Development of new GABA uptake inhibitors derived from proline or from pyrrolidin-2-yl acetic acid

GABA transporters GAT-1, GAT-2 and GAT-3 are new targets for drug design. The substitution of the nitrogen atoms in Nicopetic acid (11), Guvacine (12) and cis-4- Hydroxynicopetic acid (13) with appropriate bulky lipophilic groups resulted in very potent GABA uptake inhibitors for GAT-1 as well as for GAT-3. Pyrrolidine-2-acetic acid derivatives with the three N-substituents 24a-c (Scheme 54) also showed a highly potent inhibition at GAT-1 and GAT-3, respectively. My intention was to investigate how the potency of pyrrolindine-2-carboxylic acid derivatives and of pyrrolidine-2-acetic acid derivatives at GAT-1 and GAT-3 is influenced by the introduction of a hydroxy group or both of a hydroxy and a (4-methoxy)phenyl group at C-4. For this study, the N-substituents 24a-d were chosen. Thus, the four series of pyrrolidine derivatives 20-23 shown below were designed as potential GABA uptake inhibitors. L-trans-4-hydroxypyrrolidine [(2S,4R)-25] was chosen as a precursor, from which the four key intermediates (2S,4R)-38, (2R,4R)-38, (2S,4R)-86 and (2R,4R)-64 were synthesized. The known compounds (2S,4R)-38 and (2R,4R)-38 were prepared from (2S,4R)-25 according to literature procedures. N-protection of (2S,4R)-25 with Cbz group gave (2S,4R)-58 (90% yield). After a series of reactions electrolysis (97% yield), O-silyl protection (85%), nucleophilic addition of 1- ethoxy-1-(trimethylsilyloxy)ethene (cis-71 79%; trans-71 9%) and finally O-deprotection (88%) and N-deprotection (89%) (2R,4R)-64 was obtained in 46% overall yield [from (2S,4R)-25]. After the reaction conditions for the conversion of 70 into 71 have been optimized, the best stereoselectivity [a ratio of cis/trans 97:3; yield cis-71 74%, trans-(2S,4R)-71 1.7%] and a good yield of 88% (cis 79%, trans 9%) were achieved. BF3⋅Et2O appeared to be slightly better for a higher stereoselectivity than TiCl4. (2S,4R)-83 was obtained in 90% yield by protecting the hydroxy group of (2S,4R)-58. An Arndt-Eistert reaction (64% yield) starting from (2S,4R)-83 followed by a simultaneous N,Odeprotection (90% yield) of (2S,4R)-85 led to (2S,4R)-86 in 47% overall yield [from (2S,4R)- 25]. As illustrated in Scheme 58 and 59, (2S,4R)-38 and (2S,4R)-86, (2R,4R)-38 and (2R,4R)-64 were used as starting materials for the synthesis of the N-substituted target compounds (2S,4R)-40a-b, (2S,4S)-40a-b, (2R,4S)-40a-b, (2R,4R)-40a-b, (2S,4R)-89a-d, (2S,4S)-89a-d, (2R,4R)-89a-d and (2R,4S)-89a-d. N-alkylation of these four starting materials with the halides of 24a-d yielded the corresponding tertiary amines. Mitsunobu reactions gave access to the stereoisomers by inversion of the stereocenter at C-4 of the pyrrolidine ring. Finally upon hydrolysis, all the N-substituted pyrrolidine derivatives with a 2-carboxylic acid side chain or a 2-acetic acid side chain were obtained. In the same manners (scheme 58 and 59), the series 96 also were synthesized and finally their hydrogenolysis over Pd-C provided each of four stereoisomers 97. The N-substituted 4-oxopyrrolidine derivatives (2S)-52a-b and (2S)-100a-c (see Scheme 61) were prepared (81-92% yields) via Swern oxidation, and fortunately, the acid-sensitive Nsubstituent 24b was not affected. The N-Cbz-protected 4-oxopyrrolidine derivatives 60 and 108 (Scheme 61) were prepared in good yield (71-78%) via Jones’ oxidation, but in low yield (10-27%) via Swern oxidation. The addition reactions of the organometallic reagents to the N-substituted pyrrolidine derivatives 52a-b and (2S)-100b-c were carried out in two different ways. Depending on the starting material and the employed organometallic reagent, two different results were obtained: Under condition A [(4-MeOC6H4)MgBr at –78 °C in ether] the cis addition product (cis refers to the ester group) was formed as the major diastereomer and a good diastereoselectivity was achieved (cis/trans addition from 79:21 to 89:11; total yields 45- 65%); Under condition B [(4-MeOC6H4)MgBr/CeCl3 at –78 °C in THF], the trans addition product was obtained as a major diastereomer (cis/trans addition from 30:70 to 17:83; total yields 32-48%). In the case of the N-Cbz-protected pyrrolidine derivative (2S)-60, a single diastereomer (2S,4R)-61 was formed in 56% yield under condition B [(4-MeOC6H4)MgBr/CeCl3 in THF at – 60 °C for 4 h]. However, for the homologous (2S)-108 under the same conditions, (2S,4R)- 109 (25% yield) and a side product (5%) resulting from a simultaneous addition to the ester group were formed. The addition of (4-MeOC6H4)MgBr to (2S)-108 (at –78 °C in ether for 4 h), however, led to (2S,4R)-109 (38% yield) as a single diastereomer. Each of the N-substituted stereoisomers from the reaction above was subjected to a basic hydrolysis, which was followed by hydrogenolysis over Pd-C, where necessary, to afford the free amino acids (70-98% yields). Via the similar synthetic procedures as described above, the rest of the stereoisomers (2R,4R)- 57a-b and (2R,4S)-57a-b, (2R,4R)-104b-c and (2R,4S)-104b-c, (2R,4S)-63 and (2R,4S)-111 were obtained from (2R,4R)-39a-b, (2R,4R)-88b-c, (2R)-60 and (2R,4R)-73. The relative stereochemistry of the products obtained from the addition of the organometallic reagents to the 4-oxopyrrolidine derivatives was determined by chemical correlation and NOE measurements. NOE experiments performed with (2S,4R)-114 revealed that the phenyl group and H-2 are cis to each other. As important signals for the assignment overlapped in the 1H NMR spectrum of (2S,4R)-115, the NOE experiments were performed with (2S,4R)-111, which is the sodium salt of (2S,4R)-115. The NOE measurement revealed that the phenyl group is located cis to H- 2, thus, (2S,4R)-111 and (2S,4R)-115 being of the stereochemistry shown. The N-alkylation of (2S,4R)-114 with the bromide of 24a, and of (2S,4R)-115 with the bromide of 24c led to (2S,4R)-53a and (2S,4R)-102c, respectively. With these compounds as references, also the stereochemistry of all related compounds differing only in side chain on the amino nitrogen could be deduced. The target compounds obtained in this study were evaluated for their biological activities. Membrane fractions from frontal cortex of bovine brain (or porcine brain) were utilized to study the inhibitory potency of the test compounds regarding the GAT-1-mediated GABAuptake. For the determination of the potency as GAT-3 inhibitors, membrane fractions from brain stem of bovine brain (or porcine brain) were used. As compared to the corresponding 4-unsubstituted compounds with (2S) configuration (IC50 2.56 µM at GAT-1) and with (2R) configuration (IC50 18.5 µM), the 40a-b series containing a 4-hydroxy group showed a significant drop in the inhibitory potency at both GAT-1 and GAT-3, only one compound [(2R,4R)-40a] showed a reasonable potency at GAT-1 (IC50 9.4 µM) and no one of them for GAT-3 (IC50 > 100 µM). (2S,4S)-89a (IC50 3.29 µM at GAT-1) and (2S,4S)-89c (5.14 µM), (2S,4R)-89a (4.92 µM) and (2S,4R)-89c (3.15 µM) exhibiting a 4-hydroxypyrrolidine-2-acetic acid skeleton showed an inhibitory potency at GAT-1, which was only one order of magnitude lower than the potency of corresponding compounds with (2S) configuration without the 4-hydroxy group (with Nsubstituent 24a: IC50 0.40 µM and with N-substituent 24c: 0.34 µM). (2R,4S)-89b was the most potent inhibitor at GAT-3 (IC50 19.9 µM) of all the stereoisomers of series 89a-d and showed a much higher potency than its isomer (2R,4R)-89b (126 µM). According to these data a 4-hydroxy group is detrimental to the potency at both GAT-1 and GAT-3, and (2S)-configuration of the pyrrolidine-2-acetic acid unit is crucial for a reasonable potency at GAT-1. As compared to the 40b series, some stereoisomers of the 57b series, the latter exhibiting a (4-methoxy)phenyl group at C-4 of the pyrrolidine ring, showed an increased potency as inhibitors at GAT-1 and GAT-3 [e.g. (2S,4R)-57b: IC50 29.7 µM at GAT-3; (2R,4S)-57b: IC50 of 38.0 µM at GAT-3]. In contrast, the introduction of a (4-methoxy)phenyl group into C-4 of the 89b-c series, resulting in the compounds of 104b-c, gave rise to diverse biological results. As compared with (2R,4S)-89b, (2R,4R)-104b displayed a loss of inhibitory potency at GAT- 3 but some enhancement at GAT-1

Development of new GABA uptake inhibitors derived from proline or from pyrrolidin-2-yl acetic acid

GABA transporters GAT-1, GAT-2 and GAT-3 are new targets for drug design. The substitution of the nitrogen atoms in Nicopetic acid (11), Guvacine (12) and cis-4- Hydroxynicopetic acid (13) with appropriate bulky lipophilic groups resulted in very potent GABA uptake inhibitors for GAT-1 as well as for GAT-3. Pyrrolidine-2-acetic acid derivatives with the three N-substituents 24a-c (Scheme 54) also showed a highly potent inhibition at GAT-1 and GAT-3, respectively. My intention was to investigate how the potency of pyrrolindine-2-carboxylic acid derivatives and of pyrrolidine-2-acetic acid derivatives at GAT-1 and GAT-3 is influenced by the introduction of a hydroxy group or both of a hydroxy and a (4-methoxy)phenyl group at C-4. For this study, the N-substituents 24a-d were chosen. Thus, the four series of pyrrolidine derivatives 20-23 shown below were designed as potential GABA uptake inhibitors. L-trans-4-hydroxypyrrolidine [(2S,4R)-25] was chosen as a precursor, from which the four key intermediates (2S,4R)-38, (2R,4R)-38, (2S,4R)-86 and (2R,4R)-64 were synthesized. The known compounds (2S,4R)-38 and (2R,4R)-38 were prepared from (2S,4R)-25 according to literature procedures. N-protection of (2S,4R)-25 with Cbz group gave (2S,4R)-58 (90% yield). After a series of reactions electrolysis (97% yield), O-silyl protection (85%), nucleophilic addition of 1- ethoxy-1-(trimethylsilyloxy)ethene (cis-71 79%; trans-71 9%) and finally O-deprotection (88%) and N-deprotection (89%) (2R,4R)-64 was obtained in 46% overall yield [from (2S,4R)-25]. After the reaction conditions for the conversion of 70 into 71 have been optimized, the best stereoselectivity [a ratio of cis/trans 97:3; yield cis-71 74%, trans-(2S,4R)-71 1.7%] and a good yield of 88% (cis 79%, trans 9%) were achieved. BF3⋅Et2O appeared to be slightly better for a higher stereoselectivity than TiCl4. (2S,4R)-83 was obtained in 90% yield by protecting the hydroxy group of (2S,4R)-58. An Arndt-Eistert reaction (64% yield) starting from (2S,4R)-83 followed by a simultaneous N,Odeprotection (90% yield) of (2S,4R)-85 led to (2S,4R)-86 in 47% overall yield [from (2S,4R)- 25]. As illustrated in Scheme 58 and 59, (2S,4R)-38 and (2S,4R)-86, (2R,4R)-38 and (2R,4R)-64 were used as starting materials for the synthesis of the N-substituted target compounds (2S,4R)-40a-b, (2S,4S)-40a-b, (2R,4S)-40a-b, (2R,4R)-40a-b, (2S,4R)-89a-d, (2S,4S)-89a-d, (2R,4R)-89a-d and (2R,4S)-89a-d. N-alkylation of these four starting materials with the halides of 24a-d yielded the corresponding tertiary amines. Mitsunobu reactions gave access to the stereoisomers by inversion of the stereocenter at C-4 of the pyrrolidine ring. Finally upon hydrolysis, all the N-substituted pyrrolidine derivatives with a 2-carboxylic acid side chain or a 2-acetic acid side chain were obtained. In the same manners (scheme 58 and 59), the series 96 also were synthesized and finally their hydrogenolysis over Pd-C provided each of four stereoisomers 97. The N-substituted 4-oxopyrrolidine derivatives (2S)-52a-b and (2S)-100a-c (see Scheme 61) were prepared (81-92% yields) via Swern oxidation, and fortunately, the acid-sensitive Nsubstituent 24b was not affected. The N-Cbz-protected 4-oxopyrrolidine derivatives 60 and 108 (Scheme 61) were prepared in good yield (71-78%) via Jones’ oxidation, but in low yield (10-27%) via Swern oxidation. The addition reactions of the organometallic reagents to the N-substituted pyrrolidine derivatives 52a-b and (2S)-100b-c were carried out in two different ways. Depending on the starting material and the employed organometallic reagent, two different results were obtained: Under condition A [(4-MeOC6H4)MgBr at –78 °C in ether] the cis addition product (cis refers to the ester group) was formed as the major diastereomer and a good diastereoselectivity was achieved (cis/trans addition from 79:21 to 89:11; total yields 45- 65%); Under condition B [(4-MeOC6H4)MgBr/CeCl3 at –78 °C in THF], the trans addition product was obtained as a major diastereomer (cis/trans addition from 30:70 to 17:83; total yields 32-48%). In the case of the N-Cbz-protected pyrrolidine derivative (2S)-60, a single diastereomer (2S,4R)-61 was formed in 56% yield under condition B [(4-MeOC6H4)MgBr/CeCl3 in THF at – 60 °C for 4 h]. However, for the homologous (2S)-108 under the same conditions, (2S,4R)- 109 (25% yield) and a side product (5%) resulting from a simultaneous addition to the ester group were formed. The addition of (4-MeOC6H4)MgBr to (2S)-108 (at –78 °C in ether for 4 h), however, led to (2S,4R)-109 (38% yield) as a single diastereomer. Each of the N-substituted stereoisomers from the reaction above was subjected to a basic hydrolysis, which was followed by hydrogenolysis over Pd-C, where necessary, to afford the free amino acids (70-98% yields). Via the similar synthetic procedures as described above, the rest of the stereoisomers (2R,4R)- 57a-b and (2R,4S)-57a-b, (2R,4R)-104b-c and (2R,4S)-104b-c, (2R,4S)-63 and (2R,4S)-111 were obtained from (2R,4R)-39a-b, (2R,4R)-88b-c, (2R)-60 and (2R,4R)-73. The relative stereochemistry of the products obtained from the addition of the organometallic reagents to the 4-oxopyrrolidine derivatives was determined by chemical correlation and NOE measurements. NOE experiments performed with (2S,4R)-114 revealed that the phenyl group and H-2 are cis to each other. As important signals for the assignment overlapped in the 1H NMR spectrum of (2S,4R)-115, the NOE experiments were performed with (2S,4R)-111, which is the sodium salt of (2S,4R)-115. The NOE measurement revealed that the phenyl group is located cis to H- 2, thus, (2S,4R)-111 and (2S,4R)-115 being of the stereochemistry shown. The N-alkylation of (2S,4R)-114 with the bromide of 24a, and of (2S,4R)-115 with the bromide of 24c led to (2S,4R)-53a and (2S,4R)-102c, respectively. With these compounds as references, also the stereochemistry of all related compounds differing only in side chain on the amino nitrogen could be deduced. The target compounds obtained in this study were evaluated for their biological activities. Membrane fractions from frontal cortex of bovine brain (or porcine brain) were utilized to study the inhibitory potency of the test compounds regarding the GAT-1-mediated GABAuptake. For the determination of the potency as GAT-3 inhibitors, membrane fractions from brain stem of bovine brain (or porcine brain) were used. As compared to the corresponding 4-unsubstituted compounds with (2S) configuration (IC50 2.56 µM at GAT-1) and with (2R) configuration (IC50 18.5 µM), the 40a-b series containing a 4-hydroxy group showed a significant drop in the inhibitory potency at both GAT-1 and GAT-3, only one compound [(2R,4R)-40a] showed a reasonable potency at GAT-1 (IC50 9.4 µM) and no one of them for GAT-3 (IC50 > 100 µM). (2S,4S)-89a (IC50 3.29 µM at GAT-1) and (2S,4S)-89c (5.14 µM), (2S,4R)-89a (4.92 µM) and (2S,4R)-89c (3.15 µM) exhibiting a 4-hydroxypyrrolidine-2-acetic acid skeleton showed an inhibitory potency at GAT-1, which was only one order of magnitude lower than the potency of corresponding compounds with (2S) configuration without the 4-hydroxy group (with Nsubstituent 24a: IC50 0.40 µM and with N-substituent 24c: 0.34 µM). (2R,4S)-89b was the most potent inhibitor at GAT-3 (IC50 19.9 µM) of all the stereoisomers of series 89a-d and showed a much higher potency than its isomer (2R,4R)-89b (126 µM). According to these data a 4-hydroxy group is detrimental to the potency at both GAT-1 and GAT-3, and (2S)-configuration of the pyrrolidine-2-acetic acid unit is crucial for a reasonable potency at GAT-1. As compared to the 40b series, some stereoisomers of the 57b series, the latter exhibiting a (4-methoxy)phenyl group at C-4 of the pyrrolidine ring, showed an increased potency as inhibitors at GAT-1 and GAT-3 [e.g. (2S,4R)-57b: IC50 29.7 µM at GAT-3; (2R,4S)-57b: IC50 of 38.0 µM at GAT-3]. In contrast, the introduction of a (4-methoxy)phenyl group into C-4 of the 89b-c series, resulting in the compounds of 104b-c, gave rise to diverse biological results. As compared with (2R,4S)-89b, (2R,4R)-104b displayed a loss of inhibitory potency at GAT- 3 but some enhancement at GAT-1

The Most Essential Skills for Newly Qualified Teachers

The primary purpose of this essay is to propose the most essential skills for being a new teacher. Hence, three main sections are included in this essay. The first skill this essay would like to discuss is management skill. This section will argue two primary skills: personal and classroom management. Firstly, practical individual management skills could reduce the anxiety of entrants. Newly qualified teachers should design a work plan to prevent overpressure. Reasonable use of time is likely to enhance the satisfaction of their work. Therefore, that might reduce the school’s resignation rate, and the other management skills will emphasise students’ behaviours. Several students would like to know the last defensive line of their new teachers. Consequently, they might keep challenging the tolerance of their teachers. This is the reason why classroom management skills should be paid attention. Teachers should maintain each student’s rights so that they can have a harmonious climate in the classroom. Hence, beginning teachers should lead class management—the second section associates with the relationship between teachers and other people, including students, staff and parents. When communicating with students, teachers could apply particular methods to shorten the distance between pupils, such as appropriate humour. Furthermore, the other skilful colleagues might be regarded as beginning teachers’ teachers because of their extensive experiences. On the other hand, a harmonious relationship with parents is likely to promote children’s progress. Apart from these two skills, the third one that will be argued is the teacher’s individual teaching and development skills. Accordingly, the effective delivery of knowledge skills might decide whether or not the class is booming. Positive teaching skills should stimulate students’ critical thinking to achieve academic achievements. Moreover, beginning teachers should keep the belief that they are required to continue with professional development

The cold responsive mechanism of the paper mulberry: decreased photosynthesis capacity and increased starch accumulation

Representative gel images of proteins from the control and treatment. 2-DE was performed using 800 μg of total protein and 11 cm immobilized dry strips with linear pH gradients from 4 to 7. Gels were stained with CBB R-250. Arrow indicates proteins significantly changing in abundance in comparison with control (ANOVA, p < 0.05). Circle indicates proteins appeared after treatment. (TIFF 4732 kb

A characteristic metabolic signature of breast cancer

Among women in the U.S., breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death (after lung cancer). Metabolomics, an approach to the study of small molecules, provides insight of characteristic biochemical phenotypes in disease, and facilitates the development of novel diagnostic tools. This thesis project was to investigate the metabolic signature and to identify potential biomarkers for breast cancer using metabolomics methods. GC-TOFMS and LC-TOFMS spectra were acquired in the plasma collected from 138 breast cancer patients and 76 healthy women. Multivariate and univariate statistics methods were applied to analyze the metabolic alterations in breast cancer. Of the 41 identified differential metabolites, aspartate was the most significantly reduced in breast cancer plasma samples and obtained good predictive power for distinguishing breast cancer patients from healthy controls. An established combination of 7 markers (asparagine, hypotaurine, 5-oxoproline, cysteine, aspartate, glutamate and glutamine) was found to provide even better predictive power than aspartate alone. The altered expression of aspartate was confirmed in an independent set of serum samples and 20 pairs of breast tumor tissue and its adjacent normal tissue. It was also found that the metabolic profiles of stage I and stage IV patients can be separated in the constructed OPLS-DA model. In conclusion, breast cancer exhibits profound metabolic dysregulations and potential biomarkers in breast cancer can be identified using metabolomics approach

Hydroxychloroquine improves pregnancy outcomes of women with positive antinuclear antibody spectrum test results

Background:Empirical use of Hydroxychloroquine (HCQ) in patients with positive antinuclear antibody spectrum (ANAs) test result is controversial regarding its impact on improving perinatal outcomes. This study aimed to investigate the effect of HCQ on adverse pregnancy outcomes associated with placental dysfunction in ANAs-positive patients.Methods:The study included pregnant women with positive ANAs test result from 2016 to 2020 in our center, and divided into a weakly positive and a positive group in just ANA positive patients among them. Univariate and multivariate analyses were conducted to determine the effect of HCQ on pregnancy outcomes in each subgroup. Stratified and interactive analyses were performed to assess the value of HCQ in improving pregnancy outcomes.Results:(i) A total of 261 cases were included, accounting for 30.60% of pregnancy complicated with autoimmune abnormalities, and 65.12% of them used HCQ during pregnancy. (ii) The application of HCQ significantly reduced the incidence of early-onset preeclampsia (1.18% vs. 12.09%, p = 0.040) and small-for-gestational-age infants (10.06% vs. 25.84%, p = 0.003) in the ANAs-positive population, increased birth weight (3075.87 ± 603.91 g vs. 2847.53 ± 773.73 g, p = 0.025), and prolonged gestation (38.43 ± 2.31 vs. 36.34 ± 5.45 weeks, p &lt; 0.001). (iii) A total of 185 just ANA-positive patients were stratified according to titers. Among them, the rate of HCQ usage was significantly higher than that in the weakly positive group (81.03% vs. 58.27%, p = 0.003). (vi) Stratified univariate analysis showed that HCQ usage in the ANA-positive group could reduce the incidence of preeclampsia (2.13% vs. 27.27%, p = 0.019) and prolong gestation (38.29 ± 2.54 vs. 34.48 ± 7.68 weeks, p = 0.006). In the ANA-weakly positive group, HCQ significantly reduced the incidence of preeclampsia (6.76% vs. 28.30%, p = 0.002), early-onset preeclampsia (1.35% vs. 13.21%, p = 0.027), and small-for-gestational-age infants (7.89% vs. 35.19%, p &lt; 0.001). Multivariate regression analysis showed that HCQ significantly reduced the incidence of preeclampsia in both groups. Intergroup interaction analysis showed no significant difference in the value of HCQ in reducing the incidence of preeclampsia between the two groups.Conclusion:ANAs positivity is an important abnormal autoimmunity type in pregnancy. HCQ can be considered as a choice for improving adverse pregnancy outcomes related to placental dysfunction, such as preeclampsia, in this population

Using feature optimization and LightGBM algorithm to predict the clinical pregnancy outcomes after in vitro fertilization

BackgroundAccording to a recent report by the WHO, approximately 17.5\% (about one-sixth) of the global adult population is affected by infertility. Consequently, researchers worldwide have proposed various machine learning models to improve the prediction of clinical pregnancy outcomes during IVF cycles. The objective of this study is to develop a machine learning(ML) model that predicts the outcomes of pregnancies following in vitro fertilization (IVF) and assists in clinical treatment.MethodsThis study conducted a retrospective analysis on provincial reproductive centers in China from March 2020 to March 2021, utilizing 13 selected features. The algorithms used included XGBoost, LightGBM, KNN, Naïve Bayes, Random Forest, and Decision Tree. The results were evaluated using performance metrics such as precision, recall, F1-score, accuracy and AUC, employing five-fold cross-validation repeated five times.ResultsAmong the models, LightGBM achieved the best performance, with an accuracy of 92.31%, recall of 87.80%, F1-score of 90.00\%, and an AUC of 90.41%. The model identified the estrogen concentration at the HCG injection(etwo), endometrium thickness (mm) on HCG day(EM TNK), years of infertility(Years), and body mass index(BMI) as the most important features.ConclusionThis study successfully demonstrates the LightGBM model has the best predictive effect on pregnancy outcomes during IVF cycles. Additionally, etwo was found to be the most significant predictor for successful IVF compared to other variables. This machine learning approach has the potential to assist fertility specialists in providing counseling and adjusting treatment strategies for patients

The interactions of single-wall carbon nanohorns with polar epithelium

Single-wall carbon nanohorns (SWCNHs), which have multitudes of horn interstices, an extensive surface area, and a spherical aggregate structure, offer many advantages over other carbon nanomaterials being used as a drug nanovector. The previous studies on the interaction between SWCNHs and cells have mostly emphasized on cellular uptake and intracellular trafficking, but seldom on epithelial cells. Polar epithelium as a typical biological barrier constitutes the prime obstacle for the transport of therapeutic agents to target site. This work tried to explore the permeability of SWCNHs through polar epithelium and their abilities to modulate transcellular transport, and evaluate the potential of SWCNHs in drug delivery. Madin-Darby canine kidney (MDCK) cell monolayer was used as a polar epithelial cell model, and as-grown SWCNHs, together with oxidized and fluorescein isothiocyanate-conjugated bovine serum albumin-labeled forms, were constructed and comprehensively investigated in vitro and in vivo. Various methods such as transmission electron microscopy and confocal imaging were used to visualize their intracellular uptake and localization, as well as to investigate the potential transcytotic process. The related mechanism was explored by specific inhibitors. Additionally, fast multispectral optoacoustic tomography imaging was used for monitoring the distribution and transport process of SWCNHs in vivo after oral administration in nude mice, as an evidence for their interaction with the intestinal epithelium. The results showed that SWCNHs had a strong bioadhesion property, and parts of them could be uptaken and transcytosed across the MDCK monolayer. Multiple mechanisms were involved in the uptake and transcytosis of SWCNHs with varying degrees. After oral administration, oxidized SWCNHs were distributed in the gastrointestinal tract and retained in the intestine for up to 36 h probably due to their surface adhesion and endocytosis into the intestinal epithelium. Overall, this comprehensive investigation demonstrated that SWCNHs can serve as a promising nanovector that can cross the barrier of polar epithelial cells and deliver drugs effectively