Sexual dimorphic miRNA-mediated response of bovine elongated embryos to the maternal microenvironment.

A skewed male-to-female ratio in cattle is believed to be due to the biased embryo losses during pregnancy. The changes in biochemical secretion such as miRNAs by the embryo due to altered maternal environment could cause a sex biased selective implantation resulting in a skewed male to female ratio at birth. Nevertheless, it is still not clear whether the male and female embryos could modify their miRNA expression patterns differently in response to altered physiological developmental conditions. Therefore, this study was focused on identifying sex specific miRNA expression patterns induced in the embryo during the elongation period in response to the maternal environment. For this, in vitro produced day female and male embryos were transferred to Holsteins Frisian cows and heifers. The elongated female and male embryos were then recovered at day 13 of the gestation period. Total RNA including the miRNAs was isolated from each group of elongated embryo samples were subjected to the next generation miRNA sequencing. Sequence alignment, identification and quantification of miRNAs were done using the miRDeep2 software package and differential miRNA expression analyses were performed using the edgeR bioconductor package. The recovery rate of viable elongating embryos at day 13 of the gestation period was 26.6%. In cows, 2.8 more viable elongating male embryos were recovered than female embryos, while in heifers the sex ratio of the recovered elongating embryos was close to one (1.05). The miRNA analysis showed that 254 miRNAs were detected in both male and female elongated embryos developed either in cows or heifers, of which 14 miRNAs including bta-miR-10b, bta-miR-148a, bta-miR-26a, and bta-miR-30d were highly expressed. Moreover, the expression level of 32 miRNAs including bta-let-7c, bta-let-7b, bta-let-7g, bta-let-7d and bta-let-7e was significantly different between the male and female embryos developed in cows, but the expression level of only 4 miRNAs (bta-miR-10, bta-mR-100, bta-miR-155 and bta-miR-6119-5p) was different between the male and female embryos that were developed in heifers. Furthermore, 19 miRNAs including those involved in cellular energy homeostasis pathways were differentially expressed between the male embryos developed in cows and heifers, but no significantly differentially expressed miRNAs were detected between the female embryos of cows and heifers. Thus, this study revealed that the sex ratio skewed towards males in embryos developed in cows was accompanied by increased embryonic sexual dimorphic miRNA expression divergence in embryos developed in cows compared to those developed in heifers. Moreover, male embryos are more sensitive to respond to the maternal reproductive microenvironment by modulating their miRNA expression.

Synthetic and phytogenic antioxidants improve productive performance, antioxidant activity, gene expression, and offspring quality in breeder hens subjected to heat stress.

This study aimed to investigate the efficacy of a synthetic source (a combination of vitamin E, vitamin C, selenium, and L-carnitine) and phytogenic sources (a combination of clove, green tea pomace, and Vietnamese coriander) in overcoming heat stress (HS) damage in female breeder hens on production, blood chemistry, sperm survival in the oviduct, antioxidant properties, gene expression, and quality of offspring. One hundred SUT female breeder hens were housed in individual cages and divided into 4 treatment groups: T1) basal diets in the thermoneutral (TN) zone; T2) basal diets under HS; 3) basal diets with synthetic antioxidants under HS; and T4) basal diets with phytochemical antioxidants under HS. The result revealed that HS condition had a negative effect on reducing final body weight, egg weight, and 1-day-old chick weight while increasing water intake and FCR and altered blood chemicals in breeder hens compared to TN breeder hens (P < 0.05). However, either synthetic or phytogenic antioxidants resulted in increased egg production and hatchability, while decreasing the number of late stages of embryo death during the incubation (P < 0.05). Furthermore, the synthetic antioxidants also improved the uniformity of chicks and reduced late-stage embryo death compared with phytogenic antioxidants (P < 0.05). HS breeder hens fed with either of the antioxidant sources exhibited higher antioxidant capacity in terms of DPPH and ABTS radical scavenging (in yolk, liver, and breast meat) and FRAP radical scavenging (in yolk and liver) and lower liver malondialdehyde than HS breeder hens fed with the control diet (P < 0.05). Additionally, the gene expression of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in the liver was upregulated, whereas the expression of proinflammatory cytokines (nuclear factor-κB) and heat shock proteins (HSP70 and HSP90) was downregulated in breeder hens that received both antioxidant sources (P < 0.05). Future investigations should focus on the potential for combinations of synthetic and phytogenic antioxidants in diets for HS breeder hens.

Cellular inflammatory response in the bovine uterus by Leptospira infection may be related to embryo death and subfertility.

Bovine leptospirosis is a chronic disease that causes various reproductive disorders and consequent economic losses worldwide, particularly embryo death. Although Leptospira spp. has already been detected in the genital tract of cows, little is known about the uterine cellular immune response or the intrinsic factors that could contribute to that reproductive failure. In this context, the aim of this study was to assess the uterine cellular inflammatory response after the quantification of cytokine IL-6 in bovine uteri naturally infected with leptospires compared to uninfected. Our results demonstrated that uterine tissues infected with leptospires have higher levels of IL-6 compared to uninfected tissues (p < 0.001). It suggests that the presence of leptospires in the bovine uterus can induce a cellular inflammatory response, which may be related to embryo death and consequent subfertility.

AMPK-FOXO-IP3R signaling pathway mediates neurological and developmental defects caused by mitochondrial DNA mutations.

Pathological mutations in human mitochondrial genomes (mtDNA) can cause a series of neurological, behavioral, and developmental defects, but the underlying molecular mechanisms are poorly understood. We show here that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway plays a key role in mediating similar defects caused by different mtDNA mutations in Caenorhabditis elegans, including loss or reduction of osmotic, chemical and olfactory sensing, locomotion, and associative learning and memory, as well as increased embryonic lethality. mtDNA mutations cause reduced ATP (adenosine triphosphate) levels, activation of C. elegans AMPK AAK-2, and nuclear translocation of the FOXO transcription factor DAF-16. Activated DAF-16 up-regulates the expression of inositol triphosphate receptor ITR-1, an endoplasmic reticulum calcium channel, leading to increased basal cytosolic Ca2+ levels, decreased neuronal responsiveness, compromised synapses, and increased embryonic death. Treatment of mtDNA mutants with vitamin MK-4 restores cellular ATP and cytosolic Ca2+ levels, improves synaptic development, and suppresses sensory and behavioral defects and embryonic death. Our study provides crucial mechanistic insights into neuronal and developmental defects caused by mtDNA mutations and will improve understanding and treatment of related mitochondrial diseases.

BoHV-1 affects abortion and progesterone in dairy cows Bovine alphaherpesvirus 1 (BoHV-1) seropositivity, progesterone levels and embryo loss of 30-day-old pregnant dairy cows in Zagros Industrial Dairy Farm in Shahrekord: Examination and analysis.

BACKGROUND: Bovine alphaherpesvirus 1 (BoHV-1) is a serious disease with severe negative economic effects on the global cattle sector, especially in Iran. OBJECTIVE: This cross-sectional study was carried out to examine the seroprevalence and associated risk factors of BoHV-1 infection with progesterone levels and embryo death in 30-day pregnant dairy cattle at Zagros Industrial Dairy Farm in Shahrekord, Iran. METHODS: Between December 2017 to February 2018, blood samples were obtained from 60 dairy cow herds. To determine whether BoHV-1 was present, serum samples were examined using the ELISA for serum antibodies. To find progesterone (P4) in blood, the progesterone ELISA test was used. RESULTS: 96.7 % of sera tested positive for BoHV-1 antibodies, according to the findings. Additionally, 60.34 % of blood samples that tested positive had an experience of abortion and significantly more inseminations that resulted in pregnancy, consistent with findings from other studies conducted in Iran and other nations. CONCLUSIONS: Since this study is the first to document the risk factor for BoHV-1 infection in Shahrekord, Iran, we could infer that the virus is extensively dispersed in this area.

Silicon dioxide nanoparticles compromise decidualization via autophagy impairment to possibly cause embryo resorption.

The wide application of silicon dioxide nanoparticles (SiO2NPs) has raised concerns about their harmful effects on reproduction. The purpose of this research was to investigate the toxic effects and the possible mechanisms by which SiO2NPs affect decidualization and pregnancy progression. We found that SiO2NPs could inhibit decidualization, both in mice and in human endometrial stromal cells (HESCs). Embryo resorption was also evident in mice treated with SiO2NPs. When HESCs were treated with SiO2NPs, decidualization was inhibited and there was an increase in intracellular lysosomes and autophagosomes as well as the blockage of autophagic flux. Interestingly, a reduction of autophagosome accumulation via 3-methyladenine (3MA) significantly restored the decidualization of HESCs. In summary, our results indicate that SiO2NPs can affect embryo survival by impairing decidualization through a dysfunctional autophagic process.

Embryonic resorption rates at canine pregnancy diagnoses: A retrospective evaluation.

Pregnancy diagnosis in canines is generally performed during embryonic phase, between 19 and 35 days of gestation. At this stage embryonic resorptions can be observed, which, according to the literature, affects 11-26% of conceptuses and 5-43% of pregnancies. Resorption has been hypothesized as a physiological event in uterine overcrowding, however other factors may be involved, such as infectious or non-infectious diseases. This study aimed to retrospectively evaluate the incidence of embryo resorption at ultrasonographic pregnancy diagnosis in different dog breeds, and to identify the main factors determining the occurrence of the resorption sites. 95 pregnancy diagnoses were performed 21-30 days post-ovulation by ultrasound examination on 74 different animals. Breed, weight, and age of the bitches were recorded, and the reproductive anamnesis was collected from their medical records. The overall pregnancy rate was 91.6%. In 48.3% of pregnancies (42/87), at least one resorption site was visible, and embryonic resorption rate was 14.2% (61 resorption sites/431 total structures). Binary logistic regression showed a significant effect of age (P < 0.001), but not the size of the litter (P = 0.357), nor the size of the mother (P = 0.281) or any previous reproductive problems (P = 0.077). Age was significantly higher in pregnancies with resorptions than in normal ones (60.88 ± 18.24 and 40.27 ± 15.74 months, respectively, P < 0.001). The embryonic resorption rate was in line with previous findings, while the incidence of affected pregnancies was higher. Although resorptions may occur physiologically in pregnancies with large litters, a relationship between embryo resorption and litter size was not identified in our sample group, while aging increased the resorption rates. This, together with the occurrence of repeated embryonic resorptions in some bitches included in the study, suggests how resorptions could also be the result of pathological events. The underlying mechanisms and other factors that may be involved need further clarification.

T Cell Subsets and the Expression of Related MicroRNAs in Patients with Recurrent Early Pregnancy Loss.

This study explored the role of T cell subsets and the expression of related microRNAs in patients with recurrent early pregnancy loss (EPL). Fifty patients with EPL loss between May 2018 and May 2021 were randomly selected as the EPL group, and 50 pregnant women with normal pregnancies or normal delivery outcomes were randomly selected as the control group. The expression levels of T cell subset-related markers and T cell subset-related miRNAs, in addition to the frequencies of T cell subsets, in peripheral blood of the two groups were analyzed. In terms of T cell-related markers, the results showed that the expression levels of the transcriptional regulator TBX-21 (T-bet) and interferon regulatory factor 4 (IRF4) were significantly upregulated in peripheral blood of the patients in the EPL group (P < 0.05), whereas the expression levels of GATA binding protein 3 (GATA3) and glucocorticoid-induced tumor necrosis factor receptor (GITR) were significantly downregulated (P < 0.05). In the EPL group, the expression of mir-106b, mir-93, and mir-25 was upregulated (1.51 ± 0.129, 1.43 ± 0.132, and 1.73 ± 0.156, respectively) in regulatory T (Treg) cell-related T cell subsets, whereas the expression of miR-146a and miR-155 was downregulated (P < 0.05). The frequencies of Treg and exhausted T cells in the EPL group were significantly lower than those in the control group (P < 0.05). The cell frequencies of T helper 17 (Th17) cells and exhausted Treg cells in the EPL group were significantly higher than those in the control group (P < 0.05). In conclusion, immune cells and associated miRNA profiles can be used as prognostic biomarkers for the treatment of human reproductive disorders, such as EPL.

Metastasis-associated lung adenocarcinoma transcript 1 induces methyl-CpG-binding domain protein 4 in mice with recurrent spontaneous abortion caused by anti-phospholipid antibody positivity.

INTRODUCTION: Antiphospholipid syndrome is an autoimmune disease characterized by pregnancy-related morbidity, related to persistent positivity of antiphospholipid antibodies (APL). One of the characteristics of pregnancy-related morbidity in patients with antiphospholipid syndrome is recurrent spontaneous abortion (RSA). This study aimed to examine the mechanism through which metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) regulates methyl-CpG-binding domain protein 4 (MBD4) expression in APL-positive RSA. METHODS: Clinical samples were subjected to microarray analysis to filter differentially expressed genes. RSA mice with APL positivity were generated, followed by adenoviral vector injection to artificially upregulate MALAT1. The effects of MALAT1 on the biological behavior of trophoblast cells were assessed. The downstream mechanism of MALAT1 was analyzed using subcellular fractionation and bioinformatics prediction, and the relationship between MALAT1 and CREB binding protein (CREBBP) or MBD4 was investigated in trophoblast cells. RESULTS: MALAT1 was downregulated in APL-positive RSA patients. MALAT1 was predominantly localized in the nucleus and recruited CREBBP to mediate the MBD4 transcription. In the APL-positive RSA mice overexpressing MALAT1, the expression of soluble Fms-related tyrosine kinase 1 and anticardiolipin antibody and the embryonic resorption rate were decreased, indicating that MALAT1 reduced the occurrence of RSA in mice. Moreover, MALAT1 enhanced proliferation, migration, and invasion of trophoblast cells through recruiting CREBBP to promote MBD4 expression. Silencing of CREBBP or MBD4 increased embryonic resorption rate in RSA mice overexpressing MALAT1. DISCUSSION: MALAT1 suppresses APL-positive RSA by promoting MBD4 transcription through recruitment of CREBBP to the MBD4 promoter region.

Embryo Loss and Moral Status.

There is a significant debate over the moral status of human embryos. This debate has important implications for practices like abortion and IVF. Some argue that embryos have the same moral status as infants, children, and adults. However, critics claim that the frequency of pregnancy loss/miscarriage/spontaneous abortion shows a moral inconsistency in this view. One line of criticism is that those who know the facts about pregnancy loss and nevertheless attempt to conceive children are willing to sacrifice embryos lost for the healthy children they ultimately have. I respond to this criticism and argue that on the most plausible accounts of well-being, these embryos are not made worse off and thus not "sacrifices." I then make some more general remarks about what people's typical views about pregnancy loss show about their views toward the moral status of embryos.

Late embryo mortality in Holstein cows inseminated with Holstein or Limousine frozen semen.

The objective of this study was to compare the late embryo mortality (LEM) rate (losses approximately between 32 and 53 days of gestation) and Pregnancy Specific Protein B (PSPB) and progesterone (P4) concentrations on day 32 post AI in Holstein cows bred with either Holstein or Limousine semen. A sample size of 1082 cows per group diagnosed pregnant between 28- and 35-days post breeding was calculated. The study consisted of evaluating LEM (%) in a cohort of Holstein cows bred with Holstein semen (HO × HO) or Limousine semen (HO × LM), to compare pregnancy loss from 28 to 35 days post breeding to 50-57 days post breeding. A logistic regression model to compare embryo losses was developed considering as main explanatory variable the cohort (HO × HO embryo vs. HO × LM embryo), correcting by lactation number, breeding season, days to breeding and AI technician. HO × HO embryos had greater LEM (15.16%) than HO × LM embryos (9.79%). Cows bred in summertime had higher LEM (15.23%) than cows bred in no-summertime (9.88%). There were no differences among AI technicians. Within summertime there was no difference in LEM (%) between groups within each lactation number; yet, within no-summertime, LEM (%) was higher in HO × HO than HO × LM within each lactation number. Pregnancy SPB optical densities were significantly greater in the HO × HO than in the HO × LM (p = .023) group; yet, the concentration of P4 was not different between groups (p > .05).

Investigating protein C and S levels in pregnant women with recurrent early pregnancy loss versus normal pregnancy.

Miscarriage in the first and second trimesters of pregnancy is very common, and coagulopathy can be a contributing factor. Protein C and S deficiency are rare, inherited disorders that can increase the risk of thrombophilia. Women with these deficiencies have a higher risk of developing blood clots in the placenta, which can lead to placental insufficiency and, ultimately, to a miscarriage. We aimed to compare the levels of protein C and protein S in pregnant females with recurrent first and second-trimester pregnancy loss and normal pregnant females. We performed a detailed history, examination, and various lab tests on a cohort of 40 females with a history of recurrent first and second-trimester abortions visiting an outpatient clinic at a multi-specialty hospital in Kashmir, India. All the findings were compared with 40 women with normal pregnancies. 10% of the participants had low protein C and S levels (P=0.277), out of whom 75% (p<0.001) had intrauterine growth retardation (IUGR) on ultrasound with 67% (p<0.001) having reduced doppler flow in the umbilical artery. 0.05% of participants had isolated protein S deficiency with no concomitant IUGR seen. Patients with protein C and S deficiencies were treated with heparin and progesterone and followed up for pregnancy outcomes. Screening for protein C and S deficiency is mandatory in all cases of recurrent pregnancy loss. Treatment with low molecular weight heparin and progesterone should be initiated to ensure good fetal outcomes and prevent post-partum/postoperative catastrophic venous thromboembolism events.

Cuban Sugar Cane Wax Alcohol Exhibited Enhanced Antioxidant, Anti-Glycation and Anti-Inflammatory Activity in Reconstituted High-Density Lipoprotein (rHDL) with Improved Structural and Functional Correlations: Comparison of Various Policosanols.

Policosanols from various sources, such as sugar cane, rice bran, and insects, have been marketed to prevent dyslipidemia, diabetes, and hypertension by increasing the blood high-density lipoproteins cholesterol (HDL-C) levels. On the other hand, there has been no study on how each policosanol influences the quality of HDL particles and their functionality. Reconstituted high-density lipoproteins (rHDLs) with apolipoprotein (apo) A-I and each policosanol were synthesized using the sodium cholate dialysis method to compare the policosanols in lipoprotein metabolism. Each rHDL was compared regarding the particle size and shape, antioxidant activity, and anti-inflammatory activity in vitro and in zebrafish embryos. This study compared four policosanols including one policosanol from Cuba (Raydel® policosanol) and three policosanols from China (Xi'an Natural sugar cane, Xi'an Realin sugar cane, and Shaanxi rice bran). The synthesis of rHDLs with various policosanols (PCO) from Cuba or China using a molar ratio of 95:5:1:1 with palmitoyloleoyl phosphatidylcholine (POPC): free cholesterol (FC): apoA-I:PCO (wt:wt) showed that rHDL containing Cuban policosanol (rHDL-1) showed the largest particle size and the most distinct particle shape. The rHDL-1 showed a 23% larger particle diameter and increased apoA-I molecular weight with a 1.9 nm blue shift of the maximum wavelength fluorescence than rHDL alone (rHDL-0). Other rHDLs containing Chinese policosanols (rHDL-2, rHDL-3, and rHDL-4) showed similar particle sizes with an rHDL-0 and 1.1-1.3 nm blue shift of wavelength maximum fluorescence (WMF). Among all rHDLs, the rHDL-1 showed the strongest antioxidant ability to inhibit cupric ion-mediated LDL oxidation. The rHDL-1-treated LDL showed the most distinct band intensity and particle morphology compared with the other rHDLs. The rHDL-1 also exerted the highest anti-glycation activity to inhibit the fructose-mediated glycation of human HDL2 with the protection of apoA-I from proteolytic degradation. At the same time, other rHDLs showed a loss of anti-glycation activity with severe degradation. A microinjection of each rHDL alone showed that rHDL-1 had the highest survivability of approximately 85 ± 3%, with the fastest developmental speed and morphology. In contrast, rHDL-3 showed the lowest survivability, around 71 ± 5%, with the slowest developmental speed. A microinjection of carboxymethyllysine (CML), a pro-inflammatory advanced glycated end product, into zebrafish embryos resulted in severe embryo death of approximately 30 ± 3% and developmental defects with the slowest developmental speed. On the other hand, the phosphate buffered saline (PBS)-injected embryo showed 83 ± 3% survivability. A co-injection of CML and each rHDL into adult zebrafish showed that rHDL-1 (Cuban policosanol) induced the highest survivability, around 85 ± 3%, while rHDL-0 showed 67 ± 7% survivability. In addition, rHDL-2, rHDL-3, and rHDL-4 showed 67 ± 5%, 62 ± 37, and 71 ± 6% survivability, respectively, with a slower developmental speed and morphology. In conclusion, Cuban policosanol showed the strongest ability to form rHDLs with the most distinct morphology and the largest size. The rHDL-containing Cuban policosanol (rHDL-1) showed the strongest antioxidant ability against LDL oxidation, anti-glycation activity to protect apoA-I from degradation, and the highest anti-inflammatory activity to protect embryo death under the presence of CML.

Inheritance of paternal DNA damage by histone-mediated repair restriction.

How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegans strains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. Paternal DNA double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1 generation from ionizing radiation-treated P0 males, consequently improving the viability of the F2 generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.

Role of the hypothalamus in ghrelin effects on reproduction: sperm function and sexual behavior in male mice.

In brief: Ghrelin signals to the hypothalamus inhibit reproduction during times of food scarcity. In this study, we demonstrate that ghrelin impairs sperm quality in male mice. Abstract: Ghrelin (GHRL) is an orexigenic peptide that has been investigated as one of the signals responsible for the reproductive performance of mammals under fluctuating metabolic conditions. Central GHRL administration impairs spermatogenesis in mice by regulating the hypothalamic-pituitary-gonadal axis function. In the present study, the hypothalamus role as a mediator of GHRL effects on sperm fertilizing capacity and male sexual behavior was evaluated. After 42 days of hypothalamic GHRL infusion or artificial cerebrospinal fluid, in vitro and in vivo sperm fertilizing capacity, testicular α-tubulin, speriolin gene expression and spermatic α-tubulin protein were evaluated. Hypothalamic expression of genes Kiss1, Gpr54 and Gnrh was also studied. The second group of animals was infused with one time only GHRL or artificial cerebrospinal fluid into the hypothalamus to evaluate the effects on sexual behavior. Results demonstrated that chronic GHRL administration to male mice significantly increased the percentages of pre-implantation embryo loss and the number of post-implantation embryo loss. In relation to the gene expression, our results show a relative decrease of Kiss1, Gpr54 and Spatc1. Although no significant differences were observed in the quantitative expression of α-tubulin protein, qualitative changes in its expression pattern were observed. In addition, a dual effect on sexual behavior was observed: 40% of the treated animals showed a significant reduction in the number of mounts and intromissions, while a 60% showed a significant decrease in ejaculation latency vs control animals. In conclusion, our results provide evidence that central GHRL administration possibly induces failure in embryo development and/or implantation in the females mated with treated males, possibly because of a negative effect in the α-tubulin pattern.

Should we stop screening for chronic endometritis?

Chronic endometritis is a poorly understood infectious or inflammatory process, potentially disrupting the correct implantation of a human embryo (Puente et al., 2020). The exact prevalence is a subject of discussion and ranges across the available literature from 2% to almost 60%, with a higher suspicion of the condition being present in women with recurrent early pregnancy loss and recurrent implantation failure (Puente et al., 2020). The impact of chronic endometritis on reproductive outcomes following IVF remains questionable given the lack of proper data convincingly showing an improvement after diagnosis and treatment. This article aims to provide the reader with a critical appraisal of current diagnostic methods, treatments and patient populations to be tested for chronic endometritis.

ATG9A prevents TNF cytotoxicity by an unconventional lysosomal targeting pathway.

Cell death induced by tumor necrosis factor (TNF) can be beneficial during infection by helping to mount proper immune responses. However, TNF-induced death can also drive a variety of inflammatory pathologies. Protectives brakes, or cell-death checkpoints, normally repress TNF cytotoxicity to protect the organism from its potential detrimental consequences. Thus, although TNF can kill, this only occurs when one of the checkpoints is inactivated. Here, we describe a checkpoint that prevents apoptosis through the detoxification of the cytotoxic complex IIa that forms upon TNF sensing. We found that autophagy-related 9A (ATG9A) and 200kD FAK family kinase-interacting protein (FIP200) promote the degradation of this complex through a light chain 3 (LC3)-independent lysosomal targeting pathway. This detoxification mechanism was found to counteract TNF receptor 1 (TNFR1)-mediated embryonic lethality and inflammatory skin disease in mouse models.

Dysregulation in Multiple Transcriptomic Endometrial Pathways Is Associated with Recurrent Implantation Failure and Recurrent Early Pregnancy Loss.

Overlapping disease aetiologies associated with multiple altered biological processes have been identified that change the endometrial function leading to recurrent implantation failure (RIF) and recurrent early pregnancy loss (REPL). We aimed to provide a detailed insight into the nature of the biological malfunction and related pathways of differentially expressed genes in RIF and REPL. Endometrial biopsies were obtained from 9 women experiencing RIF, REPL and control groups. Affymetrix microarray analysis was performed to measure the gene expression level of the endometrial biopsies. Unsupervised clustering of endometrial samples shows scattered distribution of gene expression between the RIF, REPL and control groups. 2556 and 1174 genes (p value < 0.05, Fold change > 1.2) were significantly altered in the endometria of RIF and REPL patients' group, respectively compared to the control group. Downregulation in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the differentially expressed genes (DEGs) in RIF and REPL including ribosome and oxidative phosphorylation pathways. Gene Ontology (GO) analysis revealed ribosomes and mitochondria inner membrane as the most significantly downregulated cellular component (CC) affected in RIF and REPL. Determination of the dysregulated genes and related biological pathways in RIF and REPL will be key in understanding their molecular pathology and of major importance in addressing diagnosis, prognosis, and treatment issues

Temporal changes in cyclinD-CDK4/CDK6 and cyclinE-CDK2 pathways: implications for the mechanism of deficient decidualization in an immune-based mouse model of unexplained recurrent spontaneous abortion.

BACKGROUND: Deficient endometrial decidualization has been associated with URSA. However, the underlying mechanism is poorly understood. This study aimed to investigate the temporal cytokine changes and the involvement of CyclinD-CDK4/6 and CyclinE-CDK2 pathways in the regulation of the G1 phase of the cell cycle during decidualization in a murine model of URSA. METHODS: Serum and decidual tissues of mice were collected from GD4 to GD8. The embryo resorption and abortion rates were observed on GD8 and the decidual tissue status was assessed. In addition, PRL, Cyclin D, CDK6, CDK4, Cyclin E, CDK2 expression in mice were measured. RESULTS: URSA mice showed high embryo resorption rate and PRL, Cyclin D, Cyclin E CDK2, CDK4, CDK6 down-regulation during decidualization. The hyperactivated Cyclin D-CDK4/CDK6 and cyclin E/CDK2 pathways inhibit the decidualization process and leading to deficient decidualization. CONCLUSION: Insufficient decidualization is an important mechanism of URSA. which is related to the decrease of Cyclin D、Cyclin E、 CDK2、CDK4 and CDK6 in decidualization process of URSA.