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Cryptochrome (Cry) in some species could act as a quantum senser to detect the inclination angle of geomagnetic field, the function of which attributes the magnetic sensitivity of spins of unpaired electrons in radical pair (RP) in CRY generated by blue light irradiation. However, the effect of blue light on the structure and molecular behavior of Cry has not been well investigated. We conducted the size exclusion chromatography (SEC) and small-angle X-ray scattering (SAXS) analyses to inspect the molecular structure and behavior of cryptochrome 4a (ErCry4a) from European robin, a representative magnetosensory animal. The results indicated that ErCry4a could form flat-shape oligomers. Moreover, blue light irradiation induced the contraction of the ErCry4a molecule at the monomer scale and simultaneously accelerated the two-dimensional oligomerization of ErCry4a. This oligomerization may enhance the regularity of the two-dimensional arrangement of ErCry4a molecules, providing a positive effect for detecting the inclination angle.
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OBJECTIVES: Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase. METHODS: We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect. RESULTS: Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients. CONCLUSION: This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.
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A intermediate multidomain state and large crystallographic tilting of 1.78° for the (hh0)pc planes of a (001)pc-oriented single-domain Mn-doped BiFeO3 (BFMO) thin film were found when an electric field was applied along the [110]pc direction. The anomalous crystallographic tilting was caused by ferroelastic domain switching of the 109° domain switching. In addition, ferroelastic domain switching occurred via an intermediate multidomain state. To investigate these switching dynamics under an electric field, we used in situ fluorescent X-ray induced Kossel line pattern measurements with synchrotron radiation. In addition, in situ inverse X-ray fluorescence holography (XFH) experiments revealed that atomic displacement occurred under an applied electric field. We attributed the atomic displacement to crystallographic tilting induced by a converse piezoelectric effect. Our findings provide important insights for the design of piezoelectric and ferroelectric materials and devices.
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The local structure of the two-dimensional van der Waals material, Fe5-xGeTe2, which exhibits unique structural/magnetic phase transitions, was investigated by Te K-edge extended X-ray absorption fine structure (EXAFS) and Te Kα X-ray fluorescence holography (XFH) over a wide temperature range. The formation of a trimer of Te atoms at low temperatures has been fully explored using these methods. An increase in the Te-Fe distance at approximately 150 K was suggested by EXAFS and presumably indicates the formation of a Te trimer. Moreover, XFH displayed clear atomic images of Te atoms. Additionally, the distance between the Te atoms shortened, as confirmed from the atomic images reconstructed from XFH, indicating the formation of a trimer of Te atoms, i.e., a charge-ordered superstructure. Furthermore, Te Kα XFH provided unambiguous atomic images of Fe atoms occupying the Fe1 site; the images were not clearly observed in the Ge Kα XFH that was previously reported because of the low occupancy of Fe and Ge atoms. In this study, EXAFS and XFH clearly showed the local structure around the Te atom; in particular, the formation of Te trimers caused by charge-ordered phase transitions was clearly confirmed. The charge-ordered phase transition is fully discussed based on the structural variation at low temperatures, as established from EXAFS and XFH.
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Fe5-xGeTe2 is a two-dimensional van der Waals material that exhibits ferromagnetic order with a high Curie temperature (TC) of around room temperature. In addition to TC, two magnetic transitions occur with decreasing temperature, and a charge-ordered state is observed at low temperatures. We employed Ge Kα X-ray fluorescence holography (XFH) for Fe5-xGeTe2 to directly investigate the local structure in the charge-ordered state, i.e., the 3×3 superstructure. The Ge Kα XFH results revealed local atomic structures around the Ge atom, thus clarifying the simultaneous locations and arrangements of the Te, Fe, and Ge atoms. The atomic positions relative to the Ge atom are useful for understanding the coexistence of the ideal 1 × 1 structure and 3×3 superstructure found in the charge-ordered state.
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Insulin-like growth factor-1 (IGF-1) plays a crucial role in follicular growth and stimulates steroid hormone production in bovine follicles. Steroid hormones are synthesized through the actions of steroidogenic enzymes, specifically STAR, CYP11A1, HSD3B, and CYP19A1 in both theca cells (TCs) and granulosa cells (GCs), under the influence of gonadotropins. Particularly, estradiol 17ß (E2) assumes a central role in follicular development and selection by activating estrogen receptors ß (ESR2) in GCs. We assessed ESR2 mRNA expression in GCs of developing follicles and investigated the impact of IGF-1 on the mRNA expression of ESR2, CYP19A1, FSHR, and LHCGR, STAR, CYP11A1, and HSD17B in cultured GCs and TCs, respectively. Additionally, we assessed the influence of IGF-1 on androstenedione (A4), progesterone (P4), and testosterone (T) production in TCs. Small-sized follicles (< 6 mm) exhibited the highest levels of ESR2 mRNA expression, whereas medium-sized follicles (7-8 mm) displayed higher levels than large-sized follicles (≥ 9 mm) (P < 0.05). IGF-1 increased the mRNA expression of ESR2, CYP19A1, and FSHR in GCs of follicles of both sizes, except for FSHR mRNA in medium-sized follicles (P < 0.05). IGF-1 significantly elevated mRNA expression of LHCGR, STAR, CYP11A1, and CYP17B in TCs of small- and medium-sized follicles (P < 0.05). Moreover, IGF-1 augmented the production of A4 and P4 but had no impact on T production in TCs of small- and medium-sized follicles. Taken together, our findings indicate that IGF-1 upregulates steroidogenic enzymes and steroid hormone production, underscoring the crucial role of IGF-1 in follicle development and selection.
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Hormonas Esteroides Gonadales , Factor I del Crecimiento Similar a la Insulina , Folículo Ovárico , Animales , Bovinos , Femenino , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/metabolismo , Estradiol/metabolismo , Células de la Granulosa/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Folículo Ovárico/metabolismo , Progesterona/farmacología , Receptores de Estradiol/metabolismo , ARN Mensajero/metabolismo , Hormonas Esteroides Gonadales/metabolismoRESUMEN
In brief: Interferon tau (IFNT) stimulates lysosomal activation via the Janus-activated kinase in peripheral blood leukocytes during pregnancy recognition. IFNT-mediated lysosomal activation could serve as a novel marker for early pregnancy in cattle. Abstract: IFNT is important in establishing pregnancy in ruminants. Secreted IFNT in the uterus induces the expression of an interferon-stimulated gene (ISG) in uterine tissues and peripheral blood leukocytes (PBLs). In our previous study, increased lysosome and lysosomal cathepsin (CTS) activity and mRNA expression were observed in PBLs of pregnant cows on day 18 of pregnancy. However, the mechanism of IFNT stimulation in PBLs is unclear. Here, we explored the IFNT-mediated lysosomal activation mechanisms in PBLs during early pregnancy in dairy cows. PBLs collected from the peripheral blood of Holstein cows on day 18 post artificial insemination, after confirmation of their pregnancy status, were used to detect the expression of lysosomal-associated membrane protein (LAMP) 1, 2, CTSB and CTSK. Expression of all genes was significantly higher in PBLs of pregnant cows than in nonpregnant cows. In vitro IFN-mediated stimulation of PBLs collected from cows that did not undergo AI significantly increased lysosomal acidification and expression of LAMP1 and 2, as well as the activities of CTSB and CTSK. Immunodetection analysis showed an increase in LAMP1 and CTSK levels in the PBLs of day 18 pregnant cows. JAK inhibitor significantly decreased lysosomal acidification, CTSK activity, LAMP1, 2, and CTSK expression in the presence of IFNT. These results suggest that IFNT regulates lysosomal function via a type 1IFN-mediated pathway in PBLs during pregnancy recognition.
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Interferón Tipo I , Leucocitos , Femenino , Bovinos , Embarazo , Animales , Leucocitos/metabolismo , Interferón Tipo I/metabolismo , Transducción de Señal , LisosomasRESUMEN
Inelastic x-ray scattering (IXS) measurements were performed for observing the excitation of bulk plasmons in metallic liquid silicon (Si). The peak due to plasmon excitation was observed within the energy loss around 17 eV. Combined with IXS data of crystalline Si measured at several elevated temperatures, it was found that temperature dependence of the excitation energy in the crystalline solid state is explained by the electron gas including the band gap effect, whereas in the metallic liquid state near the melting point, it exhibits a departure from the electron gas; the plasmon energy takes a lower value than that of the electron gas. Such lowering of plasmon energies is reasonably explained by a model incorporating semiconducting component to the electron gas. Non-simple metallic nature in liquid silicon is highlighted by the observation of electron collective dynamics.
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Point defect chemistry strongly affects the fundamental properties of materials and has a decisive impact on device performance. The Group-V dopant is prominent acceptor species with high hole concentration in CdTe; however, its local atomic structure is still not clear owing to difficulties in definitive measurements and discrepancies between experimental observations and theoretical models. Herein, we report on direct observation of the local structure for the As dopant in CdTe single crystals by the X-ray fluorescence holography (XFH) technique, which is a powerful tool to visualize three-dimensional atomic configurations around a specific element. The XFH result shows the As substituting on both Cd (AsCd) and Te (AsTe) sites. Although AsTe has been well known as a shallow acceptor, AsCd has not attracted much attention and been discussed so far. Our results provide new insights into point defects by expanding the experimental XFH study in combination with theoretical first-principles studies in II-VI semiconductors.
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Superovulation (SOV) treatment of cows results in unovulated follicles and inconsistent quality of the recovered embryos. It has been demonstrated that luteinizing hormone (LH) secretion is suppressed during SOV treatment of cows, which may cause insufficient follicle development and variation in the development of recovered embryos and unovulated follicles. Pulsatile gonadotropin-releasing hormone/LH secretion is controlled by the activity of kisspeptin, neurokinin B and dynorphin (KNDy) neurons in the arcuate nucleus in many mammals. As neurokinin B promotes the activity of KNDy neurons, we hypothesized that senktide, a neurokinin B receptor agonist, has the potential as a therapeutic drug to improve the ovulation rate and quality of recovered embryos in SOV-treated cows via stimulation of LH secretion. Senktide was administered intravenously (30 or 300 nmol/min) for 2 h, beginning from 72 h after the start of SOV treatment. LH secretion was examined before and after administration, and embryos were collected 7 d after estrus. Senktide administration increased LH secretion in SOV-treated cows. The ratios of code 1, code 1 and 2, and blastocyst stage embryos to recovered embryos were increased by senktide (300 nmol/min) administration. Moreover, the mRNA levels of MTCO1, COX7C, and MTATP6 were upregulated in recovered embryos of senktide (300 nmol/min)-administered animals. These results indicate that the administration of senktide to SOV-treated cows enhances LH secretion and upregulates the expression of genes involved in mitochondrial metabolism in embryos, thereby improving embryo development and embryo quality.
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Neuroquinina B , Receptores de Neuroquinina-3 , Femenino , Bovinos , Animales , Receptores de Neuroquinina-3/agonistas , Neuroquinina B/metabolismo , Hormona Luteinizante/farmacología , Hormona Luteinizante/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Dinorfinas/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Kisspeptinas/metabolismo , Mamíferos/metabolismoRESUMEN
X-ray fluorescence holography (XFH) is a powerful atomic resolution technique capable of directly imaging the local atomic structure around atoms of a target element within a material. Although it is theoretically possible to use XFH to study the local structures of metal clusters in large protein crystals, the experiment has proven difficult to perform, especially on radiation-sensitive proteins. Here, the development of serial X-ray fluorescence holography to allow the direct recording of hologram patterns before the onset of radiation damage is reported. By combining a 2D hybrid detector and the serial data collection used in serial protein crystallography, the X-ray fluorescence hologram can be directly recorded in a fraction of the measurement time needed for conventional XFH measurements. This approach was demonstrated by obtaining the Mn Kα hologram pattern from the protein crystal Photosystem II without any X-ray-induced reduction of the Mn clusters. Furthermore, a method to interpret the fluorescence patterns as real-space projections of the atoms surrounding the Mn emitters has been developed, where the surrounding atoms produce large dark dips along the emitter-scatterer bond directions. This new technique paves the way for future experiments on protein crystals that aim to clarify the local atomic structures of their functional metal clusters, and for other related XFH experiments such as valence-selective XFH or time-resolved XFH.
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Holografía , Rayos X , Holografía/métodos , Fluorescencia , Proteínas , Radiografía , Cristalografía por Rayos XRESUMEN
Prostaglandin E2 (PGE2) is considered as a luteoprotective factor, influencing the corpus luteum during the early pregnant period in the bovine species. Cyclic AMP (cAMP) is activated in response to PGE2 and plays a role in many physiological processes. The maternal recognition signal, interferon τ (IFNT), induces PGE2 secretion from the endometrial epithelial cells, the function of which in stroma cells has not been completely understood. In this study, PGE2 was found to activate cAMP in the bovine endometrial stromal cells (STRs). STRs were then treated with forskolin to activate the cAMP signaling, from which RNA extracted was subjected to global expression analysis. Transcripts related to transcription regulatory region nucleic acid binding of molecular function, nucleus of cellular component, and mitotic spindle organization of biological processes were up-regulated in cAMP-activated bovine STRs. An increase in the transcription factors, NFIL3, CEBPA, and HIF1A via the cAMP/PKA/CREB signaling pathway in the bovine STRs was also found by qPCR. Knockdown of NFIL3, CEBPA, or HIF1A blocked forskolin-induced PTGS1/2 and IGFBP1/3 expression. Moreover, NFIL3 and CEBPA were localized in endometrial stroma on pregnant day 17 (day 0 = estrous cycle), but not on cyclic day 17. These observations indicated that uterine PGE2 induced by conceptus IFNT is involved in the early pregnancy-related gene expression in endometrial stromal cells, which could facilitate pregnancy establishment in the bovine.
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Dinoprostona , Células del Estroma , Embarazo , Femenino , Bovinos , Animales , Dinoprostona/metabolismo , Colforsina/farmacología , Colforsina/metabolismo , Células del Estroma/metabolismo , Células Epiteliales/metabolismoRESUMEN
To investigate possible causes of reproductive failure, we conducted global endometrial gene expression analyses in fertile and subfertile cows. Ingenuity pathway analysis showed that RICTOR and SIRT3 are significant upstream regulators for highly expressed genes in fertile cows, and are predicted to be activated upstream regulators of normal mitochondrial respiration. Canonical pathway analysis revealed that these highly expressed genes are involved in the activation of mitochondrial oxidative phosphorylation. Therefore, in subfertile cows, the inactivation of RICTOR and SIRT3 may correlate with decreased capacity of mitochondrial respiration. Furthermore, the expression levels of most mitochondrial DNA genes and nuclear genes encoding mitochondrial proteins were higher in subfertile cows. The mitochondrial DNA copy number was significantly higher in the endometrium of subfertile cows, whereas the ATP content did not differ between fertile and subfertile cows. Quantitative reverse transcription-PCR analysis demonstrated that the expression of PGC1a, TFAM, MFN1, FIS1, and BCL2L13 were significantly lower in subfertile cows. In addition, transmission electron microscopy images showed mitochondrial swelling in the endometrial cells of the subfertile cow. These results suggest that poor-quality mitochondria accumulate in the endometrium owing to a reduced capacity for mitochondrial biogenesis, fusion, fission, and degradation in subfertile cows, and may contribute to infertility.
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Infertilidad , Sirtuina 3 , Femenino , Bovinos , Animales , Biogénesis de Organelos , Sirtuina 3/metabolismo , Endometrio/metabolismo , Infertilidad/metabolismo , ADN Mitocondrial/genética , Factores de Transcripción/metabolismoRESUMEN
In brief: Spontaneous contraction of oviductal smooth muscle is essential for gamete transport to the fertilization site in mammals. This study sheds light on the mechanism of elevated contraction amplitude in the bovine oviductal isthmus just before ovulation. Abstract: Rhythmic contraction of the oviducts is essential for transporting gametes and embryos at peri-ovulation; however, its regulatory mechanism during the estrous cycle is unclear. Meanwhile, it is reported that ion currents regulate muscle contraction. Our study aimed to clarify the involvement of ion channels and gap junctions in regulating oviductal motility during the estrous cycle in cattle. The isthmic sections of bovine oviducts collected just after ovulation (0-4 days after ovulation), at the mid-late luteal stage (10-17 days), and at the follicular stage (1-3 days before ovulation) were used in the experiments. The frequency and amplitude of contraction of the oviductal strips in the longitudinal direction were examined using the Magnus system. The frequency was not different among the estrous stages. Conversely, the amplitude was significantly higher at the follicular stage. The blockers of voltage-dependent calcium channels, both IP3 receptor and ryanodine receptors, chloride channel, and gap junction reduced the amplitude. Additionally, mRNA and protein expression of GJA1, a component of the gap junction, in the smooth muscle tissues of the oviductal isthmus were significantly higher in the follicular stage. In addition, estradiol-17ß (E2; 1.0 ng/mL) significantly increased GJA1 mRNA expression in cultured smooth muscle tissues after 24 h and GJA1 protein expression in cultured smooth muscle cells after 48 h. These results suggest that local levels of E2 in the oviductal isthmus ipsilateral to an ovary with a dominant follicle support the increased contraction amplitude of bovine ipsilateral oviducts by elevating the gap junction expression.
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Trompas Uterinas , Oviductos , Femenino , Humanos , Bovinos , Animales , Oviductos/metabolismo , Trompas Uterinas/metabolismo , Ovulación , Uniones Comunicantes/metabolismo , ARN Mensajero/metabolismo , Mamíferos/metabolismoRESUMEN
Doping a typical topological insulator, Bi2Se3, with Ag impurity causes a semiconductor-metal (S-M) transition at 35 K. To deepen the understanding of this phenomenon, structural and transport properties of Ag-doped Bi2Se3 were studied. Single-crystal X-ray diffraction (SC-XRD) showed no structural transitions but slight shrinkage of the lattice, indicating no structural origin of the transition. To better understand electronic properties of Ag-doped Bi2Se3, extended analyses of Hall effect and electric-field effect were carried out. Hall effect measurements revealed that the reduction of resistance was accompanied by increases in not only carrier density but carrier mobility. The field-effect mobility is different for positive and negative gate voltages, indicating that the EF is located at around the bottom of the bulk conduction band (BCB) and that the carrier mobility in the bulk is larger than that at the bottom surface at all temperatures. The pinning of the EF at the BCB is found to be a key issue to induce the S-M transition, because the transition can be caused by depinning of the EF or the crossover between the bulk and the top surface transport.
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The oviductal epithelium consists of ciliated and non-ciliated cells, and their numbers vary depending on the segment of the oviduct and stage of the estrous cycle. Compared with the ampulla, fewer cyclic changes in the number of the two types of cells occur in the isthmus. Recently, we have reported that the epithelium in the ampullary oviduct is composed of many types of cells during different translational/transcriptional states, and their numbers change during the estrous cycle. However, detailed information regarding the epithelial cell subtypes lining the isthmic oviductal epithelium has not yet been reported. In this study, we aimed to identify the epithelial subtypes in the isthmus of the oviduct using immunohistochemistry. Some similarities and differences were observed between the ampulla and isthmus. As observed in the ampulla, epithelial cells of the isthmus expressed either FOXJ1 (ciliogenesis marker) or PAX8 (non-ciliated cell marker). The estrous cycle affected the number of Ki67+ cells but not that of ciliated cells. A relatively high rate of Ki67+ cells (60%) was observed at 1-4 days after the ovulation. Interestingly, unlike the ampulla, Ki67+/FOXJ1+ cells (12.6 ± 1.1%) were discovered in the isthmus. Double staining for Ki67 with FOXJ1, PAX8, or Centrin-1 (a centriole marker) revealed that Centrin-1 was localized on the apical surface of some Ki67+/FOXJ1+ cells. In conclusion, some epithelial cell subtypes exist in the isthmus of the oviduct and isthmus-specific cell subtypes have been identified. These region-specific cells may provide functional and morphological differences between the ampulla and isthmus of the oviduct.
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Trompas Uterinas , Oviductos , Animales , Bovinos , Femenino , Humanos , Células Epiteliales , Epitelio , Trompas Uterinas/metabolismo , Antígeno Ki-67 , Oviductos/metabolismoRESUMEN
X-ray fluorescence holography (XFH) is a relatively new technique capable of providing unique three-dimensional structural information around specific atoms that act as a light source in crystalline samples. So far, XFH has typically been applied to inorganic materials such as dopants in metals and semiconductors. Here, we investigate the possibility of using XFH to visualize the metal active site in sperm whale myoglobin (Mb), a monomeric oxygen storage heme protein. We demonstrate that the atomic images reconstructed from the hologram data of crystals of carbonmonoxy myoglobin (MbCO) are moderately consistent with the crystal structure, which is also determined in this study by X-ray crystallography in the near-atomic resolution, as well as simulation results. These results open up a new avenue for the application of XFH to local atomic and electronic structure imaging of metal-sites in biomolecules.
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Holografía , Mioglobina , Mioglobina/química , Rayos X , Holografía/métodos , Cristalografía por Rayos X , Hemo/química , Metales , Conformación ProteicaRESUMEN
Early embryo and sperm transport through the oviductal isthmus depends on the contraction and relaxation of the smooth muscle layers. Dysfunction of the oviduct transport is considered to be one of the causes of infertility. For human infertility, Chinese medicine is used in East Asia. Although there are many clinical reports regarding Tokishakuyakusan (TSS), there is little scientific evidence that it affects infertility. In this study, we investigated the effect of TSS on bovine oviductal contraction and relaxation via the G protein-coupled estrogen receptor 1 (GPER1). We collected bovine oviductal isthmic tissues at four stages of the estrous cycle, classified based on a macroscopic observation of the ovary. The Magnus method was used to monitor longitudinal contractility (frequency, contraction force, and tonus). The effects of TSS solution, GPER1 agonist (G-1), and antagonist (G-15) on oviductal contractility were examined. The protein expression level of GPER1 in the oviductal isthmic smooth muscle of each estrous stage was assessed by Western blotting. Although TSS did not affect frequency and contraction force, the tonus was significantly increased by TSS or G-1 at all stages (p < 0.05), and the effect was especially highest at days 1-4 after ovulation. The addition of G-15 significantly suppressed the TSS-induced increase of oviductal tonus at all stages (p < 0.05). There was no significant difference in GPER1 protein expression among the estrous stages. TSS affects oviductal contractility by increasing tonus via GPER1, and it may accelerate gamete and early embryo transport by contracting the oviducts longitudinally.
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Receptor alfa de Estrógeno , Infertilidad , Animales , Bovinos , Medicamentos Herbarios Chinos , Femenino , Proteínas de Unión al GTP , Humanos , Masculino , Medicina Tradicional China , Oviductos , SemenRESUMEN
In ruminants, uterine glands play key roles in the establishment of pregnancy by secreting various factors into the uterine lumen. Although a three-dimensional (3D) culture system has been used for investigating cellular functions in vitro, the detailed functions of uterine gland have not been fully elucidated. In this study, we examined the benefits of 3D culture system to examine the innate functions of bovine uterine glands. Isolated bovine uterine glands were cultured on Matrigel (2D) or in Matrigel (3D), respectively, and the mRNA levels of secreted proteins (SERPINA14, MEP1B, APOA1, ARSA, CTGF, and SPP1) were measured in isolated and cultured uterine glands. The protein expression of estrogen receptor ß (ERß) and progesterone receptor (PR) and the establishment of apico-basal polarity were examined. In isolated uterine glands, the mRNA levels of secreted proteins changed during the estrous cycle. Although uterine glands cultured in both 2D and 3D expressed ERß and PR, progesterone did not affect SERPINA14 mRNA expression. The expression of APOA1 mRNA in 2D cultured uterine glands did not respond to estrogen and progesterone. Additionally, the mRNA levels of secreted proteins in the 3D culture system were significantly higher than those in the 2D culture system, which might be attributed to the different cellular morphology between them. The locations of ZO-1 and ß-catenin in 2D cultured uterine glands were disordered compared with 3D cultured uterine glands. These results showed that the hormonal responsiveness of secreted factor expression and cellular morphology were different between 2D and 3D cultured bovine uterine glands.
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Receptor beta de Estrógeno , Progesterona , Animales , Bovinos , Receptor beta de Estrógeno/metabolismo , Ciclo Estral , Femenino , Embarazo , Progesterona/metabolismo , ARN Mensajero/metabolismo , Útero/metabolismoRESUMEN
BACKGROUND: It is necessary to find reliable and appropriate predictors of primary response to anti-TNFα therapy (infliximab and adalimumab) in inflammatory bowel disease (IBD) so as to avoid treatment failure and select optimal treatment. The aim of this study is to reveal useful predictors of the response to anti-TNFα treatment from baseline to 2 months after initial administration of anti-TNFα for individual IBD patients using our pharmacokinetic and pharmacodynamic (PK/PD) model at the time of second administration. METHODS: We retrospectively analyzed 26 IBD patients who received anti-TNFα. In the PK/PD model, inflammation was assumed to be suppressed based on the action of anti-TNFα at the rate constant of Kanti-TNFα (day-1). Kanti-TNFα0 (day-1) is Kanti-TNFα in the absence of anti-TNFα. We expressed inflammation caused by factors not affected by the action of anti-TNFα using the rate constant Kelse (day-1). Using univariate and multivariate linear regressions, we statistically analyzed factors related to the improvement of disease activity index. RESULTS: The significant correlation between Kanti-TNFα0/Kelse and the improvement of disease activity index was shown in Crohn's disease patients (univariate: estimated value 2.4; P = 0.003; and multivariate: 1.8; P = 0.012) and ulcerative colitis patients (univariate: 0.12; P = 0.011), and no other factors were significant. CONCLUSION: This is the first study to present a useful predictor of primary response to anti-TNFα of individual IBD patients at second administration. The Kanti-TNFα0/Kelse ratio may help to select the optimal therapeutic drug and avoid the improper continuous administration of anti-TNFα in the induction phase.