membranes and cristae A, and noHistological changes in the two groups were assessed after 6 h of preservation in HTK solution. H & E staining showed an abnormal linear arrangement, with widely inter- and intracellular edema in Group I A.However, the grafts in Group II showed a linear arrangement and the edema was alleviated. LDH and CK leakage were then used as a measure of tissue damage after 6 h of cold preservation in HTK solution. The LDH and CK activity in the HTK solution were significantly less in Group II B,C, indiAfter 6 h of cold ischemia preservation in solution, syngeneic graft implant surgery was performed on the mice from each group . When thThe rebeating times and the Stanford beating scores were further applied to measure the cardiac status in mouse heart transplant models. As compared to Group I, Group II showed a shorter rebeating time and a higher beating score B,C, indiTo accurately measure the ventricle function and quantify the damage to the graft function caused by 10 min of ischemic heart-beating, a pressure catheter was used to directly detect the left ventricle pressure of the graft after 10 min of restoring the sinus rhythm. The left ventricle systolic pressures (LVSPs), the left ventricle end-diastolic pressures (LVEDPs), the ±dp/dt, and the heart rates of the grafts were recorded. The grafts in Group II showed a higher-pressure peak and a pressure-changed-rate peak, as compared to Group I A. There was no significant difference in the heart rate between the two groups B. We useSince mitophagosome formation was commonly observed in Group II under transmission electron microscopic examination, further tests were performed to confirm the activation of mitophagy. A Western blot analysis of the mitophagy-related proteins, such as LC3-II and SQSTM1(P62) ,20, indiConsistent with electron microscopy, the expression of the cleaved LC3-II was significantly increased after 6 h of cold solution preservation in Group II, as compared to Group I A,C,D. To further verify that activation of mitophagy prolongs the preservation time for hearts after WI injury, rapamycin (which has been demonstrated to stimulate mitophagy ) was admAt present, hypothermic immersion preservation is still the gold standard for isolated heart preservation. However, the storage time for isolated hearts is limited to 4 to 6 h using this method ,23. ProlPrevious studies have been based on the concept that the mechanisms for warm ischemic (WI) injury are similar to that of cold ischemic (CI) injury during heart transplantation in rodents. However, developing research has demonstrated that the underlying mechanisms of WI and CI may differ. For instance, Hansen et al.  have shoThe heart is highly dependent on energy provided by mitochondrial oxidative phosphorylation. Mitochondria play an important role in maintaining essential cellular processes, including metabolite synthesis, calcium storage, and controlling the intracellular survival and death pathways . CardiacMitochondrial permeability transition (MPT) is represented by a serious swelling of the inner membrane in the mitochondrial matrix that distends the outer membrane until it ruptures ,29,30. PFurthermore, the WI time was the main difference between the two experimental surgical methods. The results from our study show that even a 10-min WI time is sufficient to make a difference in the pathological mechanism and cardiac function. This is consistent with other reports of reduced survival in heart transplant recipients with increased WI times . In factThe primary pitfall of this study is that the rodent heterotopic heart transplantation model lacks a preloaded volume. On the basis of the Frank–Starling mechanism, cardiac contractility is positively correlated to the effective preload. Because of the limitations of this model, the only preloaded volume of the left ventricle is from aortic regurgitation. Here, a new method for measuring cardiac function was applied in which a pressure catheter was used to measure the graft function more accurately than echocardiography by completely unloading the ventricle. Thus, the LVEDPs in each group approach 0 mmHg. Although the cardiac function is comparable between each group, the unloaded status may differ from a true clinical setting.In conclusion, this is the first study demonstrating that the activation of mitophagy improved isolated heart preservation, and that the WI time, resulting from a slow cooling process, can destroy mitophagy activation and affect the graft functional recovery. The present results suggest that the inevitable WI time during graft procurement in the clinical setting may lead to a different pathophysiological process in the cardiac graft during cold storage, which may be an essential factor for limiting the isolated heart preservation time. Aiming for appropriate mitophagy activation may provide a new therapeutic to further protect graft function and prolong the isolated heart preservation time. Moreover, although it is widely accepted that prompt cardiac arrest is still an essential and protective process to cardiomyocytes during cardiopulmonary bypass surgeries, the underlying mechanism of this protection remains incomplete. Our study provides a theoretical basis for the importance of appropriating mitophagy activation during warm-ischemia time in tolerating I/R injury.


It was found that nano-sized additives can affect the combustion behavior and increase the burning rate of propellants. Compared with the corresponding micro-sized ones, the nano-sized particles promote higher impact sensitivity and friction sensitivity. In this paper, 101 references are enclosed.The effects of different types of nano-sized metal particles, such as aluminum (nAl), zirconium (nZr), titanium (nTi), and nickel (nNi), on the properties of a variety of solid rocket propellants ) were analyzed and compared with those of propellants loaded with micro-sized Al (mAl) powder. Emphasis was placed on the investigation of burning rate, pressure exponent ( Re. Re92]. −1 to 36.63 mm·s−1 at 9.81 MPa and lowers the pressure exponent over the pressure range of 12–22 MPa from 0.26 to 0.12  on the performance of composite propellant  were investigated. It was found that the burning rates of propellant with nAl powder increase with larger pressures and the increasing extent over the pressure range 1.0–7.0 MPa is obviously higher than that over the pressure range 7.0–13 MPa. The pressure exponent of the nAl formulation is 0.33 (1–15 MPa), which is the lowest one among the tested samples. Moreover, comparing the samples with and without nAl powder indicates that the propellant burning rates increase effectively with decreasing size of the metal particles. Furthermore, the density of composite propellants with different nano–sized metal particles is in the range of 1.732–1.784 g·cm−3, which is larger than that of the propellant with standard Al powder (1.731 g·cm−3). Maybe this is the effect of Al oxide on the surface of nAl. The heat of explosion of composite propellant without nAl is 6045 J·g−1, which is higher than that of the samples with nZr and nTi particles (5793 and 5821 J·g−1) but lower than that of the sample with nAl particles (6104 J·g−1). The mechanical sensitivity result reveals that the use of micro-sized powder leads to a decrease in the sensitivities of friction and impact for solid propellants, while the compositions with nano-sized particles show high friction sensitivity and impact sensitivity [The burning rate data of propellants containing different nano-sized particles obtained under different pressures were collected. The effects of different nano metal powders  with 50 nm diameter, nano-sized Co (nCo) with 42 nm diameter, and nNi with 36 nm diameter powders on the thermal decomposition of AP and combustion properties of HTPB/AP propellant were investigated . It was In summary, to promote the practical applications of nano metals in solid propellants, much investigation needs to be done in the future, such as spheric coating, high-active metal-based composites, active metals, etc. Understanding of these effects opens the path to improved ballistic performance, which will be further investigated. 2 g−1) but strongly increased by decreasing size particles over the explored nanometric range; for very small particles, the appreciable decrease in active metal hinders a further increase in steady burning rate. Pressure exponents showed only minor changes within the limits of strand burner experiments conducted under standard operating conditions. Additionally, for ignition, an appreciable decrease is found for nAl particles in the range 0.1–0.2 μm, while little effect was observed for μAl. The minute nAl powder manifest a strong reactivity mainly due to their increased specific surface, notwithstanding the simultaneous decrease in active Al content  [For Al nanopowders, the steady burning rates are not affected by particles in the micrometric range (Brunauer–Emmett–Teller (BET) ≤ 2 mf wires) . Within Even if the 2P losses are mitigated, nanosized energetic ingredients with higher energy densities and faster energy release rates exhibited with respect to conventional ingredients arose great expectations in solid propulsion, but despite the intense worldwide investigation programs, use of nAl still today also entails several negative effects. Loss of active metal, clustering during manufacture and storage, EOM viscosity, possible impairment of mechanical properties, less effective acoustic damping, aging, and cost (even though it is nowadays much diminished) are more than enough to balance the expected advantages. Moreover, with increasing nAl fraction, friction sensitivity, impact sensitivity, but also the measured heat of combustion (because of higher combustion efficiency), all increase ,100,101.(1)Addition of nAl is beneficial to improve the burning rate and possibly reduce the burning rate pressure exponent, but at the same time, the low active Al content of nAl powder leads to a reduction the heat of explosion of propellants.(2)A core–shell structure of nanoparticles can be obtained, and the burning rate of solid propellants can be increased using different material coatings on the surface of nAl. The addition of nTi, nZr can increase the density of propellant, while the heat of explosion of propellant decreases.(3)Within the current rocket propulsion technology, mostly laboratory level applications of metal nanopowders are reported and often for scientific purposes; much work is needed for the applications of metal nanopowders at an industrial level.Metal nanoparticles have wide application aspects in various explosives and propulsion systems, including advanced components of pyrotechnic compositions, effective burning rate modifiers of solid propellants, etc. Based on the investigations, the following conclusions can be drawn:


Zea mays L.), i.e., Mo17 and Huang C, a sensitive and tolerant chilling stress, respectively. The combination treatments of PA inhibitors reduced the biosynthesis of putrescine (Put) in the tissues of both studied inbred lines. Application with 500 µM Co and 1000 µM Co did not result in a significant difference in Put concentrations, except in the coleoptile of Mo17. However, combining Spd to 1000 μM of PA inhibitors enhanced the Put, Spd, spermine (Spm) and total PAs in the roots, coleoptile and mesocotyls. Put and total PAs were increased by 39.7% and 30.54%, respectively, when Spd + 1000 µM Co were applied relative to their controls. Chilling stress and PA inhibitors treatments affected both inbred lines and resulted in differences in the PA contents. Results showed that enzymes involved in the biosynthesis of PAs (ornithine decarboxylase as ODC and S-adenosylmethionine decarboxylase as SAMDC) were significantly downregulated by 1000 µM Co in the tissues of both inbred lines. In contrast, the activity of PAO, a Pas degradation enzyme, was significantly improved by 1000 µM Co under chilling stress. However, Spd + 1000 µM Co significantly improved the activities of ODC and SAMDC and their transcript levels (ODC and SAMDC2). While it significantly downregulated the PAO activity and their relative genes  under chilling stress. Overall, this study elucidates the specific roles of Spd on the pathway of PA inhibitors and PA biosynthesis metabolism in maize seed development in response to chilling stress. Moreover, the Huang C inbred line was more tolerant than Mo17, which was reflected by higher activities of PA biosynthesis-related enzymes and lower activities of PAs’ degradative-related enzymes in Huang C.Chilling stress greatly inhibited the seed germination, plant growth, development and productivity in this study. The current research aimed to study the effects of different polyamine (PA) inhibitor combinations (Co), e.g., D-arginine (D-Arg), difluoromethylormithine (DFMO), aminoguanidine (Ag) and methylglyoxyl–bis-(guanyhydrazone) (MGBG) at different doses, i.e., 10 µM Co, 100 µM Co, 500 µM Co, 1000 µM Co and 1000 µM Co + 1 mM Spd (Spermidine) in two inbred lines of maize ( Agricultural crops are confronted by a number of abiotic stress factors that limit their productivity ,2,3,4,5.2O2 molecules, which act as signaling molecules to improve antioxidant systems and alleviate oxidative damages . All the results are the mean of three replicates ± standard deviation (SD) and all the data were subjected to an analysis of variance (ANOVA). When a significant  and polyamines’ degradation (PAO) as affected by the PA inhibitors and chilling stress are illustrated in ADC1, ADC2 and ODC genes in different tissues of both maize inbred lines under PA inhibitors and chilling stress. The expression level of ADC1 gene was significantly downregulated in roots and mesocotyls of both inbred lines when 1000 µM Co. and Spd + 1000 µM Co. were applied , indicating that the Spd and Spm synthesis was higher in the shoot, while Put synthesis was more in roots. This demonstrates the significant increase in root viability, length and root mortality during germination in the seeds primed with exogenous Spd under water stress [PAs are endogenous plant growth regulators that can stimulate plant growth and development under different abiotic stresses ,71,72. Sr stress . A similr stress  reportedr stress . In the r stress . Interesr stress . Howeverr stress .Put and Spd concentrations were highly increased upon being treated with the Spd and 1 mM combination as compared with those treated with the 1000 μM combination. This statement supports the potential resources for the conversion of Spd to Put and can be used a physiological signal in maize under chilling stress. These results are consistent with the previous study, reporting that the conversion efficiency of Spd to Put might be related with the absorption and transportation of Spd in seedlings tissues . The preIn the present study, Spd treatments inhibited the PA inhibitors’ effects and simultaneously improved the PA biosynthesis-related enzymes such as ADC, ODC, SAMDC and Spd synthase under chilling stress conditions. These enzymes have differential responses to the different stresses; as such, ADC is more specifically responsive to environmental stress, while ODC is more responsive to any kind of stress ,39. SimiADC1, ADC2, ODC and SAMDC2 transcripts and SPDS, and decreased the relative expression of PAO1, PAO2 and PAO3 genes, irrespective of the chilling stress and PA inhibitors. These genes were also upregulated in rice seedlings exposed to chilling stress [ADC2 gene were downregulated by the induction of ODC1 gene under salinity stress, suggesting that the involvement of ADC pathway for the PA biosynthesis in higher plants under abiotic stresses [ADC, SPDS1, SPDS2 and SPMS genes was observed in the chilling-tolerant and chilling-sensitive genotypes, respectively, whereas the expression of ODC genes decreased significantly in all genotypes under chilling stress [ADC2 genes were upregulated in Arabidopsis thaliana and rice [Arabidopsis thaliana maintained higher levels of Spd contents and enhanced the plant tolerance to chilling, suggesting that Spd plays an important role as an osmolyte regulator in stress signaling pathways, which boosts stress tolerance mechanisms in plants under stress conditions [SAMDC2, leading to efficient conversion that resulted in the reduction of Put and Spd levels [PAO genes have been investigated in different plant species such as A. Thaliana [In order to investigate the molecular mechanisms of PA biosynthesis in response to chilling stress further, the transcript levels of their genes were analyzed in the present study. The genetic manipulation of crop plants with genes encoding enzymes of PA biosynthetic pathways may provide better stress tolerance to crop plants . These gg stress . Previoustresses . Similarg stress . Anotherand rice ,88. Morenditions . The decd levels . These PThaliana , tobaccoThaliana , rice [9Thaliana , barley Thaliana  and maizThaliana .In conclusion, chilling stress can reduce the polyamine (PA) contents through decreasing the activities of enzymes taking part in PA biosynthesis and increasing the degradation of the PAs through the PAO enzyme in both maize inbred lines. The application of all studied PA inhibitor combinations resulted in the reduction of PA biosynthesis and increase of polyamines’ degradation. The PA inhibitors in combination with Spd treatments enhanced the levels of PA contents, enzymes related to PA biosynthesis and their relative gene expressions in roots, coleoptiles and mesocotyls under chilling stress. Both inbred lines showed different patterns to the biosynthesis and degradation of PAs under chilling stress and a supply of PA inhibitors. The enhanced seed development of both maize inbred lines under the PA inhibitors and chilling stress is closely associated with the elevated biosynthesis of Spd, Spm and Put in maize tissues. This suggested that Spd can maintain the balance between the activation and degradation processes of PA biosynthesis by controlling related enzymes’ activities as well as transcription levels under chilling stress. The present study confirmed the involvement of PAs in the regulation of growth, development and chilling tolerance of maize seedlings, which may have implications for maize cultivation in low-temperature conditions, although field investigations are prerequisites to broaden laboratory findings.


Background: Inhaled drugs have been available in the market for several years and for several diseases. Drugs for chronic obstructive pulmonary disease, cystic fibrosis, and diabetes have been used for several years. In the field of drug modification, these drugs range from tablets to aerosol. Methods: Milling as used to break down the tablets to powder and nebulisers are used to produce aerosol droplets. A mastersizer was used to measure the mass median aerodynamic diameter of the aerosol droplets. Results: Apremilast produced mmad diameters (2.43 μm) without any statistical difference between the different jet-nebulizers. The residual cup B contributed to greater mmad diameters as the 95% interval of mean values, based on those the ANOVA mean square clearly indicated, followed by cups C and F. The previous interval plot is much better clarified when the interaction means between drug and residual cap are plotted. The residual cups B, C and F produce mmad between (2.0–3.2). Conclusion: In the current research study we demonstrated our methodology to create apremilast powder and produce apremilast aerosol droplets with different nebulisers and residual cups. Inhaled medications have been available in the market for several years. The most common drugs administered through inhalation are the drugs used for chronic obstructive pulmonary disease (COPD) or bronchoconstriction ,2. InhalThe following drug was purchased: apremilast 30 mg/L tablet.® (5–7 L/min and 35 psi), Maxineb® (6 L/min and 35 psi), and Invacare® (4–8 L/min and 36 psi) (Three nebulizers were chosen from our department for the experiment: Sunmist 36 psi) .Seven residual cups were included. Four had a capacity of ≤6 mL and three with a capacity of ≤10 mL. The large residual cups were A, D, and E .The small residual cups were C, F, B and J . We used® NE-U07, Tokyo, Japan with a 10 mL medication cup. The second was a portable GIMA, Gessate, Italy  with the following operating specifications; Particle size: 3–5 μm, Frequency: 2.5 MHz, Medication Cup Capacity: 1–6 mL. The third was a portable EASYneb® II, FLAEMNUOVA, Martino, Italy with the following operating specifications; drug max capacity: 8 mL, particle size: 2.13 μm mass median aerodynamic diameter (ΜΜAD) (The following ultrasound nebulizers were available in our department. The first was Omronr (ΜΜAD) .The ultrasound nebulizers were filled with different concentrations and the measurements were performed with the mastersizer. Two factors were found to influence the MMAD response when jet nebulizers were used: drug type and residual cup design plus their interaction effect. On the other hand the MMAD for the ultrasound nebulizers was influenced by the drug concentration and ultrasound nebulizer model.A laser scattering apparatus  equipped with a Scirocco dry accessory module  was used for the determination of the mass median diameter of the produced particles ,24,25,26The apremilast tablets were milled in a planetary ball mill  equipped with Agate bowls (500 mL) and 8 balls  with a rotational speed of approximately 800 rpm which results in an acceleration of about 7.5 g. We initiated our milling at 20 min and we acquired a mass median aerodynamic diameter (MMAD) of 3.2 μm.10 variable since both the size frequency distribution and the boxplot information suggested so  or asthma, deposition and absorption depends on status of the patients. We have different aerosol production systems for stage III and IV COPD and patients with asthma exacerbation. There is also cases wherein a patient has pulmonary infection, which again modifies the deposition and absorption of a drug. All of these factors have been extensively investigated with inhaled antibiotics and insulin ,19. BronApremilast acts as a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4) and inhibits spontaneous production of TNF-alpha from human rheumatoid synovial cells. Apremilast is typically used against active psoriatic arthritis.  It is alIn this current study, we investigated drug solutions for possible future treatments. One limitation of the study was that we did not investigate the safety our drug dilution. It was observed that large concentrations >8 mL were not necessary as in our previous studies and it is only matter of how much concentration of the drug we want to deliver. Once again, the residual cup design plays an important role in the production of the aerosol droplet size and of course the drug formulation. Certainly, we can try additional local aerosol therapies for psoriasis and local administration has possible advantages. However, future experiments have to present data for a reason to use this method of administration. We should have firstly the opinion from psoriasis patients if they want another route of administration and a fast-activating drug for psoriasis.It is possible to modify apremilast tablet to powder and produce aerosol droplets with apremilast. However, certain questions remain (namely whether the drug is safe for the lung parenchyma and whether we need fast systemic administration of this drug for treatment of psoriasis or other diseases).


The growing problem of obesity in dogs has become an epidemic that affects their quality of life. This study shows for the first time the changes in salivary metabolites in dogs with obesity using a targeted metabolomic approach. The analysis revealed alterations in 27 metabolites classified as amino acids, glycerides, sphingolipids, glycerophospholipids, and acylcarnitines. Some of the changes in the metabolites found in the saliva of obese dogs are associated with insulin resistance, which is usually related to obesity. These results indicate that saliva can show changes in its metabolites in canine obesity, making it a valuable source of biomarkers for this condition.Obesity is a common problem in pet dogs, affecting half of the general population in some countries. Excess body weight causes several disorders and has a negative impact on dogs’ quality of life. The use of metabolomics allows the identification of metabolite traces from the metabolic pathways involved in pathological processes. This study aimed to evaluate salivary metabolite variations in dogs with obesity. The salivary samples of 19 dogs were analyzed using a targeted metabolomic approach, through which 234 metabolites were quantified. Of these, multivariate analysis identified 27 different metabolites altered in dogs with obesity compared with control dogs. These metabolites were mainly classified as amino acids, glycerides, sphingolipids, glycerophospholipids, and acylcarnitines. Some of the changes in these metabolites reflect the insulin resistance status related to obesity in dogs. Overall, it can be concluded that the salivary metabolome of obese dogs reflects the metabolic changes occurring in obesity and could be a source of potential biomarkers for this complex condition. Obesity has become a common problem in dogs, with a prevalence exceeding half of the general population in some countries . It is dHowever, other biofluids have been considered to be of interest in the study of obesity. For example, saliva has some advantages over serum, since it is easy to obtain and its sampling is stress-free and painless for dogs, allowing the easy collection of multiple samples . In the Metabolomics enables the simultaneous measurement of a high number of metabolites present in a biological sample and can reveal specific alterations in a pathophysiological process . UntargeThis study aimed to investigate the salivary metabolome of obese dogs through a targeted metabolomic approach.The dogs enrolled in this study were experimental Beagles from a colony of the University of Murcia (Spain). Nineteen castrated male Beagle dogs were selected and divided into two groups: obese and control. The obese dogs developed nutritional obesity before the beginning of this study as a result of being fed ad libitum over six months with a hyperenergetic commercial diet   composed of 30% protein, 15% fat, 3% fiber, 8% ash, and 1.5% Omega 6. The ingredients were cereals (including 4% whole wheat and 4% corn), meat and animal by-products , byproducts of vegetable origin, oils and fats, vegetable protein extracts, and mineral substances. The nutritional additives were vitamin A, vitamin D3, vitamin E, iron sulphate monohydrate, potassium iodide, copper sulphate pentahydrate, manganous sulphate monohydrate, zinc sulphate monohydrate, sodium selenite, and antioxidants. Drinking water was available ad libitum. The physical parameters indicated that all dogs were overweight or obese, as defined by the 5-scale body condition score (BCS), according to which a score greater than four is globally recognized as an indicator of obesity . The fatg for 20 min at 4 °C. The saliva samples were transferred to a 1.5 mL Eppendorf tube and stored at −80 °C until the metabolomic analysis.Saliva samples were obtained in all dogs by introducing a small sponge into the dog’s mouth until it was thoroughly moist. No dogs used in this study showed any clinical signs of periodontitis. Sponges were placed in collection devices  and stored with ice until their arrival at the laboratory, where they were centrifuged at 3000× At the same time, a blood sample was taken from each dog to perform a biochemical analysis to rule out any organ-related disease. All dogs were subjected to a 12 h fast before the blood and saliva sample collections.The procedures were approved by the University of Murcia’s ethics committees and the Ministry of Agriculture, Livestock, Fishing, and Aquaculture of the Region of Murcia (A13170503).v/v/v)) for 20 min and subsequently dried for 60 min using a vacuum manifold. Metabolites were then extracted with 300 μL of 5 mM ammonium acetate solution in methanol by shaking for 30 min at 450 rpm, then eluted using a vacuum manifold. A total of 150 µL of extracts was transferred from the capture plate to another empty 96-deepwell plate and diluted with water (50:50 v/v) for the liquid chromatography–mass spectrometry (LC–MS) analysis. The original plate was diluted with 250 μL of FIA mobile phase (10 mL ampule Biocrates FIA mobile phase in 290 mL of methanol) for flow injection analysis–mass spectrometry (FIA–MS). Both the LC and FIA plates were securely covered with silicon mats and shaken for 5 min at 500 rpm before the analysis.Sample preparation was performed using the AbsoluteIDQ p400 HR kit  according to the manufacturer’s instructions. In brief, 10 μL of each saliva sample, quality control samples, blank, and zero samples (PBS) was added to the plate containing the internal standard mix. The plate was then dried for 30 min with a vacuum manifold. The samples were derivatized using 50 µL of 5% derivatization solution (phenylisothiocyanate (PITC) in water: ethanol: pyridine  system coupled with a Thermo Scientific Q Exactive Orbitrap mass spectrometer with the LC-MS instrument methods and parameters provided along with the kit . Metabolites were identified and quantified using a standard workflow, using the MetIDQ™ software provided by Biocrates Life Sciences AG, Innsbruck, Austria. Differences between BCS and BF in obese and control groups were investigated using the Mann–Whitney test, and the results were expressed as the median and the inter-quartile range (IQR). A non-parametric distribution of the data was assumed due to the small sample size of the groups. All the analyses were conducted with GraphPad Prism software .p-value) values were displayed versus the means of metabolite fold changes (FCs) within individual measured metabolite concentrations in a Volcano plot. Only metabolites with p-values lower than 0.05 were reported. Diagnostic models were constructed using partial least squares–discriminant analysis (PLS–DA), and the quality of the model was evaluated using accuracy, R2, and Q2. The variable importance of projection (VIP) values was calculated from the PLS–DA model. Only metabolites with VIP values >1 were considered discriminants. By using hierarchical clustering analysis (HCA), we further observed whether these metabolites could define the dogs’ obese metabolic status based on their relative concentration. Subsequently, the set of statistically significant metabolites between the groups was submitted to metabolite set enrichment analysis (MESA), which was also performed using the MetaboAnalyst platform.To ensure data quality, several statistical methods were applied to the AbsoluteIDQ p400 data (MetIDQ™ software results–exported data) to identify differences between the groups. Data processing, statistical analysis, and data visualization were performed using the MetaboAnalyst software (web version 5.0). The analysis included data normalization and transformation, followed by univariate statistics with significant testing. Of the 408 metabolites measured with the Biocrates p400 Kit, those that were not identified or whose concentration was below the limit of detection (LOD) were excluded from further analysis. Subsequently, missing value imputation was used to replace missing values by 1/5 of the minimum positive value for each variable while maintaining the overall data structure. The study data were further processed by a log2 transformation to correct heteroscedasticity and skewness and to improve interpretability and visualization. To identify metabolites that significantly differed between the groups, we performed a Student’s t-test. The resulting -log10 (The group of obese dogs was integrated by ten dogs with a mean BCS of 4.5 (range: 4–5), with a mean body fat mass percentage of 42.13% (range: 33.04–47.60%), and a mean age of 5.2 years (range: 4–9 years). The control group was composed of nine dogs with a mean BCS of 3.1 (range: 3–3.5), with a mean body fat mass percentage of 13.80% (range: 7.5–20.10%), and a mean age of 5.8 years (range: 4–6 years). BCS and body fat mass were significantly higher in dogs with obesity than in control dogs . A complThe targeted metabolomics analysis allowed the identification and quantification of a total of 234 different compounds. Multivariate analysis using PLS–DA suggested a robust separation between the groups   that wast-test and FC analysis were applied and depicted in a Volcano plot  , which mThe different types of glycerides showed diverse behavior in the saliva of obese dogs. Some diglycerides (DG) and triglycerides (TG), such as DG (42:0), TG (44:1), TG (53:3), TG (50:3), and TG (53:6), decreased, but others increased, such as TG (52:7) and DG (36:2). Previous reports have indicated that obesity induces the elevation of selected components of glycerides and predisposes to T2DM ,23. HoweSalivary sphingolipids were significantly increased in the obese group compared to the control. Sphingomyelin plays a role in cell apoptosis by its hydrolysis into ceramide, which is in turn responsible for the induction of apoptosis and involvement in inflammatory processes . CeramidPhosphatidylcholines (PC) belong to the glycerophospholipids family, which are the main constituents of cellular membranes and are essential for cellular signal transduction . In our Finally, the two ACs found in our study were increased in the saliva of obese dogs compared to normal dogs. The ACs were positively correlated with the fat-free mass index in a previous study in humans ; furtherAlthough our targeted metabolomics approach revealed specific metabolites and pathways in canine saliva affected by obesity, this study has some limitations. We employed an experimental model of obesity in dogs. Although this allowed better control over experimental conditions, our findings should be confirmed through a clinical study of dogs with obesity. Furthermore, the diet used for the obesity development was a commercial formula and complete information about its ingredients and processing was not available. In addition, the dogs included in the study were all castrated males of only one breed. This precluded the possibility of studying the effect of sex hormones in the salivary metabolome of dogs. Further studies should also be performed with non-castrated animals of different breeds. Finally, this was a pilot study conducted using a small sample size, and the results should be interpreted with caution and validated with a larger number of samples. Obese dogs showed changes in their salivary metabolome under our experimental conditions. Namely, there was an increase in five amino acids  that could be related to insulin resistance and obesity in dogs. Furthermore, alterations in lipids were also detected, with an upregulation of sphingolipids  that may also be involved in the development of insulin resistance. Globally, it can be stated that the salivary metabolome of obese dogs can reflect the metabolic changes occurring during obesity status and could be a source of potential biomarkers for this condition.


Oral antiplatelet therapy is the cornerstone of treatment for acute myocardial infaction (AMI). However, detailed usage data on oral antiplatelet therapy are lacking.Using data from a nationally representative sample of patients with AMI, the detailed usage of oral antiplatelet therapy was analyzed in 40,202 consecutive eligible patients.P < 0.05). The proportion of patients taking loading doses of aspirin was highest in the western region, and that of patients taking loading doses of P2Y12 inhibitors was highest in the eastern region (P < 0.05). In addition, 76.7% of patients with ST-elevation MI and 91% of patients with non-ST-elevation MI received 300-mg loading dose of clopidogrel.The proportions of patients with AMI taking loading doses of aspirin and P2Y12 inhibitors were relatively low , whereas approximately 90% of patients received maintenance doses of aspirin, P2Y12 inhibitors, and dual antiplatelet therapy. The proportions of patients taking loading doses of aspirin and P2Y12 inhibitors gradually decreased with age. Male sex, an educational level of at least college, an interval from onset to treatment of < 24 h, and primary PCI use were associated with a higher proportion of patients taking a loading dose of antiplatelet therapy, whereas those receiving conservative treatment had a lower rate of antiplatelet use (all The proportion of patients with AMI receiving loading doses of aspirin and P2Y12 inhibitors during hospitalization was relatively low, and this rate was affected by many factors, such as age, sex, educational level, region of residence, and the interval from onset to treatment. The underutilization of guideline-based P2Y12 inhibitors was also problematic. Hence, quality improvement initiatives are needed to enhance adherence to guidelines to improve consistent use of oral antiplatelet therapy.Trial registration The Chinese Acute Myocardial Infarction Registry; Trial registration number: ChiCTR-ONC-12002636; Registered 31 October 2012; http://www.chictr.org.cn/showproj.aspx?proj=6916The online version contains supplementary material available at 10.1186/s12872-021-02115-1. DespTo date, few studies have explored this issue in China. The rate of aspirin use among patients with acute coronary syndrome (ACS) at the time of hospital discharge exceeded 90% between 2004 and 2006 in China according to the Clinical Pathways for Acute Coronary Syndromes in China (CPACS) study . The earHowever, detailed data regarding oral antiplatelet therapy such as the use of the loading and maintenance doses and receipt of dual antiplatelet therapy (DAPT) among Chinese patients with AMI in recent years are extremely limited. Thus, this study investigated the detailed use of oral antiplatelet therapy among hospitalized patients with AMI in a “real-world” contemporary era and determined whether oral antiplatelet use in patients with AMI accorded with current guidelines by analyzing a consecutive national sample derived from the Chinese acute myocardial infarction (CAMI) registry.The CAMI registry is a prospective, nationwide, multicenter observational study of patients with AMI (NCT01874691). This project was approved by the institutional review board central committee at Fuwai Hospital, National Center for Cardiovascular Diseases of China  and conducted out in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from eligible patients before registration. Patient enrollment started in 2013. The registry covered all provinces and municipalities across mainland China (excluding Hong Kong and Macau), which made it likely representative of routine real-world clinical AMI care in China.The treatment strategies for patients with ST-elevation myocardial infarction (STEMI) included primary percutaneous coronary intervention (PCI), thrombolysis, elective PCI, and conservative treatment. Primary PCI, defined as an emergent percutaneous catheter intervention in the setting of STEMI, without previous fibrinolytic treatment,was the preferred reperfusion strategy in patients with STEMI, provided that it can be performed expeditiously  by an experienced team and completed regardless of whether the patient presents to a PCI-capable hospital. Thrombolysis is an important reperfusion strategy, particularly in settings in which primary PCI cannot be offered to patients with STEMI within the recommended timeline. Elective PCI was defined as appropriate for percutaneous catheter intervention in the setting of STEMI and totally occluded arteries > 24 h after symptom onset in patients without signs of ischemia (regardless of whether fibrinolysis was performed). Conservative treatment was defined as treatment given to non-reperfused patients with STEMI that served as the only medications used as therapy , 12. TheIn the CAMI registry, eligible patients must be admitted within 7 days of acute ischemic symptoms with a primary clinical diagnosis of AMI, including STEMI or NSTEMI. The inclusion criteria must meet the guidelines of the third Universal Definition for Myocardial Infarction 2012). Types 1, 2, 3, 4b, and 4c are included, and types 4a and 5 are not eligible for the registry. From January 2013 to January 2016, 41,375 patients were enrolled. In the present study, 1063 patients with an uncertain AMI status and 110 patients with missing data were excluded sequentially. Finally, 40,202 eligible patients with AMI were included in the present study .Patients’ baseline characteristics, medical history, treatments, and complications were evaluated. Continuous variables were presented as the mean ± standard deviation and compared using analysis of variance. Categorical variables were presented as counts and percentages and compared with the chi-squared test or Fisher’s exact test. Non-normally distributed variables were presented as the median and interquartile range and compared using Wilcoxon’s rank sum test. For all analyses, two-tailed P < 0.001). The NSTEMI group also had lower rates of current smokers, onset-to-visit time < 24 h, and receipt of primary PCI .A total of 40,202 patients diagnosed with AMI were consecutively enrolled in the CAMI registry from January 2013 to January 2016. Of these, 30,179 patients had STEMI, and 10,023 patients had NSTEMI. The baseline patient characteristics are presented in Table P < 0.001). Conversely, the proportions of patients taking maintenance doses of aspirin and DAPT did not differ between the groups (Table The proportions of patients taking loading doses of aspirin and P2Y12 receptor inhibitors were both higher in the STEMI group than in the NSTEMI group (both P < 0.05), especially among patients aged > 75 years . In the STEMI group, the proportions of patients taking maintenance doses of aspirin and DAPT were higher in patients age between 55 and 65  than in those > 75 years old ; whereas the proportions of patients taking maintenance doses of P2Y12 receptor inhibitors did not differ between the age groups . Among the NSTEMI group, the proportions of patients taking maintenance doses of aspirin, P2Y12 receptor inhibitors, and DAPT were higher in patients aged 55–65 than in those aged > 75 years . In the STEMI group, the proportions of patients taking maintenance doses of aspirin and DAPT were both higher in men than in women (P < 0.05), but the rate of maintenance P2Y12 receptor inhibitor treatment did not differ between the sexes. In the NSTEMI group, the proportions of patients taking maintenance doses of aspirin, P2Y12 receptor inhibitors, and DAPT were all higher in men than in women . Conversely, in the NSTEMI group, the proportion of patients taking maintenance doses of aspirin was higher among those with at least a college education (P < 0.05), whereas no difference in the use of maintenance doses of P2Y12 receptor inhibitors and DAPT were observed according to the educational level.The proportions of patients taking loading doses of aspirin and P2Y12 receptor inhibitors were higher among those with at least a college education than in those with less education P < 0.0, Fig. 5.P < 0.05). In both the STEMI and NSTEMI groups, the proportions of patients taking maintenance doses of aspirin and DAPT did not differ according to the interval from onset to treatment . Meanwhile, the proportion of patients taking maintenance doses of P2Y12 receptor inhibitors and DAPT was highest in the eastern region and lowest in the western region (P < 0.05).The proportions of patients taking loading and maintenance doses of aspirin, P2Y12 receptor inhibitors, and DAPT were differed according to the region of residence  The use of oral antiplatelet drugs during hospitalization had increased in Chinese patients with AMI in recent years. (2) In this study of a nationally representative sample of hospitalized patients in China, the usage of oral antiplatelet therapy by patients with AMI was affected by many factors, such as age, sex, educational level, regions, time since onset and treatment strategies. (3) Among patients with AMI, the most commonloading and maintenance doses of clopidogrel were 300 and 75 mg, respectively, from 2013 to 2016.P < 0.001) [The epidemiological characteristics and real-world oral antiplatelet treatment of AMI have not been well studied in Asian countries despite its importance in public health. The CPACS registry found that 93% of all patients with ACS were prescribed aspirin, but only 44.6% of patients were prescribed clopidogrel at hospital discharge between September 2004 and May 2006 . In the < 0.001) . In the < 0.001) –10, 15. In the present study, the utilization ratio of oral antiplatelet therapy in Chinese patients with AMI during hospitalization was affected by many factors, such as age, sex, educational level, region of residence, treatment strategy, and time from onset to treatment. As we know, longer time from onset to treatment may influence the selection of treatment strategys, and patients with lower educational levels may have worse economic conditions, which can also influence the choice of treatment. In our study, patients with lower educational level and a longer time from onset to treatment were less likely to receive oral antiplatelet therapy, especially loading doses of antiplatelet drugs. Meanwhile, patients who underwent primary PCI were more likely to receiving loading doses of oral antiplatelet therapy, patients who underwent elective PCI were more likely to receiving maintenance doses of oral antiplatelet therapy and DAPT, and patients who received conservative treatment were less likely to receiving oral antiplatelet therapy. Meanwhile, older and female patients were also less likely to receive oral antiplatelet therapy, especially loading doses of antiplatelet drugs, in our study. Economic development is imbalanced among the regions of China. In our study, the utilization rate of both loading and maintenance doses of P2Y12 receptor inhibitors was higher in the eastern region than that in other regions. The reason for this finding may be the relatively high price of P2Y12 receptor inhibitors based on the better economic condition in the eastern region.In the clinic, individualized treatment with oral antiplatelet drugs is necessary to balance the risks of bleeding and ischemia within the context of the available evidence. Clinical factors increasing the risk of bleeding  and ischemia  should be considered in the recommendation of oral antiplatelet therapy –23. In cIn 2010, Chinese guidelines for patients with STEMI recommended an oral aspirin loading dose of 300 mg, followed by a maintenance dose of 100 mg/day, and an oral clopidogrel loading dose of 300 mg, followed by a maintenance dose of 75 mg/day . The 201The patients in our study were enrolled between 2013 and 2016. Among the patients with AMI, the most common loading and maintenance doses of clopidogrel were 300 and 75 mg, respectively. Because this study was descriptive in nature, we could not identify the reasons for the usage habits of P2Y12 receptor inhibitors. In the ESC 2012 or ACC 2013 guidelines, the loading dose of clopidogrel was initially recommended as 600 mg; however, the Chinese guidelines only updated the high loading dose of clopidogrel in 2015, which may partly explain the use of a low clopidogrel loading dose of 300 mg. At the same time, it was only in 2015 that the Chinese guidelines recommended the use of ticagrelor, which may explain the low use of this drug. In addition, the common reason for the low use of high-dose loading clopidogrel and ticagrelor is the risk of bleeding. The ACC/AHA guidelines for STEMI and NSTEMI are widely upheld in China, and China's own guidelines are widely recognized; however, these findings suggest a significant gap between evidence and practice, which may, in large part, be attributable to a lack of familiarity with current treatment recommendations. The PROGRESS trial investigated the adherence to ticagrelor therapy in patients after ACS . AdherenAs the first prospective national registry study of patients with AMI in China, the CAMI registry study revealed current problems in the Chinese health care system. Data were valuable, specific, and updated, and they were based on a large population base. The CAMI study has five steps to support data quality control in the registry . NeverthThere was a progressive improvement in the use of oral antiplatelet treatment for patients with AMI in China, and this improvement was also affected by many factors, such as age, sex, educational levels, and treatment strategies. However, under utilization of the guideline-based P2Y12 receptor inhibitors for AMI is a major problem in China. The guideline-based oral antiplatelet therapies in patients with AMI in China present an important clinical implication; thus, national policies and initiatives are necessary to enhance adherence to the guidelines to improve oral antiplatelet therapy.Additional file 1:Figure 1. Rate of loading doses of P2Y12 receptor inhibitor use among patients with acute myocardial infarction. A, loading doses in the STEMI group. B, loading doses in the NSTEMI group. STEMI, ST-elevation myocardial infarction; NSTEMI, non- ST-elevation myocardial infarctionAdditional file 2:Figure 2. Rate of maintenance doses of P2Y12 receptor inhibitor use among patients with acute myocardial infarction. A, maintenance doses in the STEMI group; B, maintenance doses in the NSTEMI group. STEMI, ST-elevation myocardial infarction; NSTEMI, non- ST-elevation myocardial infarction


Dermatomal somatosensory evoked potentials (DSEPs) are used to evaluate abnormalities of the somatosensory tract. There have been some studies on the diagnostic value of DSEP in radiculopathy, but it is still controversial. The purpose of our study is to evaluate the diagnostic implication and clinical relevance of DSEPs in patients with radiculopathy by comparing DSEP findings to radiculopathy symptoms and intervertebral foramen (IVF) or spinal canal stenosis in lumbar magnetic resonance imaging (MRI). n = 59) who were examined by DSEP (each L4 and L5 dermatome) and lumbar MRI. Radiculopathy symptoms and DSEPs results were compared. For the evaluation of IVF and spinal canal size, sagittal  and axial MR images were selected at the most stenotic level. The sizes of the IVF and spinal canal were measured by the pixel counts of selected MR images. In addition, stenosis severity was morphologically graded on a 4-point scale. DSEP results were compared with the size and grade of the IVF or spinal canal stenosis.  This retrospective study reviewed the medical records of patients ( DSEPs showed high sensitivity for radiculopathy symptoms. The IVF size at L4/5 and L5/S1 (pixel counts) was significantly related to either L4 or L5 dermatomal somatosensory pathway dysfunction, respectively. However, spinal stenosis (pixel counts and grade) and IVF stenosis grade were not significantly related to DSEPs.  This paper could be helpful in the electrophysiologic diagnosis of lumbar radiculopathy. Dermatomal somatosensory evoked potentials (DSEPs) are used to evaluate abnormalities of the somatosensory tract, which extends from the peripheral sensory nerve to the cerebral cortex, by recording cerebral evoked responses from cutaneous stimulation of areas of known dermatomal innervation, providing a pure sensory input to any level of the spinal cord . Dawson Radiculopathy refers to a set of conditions caused mainly by the pinching of a nerve root in the spinal column. This can result in pain, weakness, numbness, or difficulty controlling specific muscles , 6. The Needle electromyography (EMG) is the useful electrophysiologic method of diagnosing spinal radiculopathy. Through needle EMG, it is possible to identify sings of motor denervation such as positive sharp wave and fibrillation and to specify the compressed nerve roots . HoweverIn the diagnosis of radiculopathy, many studies have examined the diagnostic value of DSEPs –13. HoweThere have been some studies on the diagnostic value of DSEPs compared to imaging, but it is still controversial , 15. Then = 59) who were clinically suspected to have L4 or L5 lumbar radiculopathy as they had not only low back pain but also radiating pain and numbness or weakness of the lower extremities. Inclusion criteria were patients who have radiating pain of lower extremity and were examined by DSEP and lumbar spine MRI from 2017 to 2019. Exclusion criteria were patients with myelopathy or peripheral neuropathy in nerve conduction study (NCS). The medical records of 59 patients with 236 DSEP findings  were reviewed.This retrospective study was approved by the institutional ethics committee of Jeonbuk National University Hospital . We reviewed the medical records of patients  were divided into normal, delayed latency (delay), and absent response (absence) groups  machine , for which the intensity of stimuli was set at 2.5 times the sensory threshold. The sweep velocity, sensitivity, filter setting, stimulation duration time, and stimulation frequency were set at 10 ms/division, 5 uV/division, 20–1500 Hz, 0.1 ms, and 3 Hz, respectively. Encephalographic needle electrodes were used to record DSEPs. Active recording electrodes were placed on C3′ or C4′ based on the 10–20 international encephalographic system. A reference electrode was placed on Fz. It reduces the influence of subcortical far-field potentials and results in a clear cortical response compared to the noncephalic reference . A groun) groups . Since tFor the evaluation of IVF and spinal canal sizes, sagittal images to measure IVF size and axial images to measure spinal canal size were selected. Each image was selected at the narrowest bilateral L4/5 and L5/S1 IVF and the most stenotic axial level above the IVF corresponding to the DSEP level. In other words, when L4 DSEPs were analyzed, the lumbar spinal canal stenosis was measured at or above the L4/5 intervertebral disc level. When L5 DSEPs were analyzed, the lumbar spinal canal stenosis was measured at or above the L5/S1 intervertebral disc level. The size was defined by pixel counts in the sagittal view of the IVF and the axial view of the thecal sac area using the Magnetic Lasso Tool in Adobe Photoshop CC 2019  with reference to previous study measuring specific anatomic areas on MRI image with pixel counts [IVF stenosis was graded on a 4-point scale according to morphological features on MRI. Grade 0 refers to the absence of foraminal stenosis. Grade 1 refers to mild foraminal stenosis showing perineural fat obliteration surrounding the nerve root in two opposing directions . This involves contact with the superior and inferior portions of the nerve root or anterior and posterior portions of the nerve root. No evidence of morphological change in the nerve root is shown. Grade 2 refers to moderate foraminal stenosis showing perineural fat obliteration surrounding the nerve root in four directions without morphological change in both the vertical and transverse directions. Grade 3 refers to severe foraminal stenosis showing nerve root collapse or morphological change . Spinal p ≤ 0.05.Statistical analysis was performed using SPSS 23.0 for Windows . Data are presented as means (SDs) for continuous variables and frequencies for categorical variables. The general characteristics of the subjects were analyzed using descriptive statistics. Based on radiculopathy symptoms and DSEP results, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were obtained. Effects of IVF stenosis and lumbar spinal canal stenosis on DSEP results were analyzed using logistic regression analysis. Intergroup differences between the normal, delay, and absence groups were analyzed using a ranked analysis of covariance (ANCOVA), with age and sex as covariates. Each ranked ANCOVA was followed by planned multiple pairwise comparisons with Bonferroni correction to This retrospective study reviewed 59 patients , positive predictive value (82.7%), negative predictive value (70.0%), and a relatively low specificity (45.2%) .p=0.01) and L5 DSEPs (p=0.029). However, the effect of lumbar spinal canal stenosis  on DSEPs was not significant. Neither IVF stenosis nor spinal canal stenosis grades were associated with DSEP results  on DSEPs was significant in L4 ( results .n = 118) were identified as either normal (n = 74), delayed latency , or absent . The mean IVF sizes were smaller in the delay and absence groups than in the normal group . The differences between the three groups were significant (p=0.001). In post hoc analysis . However, there was no significant difference between the delay and absence groups (p=1.000).Depending on the results of L4 DSEP, cases of L4/5 IVF  were identified as normal (n = 31), delayed latency , or absent . The mean IVF sizes were smaller in the delay and absence groups than in the normal group . The differences between the three groups were significant (p=0.022). In post hoc analysis (p=0.024) but not between the normal and absence groups or delay and absence groups .Depending on the results of L5 DSEP, cases of L5/S1 IVF  and relatively low specificity (45.2%) when compared to radiculopathy symptoms, and IVF size had an effect on DSEP results. In addition, the IVF size was significantly smaller with abnormal DSEP results. However, the size or grade of spinal canal stenosis and the grade of IVF stenosis were not associated with DSEP results.In patients with radiculopathy, electrodiagnostic studies, including needle EMG and NCS, are strongly recommended tests for the diagnosis of radiculopathy; EMG still represents the gold standard for the diagnosis of radiculopathy . HoweverVarious studies have been conducted on radiculopathy and DSEPs. Some studies have shown that DSEPs have increased diagnostic sensitivity to cervical radiculopathy and showed usability as a follow-up study according to improvement , 26. In Our study showed a significant difference in IVF size between normal and delayed or absent DSEP results, but IVF stenosis grade was not significantly related to DSEP results Tables  and 4. TOur DSEP data showed a meaningful relationship with IVF stenosis. However, no significant results were found in the relationship between spinal canal stenosis and DSEP results Tables  and 4. In = 20 in L4 DSEP level and n = 15 in L5 DSEP level). Second, this study did not document the signs of denervation on the EMG. Third, if DSEP is performed in the diagnostic phase without lumbosacral MRI, it may be a time-consuming approach that requires examination of many suspected lesion levels . The needle EMG, on the other hand, makes it possible to detect pathologic signs in the muscles pertaining to the lumbosacral roots in a shorter time.There are some limitations to this study. The first limitation is the relatively small sample size. It is likely that the smaller sample size of those with absent DSEP results reduced our statistical power (Our results showed that L4/5 and L5/S1 IVF size was significantly related to L4 or L5 dermatomal somatosensory pathway dysfunction, respectively. DSEPs showed a high sensitivity for suspected lumbar radiculopathy. Thus, we suggest that DSEP studies could be helpful in the electrophysiologic diagnosis of lumbar radiculopathy.


The ovarian reserve is one of the most important indicators of female fertility. It allows for the evaluation of the number of viable oocytes. This parameter is actively used in pregnancy planning and in assisted reproductive technology application, as it determines chances of successful fertilization and healthy pregnancy. Due to increased attention towards diagnostic tests evaluating the ovarian reserve, there has been a growing interest in factors that influence the state of the ovarian reserve. True reasons for pathological changes in the ovarian reserve and volume have not yet been explored in depth, and current diagnostic screening methods often fall short in efficacy. In the following review we analyze existing data relating to the study of the ovarian reserve through genetic testing, determining specific characteristics of the ovarian reserve through genetic profiling. We explore existing studies dedicated to finding specific genetic targets influencing the state of the ovarian reserve. With age, the ovarian reserve tends to naturally diminish and normally does not present with pathological changes. Environmental impact, physiological, hormonal, iatrogenic and other factors determine the state of the ovarian reserve. Recently, genetic defects have been directly associated with a significant reduction in the ovarian reserve . In caseGenetic profiles FMR1, EIF4ENIF1, BRCA1/2, H19, HMGB2, ADR-α1, 2, ADR-β2, NR5A1, ATG7, ATG9A, KHDRBS1, FIGLA, 22q11.2, SPO11, HFM1, GDF9, TP53 have been shown to play a key role in ovarian reserve determination [The PubMed, Scopus, Web of Science and eLibrary databases were searched using the following key words and their combination: “ovarian reserve”, “ovarian reserve AND genetics”, “ovarian reserve AND gen”, “ovarian reserve AND genetic”, “ovarian reserve AND epigenetic NOT cancer”, “ovarian reserve AND genetic screening” and “diminished ovarian reserve”. Original studies were included in this review. Meta-analyses and systematic reviews were screened for references applicable to our search criteria.Low ovarian reserve is an increasing social problem, as many women are at high risk for early decline of the ovarian reserve. A low reserve is one of the leading causes of female infertility and up to 26% of women who are undergoing fertility treatment with assisted reproductive technology (ART) have a diminished ovarian reserve (DOR) . DiagnosCurrent data is unanimous that polycystic ovary syndrome (PCOS) is characterized by an increase in the level of sex hormones. This underlined the importance of dose reduction of administered gonadotropins in order to avoid ovarian hyperstimulation . In obesIn this review, we delineate several categories of genetic factors according to their influence on the ovarian reserve (OR).FMR) are a family of regulator genes located in the X chromosome. The Fragile X Mental Retardation 1 (FMR1) gene is commonly associated with neuropsychiatric disorders, but it has been shown to play a role in other pathologies as well. Apart from classical FMR1 disorder symptoms (tremor and ataxia), ovarian dysfunction is also common [FMR1 mutations provoke different pathological changes along with the decline of the ovarian reserve.Fragile X Mental Retardation Genes (o common . FMR1 muFMR1 gene contains a 5’-UTR triplet repeat (GGG) region, the length of which varies individually. It has been shown that FMR1 gene expression depends on the length and number of these triplet repeats [FMR1 gene are identified according to the number of GGG repeats . They are also found in genes that are responsible for bone morphogenetic proteins – BMPs (gene TR53) [Single-nucleotide polymorphisms are another form of genetic variability. They are caused by point mutations, so they exist in high abundance in human genome. They are found in genes coding the receptors of the Anti-Müllerian hormone – AMH (AMHR2), Follicle-stimulating hormone – FSH (FSHR), luteinizing hormone – LH (LHCGR), estrogen (ESR), growth and differentiation factors ne TR53) , 21. SNP , 21. SNSNPs of FSH receptor are considered to be potential diagnostic genetic markers of POR , as FSH ESR1 gene is located in the 6th chromosome and is responsible for coding the ESR protein, which plays an important role in regulating granulosa cell proliferation and folliculogenesis. SNPs of gene ESR1 have been shown to cause POR, but existing data is contradictive. Some research shows a direct correlation between ESR1 SNPs and POR [ESR1 SNPs alone may not contribute entirely to POR.The  and POR , but oth and POR . This diGDF9, C398G, C447T, BMP15 have been shown to negatively impact ovarian response among females who are subject to controlled ovarian hyperstimulation. Existing data shows that GDF9 polymerphisms plays an important role in different stages of folliculogenesis [GDF9 and BMP15 belong to a superfamily of transforming growth factors (beta) [GDF9 and BMP15 have been identified: c.-9C > G (rs3810682), BMP15:c.328 + 905A > G (rs3897937), BMP15:c.852C > T (rs17003221); GDF9:c.134-694G > A (rs4705974), GDF9:c.-31-951G > A (rs11748063), GDF9:c.-152G > C (rs30177), GDF9:g.1073C > T (rs803224) [TR53 has also been shown to impact the state of the ovarian reserve and consequently the results of in vitro fertilization [Polymorphisms in genes ogenesis . GDF9 ans (beta) . The SNPs803224) , 37. Thes803224) . Polymor9C > G rs10682, BMmiRNA and piRNA have been shown to have an impact on granulosa cells with low ovarian volume because of RNA interference (RNAi) and various epigenetic rearrangements which determine genetic expression, making them an important target in genetic diagnostics and targeting in DOR .The impact of miRNA-106a on the pathogenesis of DOR is actively studied. Its’ action results in the lowering of the viability of granulosa cells and stimulate apoptosis through activation of apoptosis signal-regulating kinase 1 (ASK1) . AdditioThe decline of long non-coding RNA H19  in the blood serum has been shown to be connected with the decline of AMH and an increased risk of extreme POR, therefore acting as a potential biomarker of POR and DOR . FurtherFIGLA) , have been shown to cause a decline in the ovarian reserve [ATG7 and ATG9A genes (connected with programmed cell death) cause reduced biosynthesis of autophagosomes  which may lead to DOR through folliculogenesis dysregulation [JAK1) in regulating activation of primary follicles and supporting the ovarian reserve. A range of integrated inner pathways, including JAK-STAT, have been shown to be responsible for regulation of the ovarian reserve, primary follicle growth and female fertility [Biallelic mutations of Folliculogenesis Specific BHLH Transcription Factor (FIGLA) gene  have been shown to play a critical role in ovarian pathogenesis. Thus, a range of changes in sirtuin genetic profiles such as Interestingly, among women with low ovarian volume the influence of ADR-α1, 2 and ADR-β2 are predetermined by the depletion of gene expression and this has been shown to result in ovarian aging and DOR .BRCA mutations cause a decline of the ovarian reserve and premature ovarian aging, accumulation of mutations in the DNA of female germ cells and primary follicle atresia. BRCA1/2 are responsible for homologous recombination of DNA and influence DNA repair (double-strand break – DSB), which are caused by ataxia–telangiectasia (AT). BRCA and AT DNA repair have been shown to play an important role the process of early onset ovarian dysfunction. BRCA1/2 and AT-related DSB and DNA repair tend to weaken with age in different oocytes [BRCA1/2 mutations have low ovarian volumes and early menopause [Recent studies show that  oocytes . The numenopause . ExistinHFM1). This pathological mutation is associated with DOR and causes defects of RNA splicing [KHDRBS1 is one of the reasons of such pathological changes. They appear in the form of delayed puberty and considerable depletion of secondary and pre-antral follicles. Thus, a more detailed examination of mutation will help to understand etiology, a molecular mechanism of pathological changes in the ovarian reserve [Whole exome sequencing allowed to identify a new heterozygous missense mutation in the HFM-1 (human homologue of yeast Mer3) gene , which manifests itself as a progressive neurodegenerative disease with pronounced manifestations. tremor, ataxia, dementia, behavioral changes, and much more. Clinical manifestations include cerebellar ataxia, action tremor, parkinsonism, cognitive impairment, psychiatric disorders, peripheral neuropathy, and autonomic dysfunction of varying in severity, are possible. In women, due to the presence of a second X chromosome, this syndrome does not develop, however, it is known that carriers are more likely to suffer from depression and anxiety disorders. They also have an increased risk of developing primary ovarian failure [SIRT gene family, as well as other epigenetic disorders, have multiple aggravating consequences, including premature aging, neurodegenerative diseases, cancer, oxidative stress, and autophagy [It is important to understand that the reviewed genes are not specific to the reproductive system, but also have a complex effect on the body, as most genetic profiles do.  failure . This asutophagy .BRCA genetic expression products are known regulators of cellular repair and lifecycle, maintaining the stability of the genome. BRCA1/2 mutations lead to disturbances in the mechanisms of molecular repair and cell division. Carriers have an increased risk of cancers of the breast, ovaries, fallopian tubes, peritoneum, prostate, pancreas, stomach, gallbladder and bile ducts, and melanoma. If the mutation is inherited from both parents, Fanconi anemia, malignant tumors and acute myeloid leukemia may develop [ develop .BMP gene cluster expression, is a growth factor and morphogenetic signaling protein family that is involved in structural organization of tissues. BMPs act on cells through specific BMP receptors (BMPRs) and play an important role in the development of the heart, central nervous system, and skeleton. Impaired BMR signaling can have pathologic effects on a developing embryo. Mutations in BMP and BMP inhibitors cause a number of diseases [Bone morphogenetic protein (BMP), a product of diseases .TP53 gene, a transcription factor that regulates the cell cycle. p53 functions as a tumor suppressor and the TP53 gene is regarded as an anti-oncogene. Numerous studies have shown that imbalances in the expression of p53 isoforms and mutations in the TP53 gene cause such debilitating disorders as cancer, premature aging and degenerative diseases [The p53 protein is an expression product of the diseases .ADR cluster genes are involved in the regulation of lipid and carbohydrate metabolism, blood pressure, and heart function through expression products—adrenergic receptors. Mutations and polymorphisms of these genes can lead to the development of various diseases: arterial hypertension, heart disorders, ischemia, obesity, type I and II diabetes mellitus and insulin resistance [The sistance , 60.KHDPBS gene expression belongs to the STAR  family and regulates the splicing of target genes, which plays an important role in the formation of contacts and myelination in the nervous system. STAR products are also involved in the embryonic development of the nervous system. Disorders of KHDPBS genes are associated with diseases such as schizophrenia and autism, as well as with other neurodegenerative pathologies [The protein product of hologies .NRIP1, XPO1 and MACF1, which have been shown to be related to ovarian functioning, but their role in the human body is not fully understood [EIF4ENIF1 has been discovered recently, and is identified in patients with low ovarian volume, prompting investigation and increased interest to the role of genetic factors in ovarian homeostasis [NR5A1 have been shown to influence the decline of the ovarian reserve, causing primary ovarian insufficiency, which can cause primary ovarian insufficiency (POI) and infertility [Recent studies have identified new candidate genes which may be involved in ovarian pathogenesis Fig. . These iderstood . A new geostasis . New varertility . Besidesertility .Fig. 6NeGenetic factors should be taken into account in the treatment and diagnosis of ovarian reserve pathology. Identifying genetic predisposition to early ovarian reserve depletion may serve beneficial in family planning. Existing data show an abundant amount of research on genetic and epigenetic profiles which may influence ovarian reserve formation and consistency. More so, several specific genetic markers have been identified to be associated with ovarian reserve depletion through several important pathological pathways. Further research is needed to evaluate the unsupported conclusions and unproven correlations between genetic mutations and ovarian reserve stability. Inconsistent data shows that the ovarian reserve is subjected to a multifactorial influence, and disruption of separate factors may not consistently lead to ovarian reserve pathology.