The proper conceptus elongation in ruminants is critical for the successful placentation and esta... more The proper conceptus elongation in ruminants is critical for the successful placentation and establishment of pregnancy. We have previously shown that the trophectoderm-specific knockdown of LIN28A/B in day 9 ovine blastocysts resulted in increased let-7 miRNAs and reduced conceptus elongation at day 16 of gestation. In this current study, by transcriptome analysis of LIN28A knockdown (AKD) or LIN28B knockdown (BKD) trophectoderm (TE), we explored the downstream target genes of the LIN28-let-7 axis and their roles in the placental and fetal development. We identified 449 differentially expressed genes (DEGs) in AKD TE and 1214 DEGs in BKD TE compared to non-targeting control (NTC). Our analysis further revealed that 210 downregulated genes in AKD TE and 562 downregulated genes in BKD TE were the potential targets of let-7 miRNAs. Moreover, 16 downregulated genes in AKD TE and 57 downregulated and 7 upregulated genes in BKD TE were transcription factors. The DEGs in AKD and BKD TE sh...
Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development... more Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced...
Mammalian reproductive health affects the entire reproductive cycle starting with the ovarian fun... more Mammalian reproductive health affects the entire reproductive cycle starting with the ovarian function through implantation and fetal growth. Various environmental and physiological factors contribute to disturbed reproductive health status leading to infertility problems in mammalian species. In the last couple of decades a significant number of studies have been conducted to investigate the transcriptome of reproductive tissues and organs in relation to the various reproductive health issues including endometritis, polycystic ovarian syndrome (PCOS), intrauterine growth restriction (IUGR), preeclampsia, and various age-associated reproductive disorders. Among others, the post-transcriptional regulation of genes by small noncoding miRNAs contributes to the observed transcriptome dysregulation associated with reproductive pathophysiological conditions. MicroRNAs as a class of non-coding RNAs are also known to be involved in various pathophysiological conditions either in cellular cy...
Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans... more Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans. The majority of pregnancy complications initiate due to abnormal placental development and function. During the last decade, the role of microRNAs (miRNAs) in regulating placental and fetal development has become evident. Dysregulation of miRNAs in the placenta not only affects placental development and function, but these miRNAs can also be exported to both maternal and fetal compartments and affect maternal physiology and fetal growth and development. Due to their differential expression in the placenta and maternal circulation during pregnancy complications, miRNAs can be used as diagnostic biomarkers. However, the differential expression of a miRNA in the placenta may not always be reflected in maternal circulation, which makes it difficult to find a reliable biomarker for placental dysfunction. In this review, we provide an overview of differentially expressed miRNAs in the placen...
Intrauterine growth restriction (IUGR) occurs in 15–20% of pig neonates and poses huge economic l... more Intrauterine growth restriction (IUGR) occurs in 15–20% of pig neonates and poses huge economic losses to the pig industry. IUGR piglets have reduced skeletal muscle growth, which may persist after birth. Prenatal muscle growth is regulated by complex molecular pathways that are not well understood. MicroRNAs (miRNAs) have emerged as the main regulators of vital pathways and biological processes in the body. This study was designed to identify miRNA–mRNA networks regulating prenatal skeletal muscle development in pigs. We performed an integrative miRNA–mRNA transcriptomic analysis in longissimus dorsi muscle from IUGR fetuses and appropriate for gestational age (AGA) fetuses at 63 days post conception. Our data showed that 47 miRNAs and 3257 mRNAs were significantly upregulated, and six miRNAs and 477 mRNAs were significantly downregulated in IUGR compared to AGA fetuses. Moreover, 47 upregulated miRNAs were negatively correlated and can potentially target 326 downregulated genes, w...
Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost... more Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost between fertilization and birth. Successful embryo implantation and placental development requires rapid proliferation, invasion, and migration of trophoblast cells. In recent years, microRNAs (miRNAs) have emerged as key regulators of molecular pathways involved in trophoblast function. A miRNA binds its target mRNA in the 3ʹ-untranslated region (3ʹ-UTR), causing its degradation or translational repression. Lethal-7 (let-7) miRNAs induce cell differentiation and reduce cell proliferation by targeting proliferation-associated genes. The oncoprotein LIN28 represses the biogenesis of mature let-7 miRNAs. Proliferating cells have high LIN28 and low let-7 miRNAs, whereas differentiating cells have low LIN28 and high let-7 miRNAs. In placenta, low LIN28 and high let-7 miRNAs can lead to reduced proliferation of trophoblast cells, resulting in abnormal placental development. In trophoblast ce...
LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferat... more LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which si...
Aims Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been imp... more Aims Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up‐regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression.Methods The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6‐hydroxychlorzoxazone in serum and urine were analysed by high‐performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase‐polymerase chain reaction.Results The mean ± s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentrat...
Malignant epithelioid tumors have been described in various organ systems, but are rarely seen in... more Malignant epithelioid tumors have been described in various organ systems, but are rarely seen in the brain. They are aggressive tumors and have high mortality. In certain cases, the immunohistochemistry (IHC) findings may not be sufficient to clarify the diagnosis. In these cases, next-generation genetic sequencing may play a role in clarifying the diagnosis. In addition to lab testing, a thorough history and physical exam are necessary to rule out other sources of the tumor such as melanoma. Patients presenting with neurological symptoms are cared for by a wide variety of physicians, hence it is important to raise awareness of rare tumors in order to provide timely and appropriate management and referral for these patients. We present the case of a middle-aged woman who was diagnosed with a 'malignant epithelioid neoplasm' of the brain, a rare variety of tumors. We also give the clinical course of this illness.
Stool, gastric biopsy, and serum samples were collected from 22 subjects. DNA from stool was extr... more Stool, gastric biopsy, and serum samples were collected from 22 subjects. DNA from stool was extracted, amplified, and hybridized with primers specific for the 16S rRNA gene of Helicobacter pylori. DNA from gastric biopsy specimens was analyzed similarly for comparison. ...
The proper conceptus elongation in ruminants is critical for the successful placentation and esta... more The proper conceptus elongation in ruminants is critical for the successful placentation and establishment of pregnancy. We have previously shown that the trophectoderm-specific knockdown of LIN28A/B in day 9 ovine blastocysts resulted in increased let-7 miRNAs and reduced conceptus elongation at day 16 of gestation. In this current study, by transcriptome analysis of LIN28A knockdown (AKD) or LIN28B knockdown (BKD) trophectoderm (TE), we explored the downstream target genes of the LIN28-let-7 axis and their roles in the placental and fetal development. We identified 449 differentially expressed genes (DEGs) in AKD TE and 1214 DEGs in BKD TE compared to non-targeting control (NTC). Our analysis further revealed that 210 downregulated genes in AKD TE and 562 downregulated genes in BKD TE were the potential targets of let-7 miRNAs. Moreover, 16 downregulated genes in AKD TE and 57 downregulated and 7 upregulated genes in BKD TE were transcription factors. The DEGs in AKD and BKD TE sh...
Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development... more Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced...
Mammalian reproductive health affects the entire reproductive cycle starting with the ovarian fun... more Mammalian reproductive health affects the entire reproductive cycle starting with the ovarian function through implantation and fetal growth. Various environmental and physiological factors contribute to disturbed reproductive health status leading to infertility problems in mammalian species. In the last couple of decades a significant number of studies have been conducted to investigate the transcriptome of reproductive tissues and organs in relation to the various reproductive health issues including endometritis, polycystic ovarian syndrome (PCOS), intrauterine growth restriction (IUGR), preeclampsia, and various age-associated reproductive disorders. Among others, the post-transcriptional regulation of genes by small noncoding miRNAs contributes to the observed transcriptome dysregulation associated with reproductive pathophysiological conditions. MicroRNAs as a class of non-coding RNAs are also known to be involved in various pathophysiological conditions either in cellular cy...
Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans... more Pregnancy complications are a major cause of fetal and maternal morbidity and mortality in humans. The majority of pregnancy complications initiate due to abnormal placental development and function. During the last decade, the role of microRNAs (miRNAs) in regulating placental and fetal development has become evident. Dysregulation of miRNAs in the placenta not only affects placental development and function, but these miRNAs can also be exported to both maternal and fetal compartments and affect maternal physiology and fetal growth and development. Due to their differential expression in the placenta and maternal circulation during pregnancy complications, miRNAs can be used as diagnostic biomarkers. However, the differential expression of a miRNA in the placenta may not always be reflected in maternal circulation, which makes it difficult to find a reliable biomarker for placental dysfunction. In this review, we provide an overview of differentially expressed miRNAs in the placen...
Intrauterine growth restriction (IUGR) occurs in 15–20% of pig neonates and poses huge economic l... more Intrauterine growth restriction (IUGR) occurs in 15–20% of pig neonates and poses huge economic losses to the pig industry. IUGR piglets have reduced skeletal muscle growth, which may persist after birth. Prenatal muscle growth is regulated by complex molecular pathways that are not well understood. MicroRNAs (miRNAs) have emerged as the main regulators of vital pathways and biological processes in the body. This study was designed to identify miRNA–mRNA networks regulating prenatal skeletal muscle development in pigs. We performed an integrative miRNA–mRNA transcriptomic analysis in longissimus dorsi muscle from IUGR fetuses and appropriate for gestational age (AGA) fetuses at 63 days post conception. Our data showed that 47 miRNAs and 3257 mRNAs were significantly upregulated, and six miRNAs and 477 mRNAs were significantly downregulated in IUGR compared to AGA fetuses. Moreover, 47 upregulated miRNAs were negatively correlated and can potentially target 326 downregulated genes, w...
Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost... more Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost between fertilization and birth. Successful embryo implantation and placental development requires rapid proliferation, invasion, and migration of trophoblast cells. In recent years, microRNAs (miRNAs) have emerged as key regulators of molecular pathways involved in trophoblast function. A miRNA binds its target mRNA in the 3ʹ-untranslated region (3ʹ-UTR), causing its degradation or translational repression. Lethal-7 (let-7) miRNAs induce cell differentiation and reduce cell proliferation by targeting proliferation-associated genes. The oncoprotein LIN28 represses the biogenesis of mature let-7 miRNAs. Proliferating cells have high LIN28 and low let-7 miRNAs, whereas differentiating cells have low LIN28 and high let-7 miRNAs. In placenta, low LIN28 and high let-7 miRNAs can lead to reduced proliferation of trophoblast cells, resulting in abnormal placental development. In trophoblast ce...
LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferat... more LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which si...
Aims Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been imp... more Aims Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up‐regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression.Methods The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6‐hydroxychlorzoxazone in serum and urine were analysed by high‐performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase‐polymerase chain reaction.Results The mean ± s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentrat...
Malignant epithelioid tumors have been described in various organ systems, but are rarely seen in... more Malignant epithelioid tumors have been described in various organ systems, but are rarely seen in the brain. They are aggressive tumors and have high mortality. In certain cases, the immunohistochemistry (IHC) findings may not be sufficient to clarify the diagnosis. In these cases, next-generation genetic sequencing may play a role in clarifying the diagnosis. In addition to lab testing, a thorough history and physical exam are necessary to rule out other sources of the tumor such as melanoma. Patients presenting with neurological symptoms are cared for by a wide variety of physicians, hence it is important to raise awareness of rare tumors in order to provide timely and appropriate management and referral for these patients. We present the case of a middle-aged woman who was diagnosed with a 'malignant epithelioid neoplasm' of the brain, a rare variety of tumors. We also give the clinical course of this illness.
Stool, gastric biopsy, and serum samples were collected from 22 subjects. DNA from stool was extr... more Stool, gastric biopsy, and serum samples were collected from 22 subjects. DNA from stool was extracted, amplified, and hybridized with primers specific for the 16S rRNA gene of Helicobacter pylori. DNA from gastric biopsy specimens was analyzed similarly for comparison. ...
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