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Abstract Background Intrauterine adhesions (IUA) are a challenging clinical problem in reproductive infertility. The most common causes are intrauterine surgery and abortions. We aimed to investigate whether early second-look office hysteroscopy can prevent IUA. Methods A single-center, prospective, two-armed, randomized controlled trial was designed to explore the efficacy of early office hysteroscopy after first-trimester induced abortion (suction dilatation and curettage [D&C]) and to further analyze fertility outcomes. Women aged 20–45 years undergoing suction D&C and desiring to conceive were recruited. Between October 2019 and September 2022, 66 women were enrolled, of whom 33 were allocated to group A (early hysteroscopy intervention). The women in intervention group A were planned to receive 2 times of hysteroscopies (early and late). In group B, women only underwent late (6 months post suction D&C) hysteroscopy. Results The primary outcome was the IUA rate assessed using office hysteroscopy 6 months after artificial abortion. Secondary outcomes included menstrual amount/durations and fertility outcomes. In intervention group A, 31 women underwent the first hysteroscopy examination, and 15 completed the second. In group B (late hysteroscopy intervention, 33 patients), 16 completed the hysteroscopic exam 6 months after an artificial abortion. Twenty-one women did not receive late hysteroscopy due to pregnancy. The IUA rate was 16.1% (5/31) at the first hysteroscopy in group A, and no IUA was detected during late hysteroscopy. Neither group showed statistically significant differences in the follow-up pregnancy and live birth rates. Conclusions Early hysteroscopy following suction D&C can detect intrauterine lesions. IUA detected early by hysteroscopy can disappear on late examination and become insignificant for future pregnancies. Notably, the pregnancy outcomes showed a favorable trend in the early hysteroscopy group, but there were no statistically significant differences. Trial registration ClinicalTrials.gov , ID: NCT04166500. Registered on 2019-11-10. https://clinicaltrials.gov/ct2/show/NCT04166500 .

ABSTRACT The dissemination of antibiotic resistance genes (ARGs) through plasmids is a major mechanism for the development of bacterial antimicrobial resistance. The adaptation and evolution mechanisms of multidrug-resistant (MDR) plasmids with their hosts are not fully understood. Herein, we conducted experimental evolution of a 244 kb MDR plasmid (pJXP9) under various conditions including no antibiotics and mono- or combinational drug treatments of colistin (CS), cefotaxime (CTX), and ciprofloxacin (CIP). Our results showed that long-term with or without positive selections for pJXP9, spanning approximately 600 generations, led to modifications of the plasmid-encoded MDR and conjugative transfer regions. These modifications could mitigate the fitness cost of plasmid carriage and enhance plasmid maintenance. The extent of plasmid modifications and the evolution of plasmid-encoded antibiotic resistance depended on treatment type, particularly the drug class and duration of exposure. Interestingly, prolonged exposure to mono- and combinational drugs of CS and CIP resulted in a substantial loss of the plasmid-encoded MDR region and antibiotic resistance, comparable to the selection condition without antibiotic. By contrast, combinational treatment with CTX contributed to the maintenance of the MDR region over a long period of time. Furthermore, drug selection was able to maintain and even amplify the corresponding plasmid-encoded ARGs, with co-selection of ARGs in the adjacent regions. In addition, parallel mutations in chromosomal arcA were also found to be associated with pJXP9 plasmid carriage among endpoint-evolved clones from diverse treatments. Meanwhile, arcA deletion improved the persistence of pJXP9 plasmid without drugs. Overall, our findings indicated that plasmid-borne MDR region deletion and chromosomal arcA inactivation mutation jointly contributed to co-adaptation and co-evolution between MDR IncHI2 plasmid and Salmonella Typhimurium under different drug selection pressure.IMPORTANCEThe plasmid-mediated dissemination of antibiotic resistance genes has become a significant concern for human health, even though the carriage of multidrug-resistant (MDR) plasmids is frequently associated with fitness costs for the bacterial host. However, the mechanisms by which MDR plasmids and bacterial pairs evolve plasmid-mediated antibiotic resistance in the presence of antibiotic selections are not fully understood. Herein, we conducted an experimental evolution of a large multidrug-resistant plasmid in a Salmonella enterica Typhimurium host under single and combinatorial drug selection pressures. Our results show the adaptive evolution of plasmid-encoded antibiotic resistance through alterations of the MDR region in the plasmid, in particular substantial loss of the MDR region, in response to different positive selections, especially mono- and combinational drugs of colistin and ciprofloxacin. In addition, strong parallel mutations in chromosomal arcA were associated with pJXP9 carriage in Salmonella Typhimurium from diverse treatments. Our results thus highlight promoting the loss of the plasmid’s MDR region could offer an alternative approach for combating plasmid-encoded antibiotic resistance.

Objective: The POSEIDON criteria stratified patients with poor ovarian response into four subgroups with exclusive characteristics and assisted reproductive technology success rates. However, limited studies focused on miscarriage in the POSEIDON population. This study aimed to explore whether the miscarriage rate different among low prognosis patients according to POSEIDON criteria. Materials and methods: This is a retrospective observational study. All clinical pregnancies achieved after in vitro fertilization or intracytoplasmic sperm injection treatment between January 1998 and April 2021 were analyzed. The primary outcome was miscarriage, defined as the pregnancy loss before 20 weeks of gestation age. Miscarriage rate was estimated per clinical pregnancy and gestational sac. Results: A total of 1222 clinical pregnancies from 1088 POSEIDON patients met the inclusion criteria. The miscarriage rates per clinical pregnancy in each POSEIDON subgroup were as follows: Group 1: 11.7 %, Group 2: 26.5 %, Group 3: 20.9 %, and Group 4: 37.5 %. The miscarriage rate per gestational sac showed a similar trend as the clinical miscarriage rate. Multivariate regression analysis showed that advanced maternal age is an independent factor for miscarriage (Group 2 vs. 1: OR 2.476; Group 4 vs. 3: OR 2.252). Patients with diminished ovarian reserve (DOR) have higher miscarriage risks but without significance (Group 3 vs. 1: OR 1.322; Group 4 vs. 2: OR 1.202). Conclusion: Miscarriage rates differed among low prognosis patients according to the POSEIDON criteria. Age remains a determined risk for miscarriage. DOR might be a potential factor for miscarriage, but it didn't account for a significant impact in POSEIDON patients.

ABSTRACTThe Hippo kinases MST1 and MST2 initiate a highly conserved signaling cascade called the Hippo pathway that limits organ size and tumor formation in animals. Intriguingly, pathogens hijack this host pathway during infection, but the role of MST1/2 in innate immune cells against pathogens is unclear. In this report, we generated Mst1/2 knockout macrophages to investigate the regulatory activities of the Hippo kinases in immunity. Transcriptomic analyses identified differentially expressed genes (DEGs) regulated by MST1/2 that are enriched in biological pathways, such as systemic lupus erythematosus, tuberculosis, and apoptosis. Surprisingly, pharmacological inhibition of the downstream components LATS1/2 in the canonical Hippo pathway did not affect the expression of a set of immune DEGs, suggesting that MST1/2 control these genes via alternative inflammatory Hippo signaling. Moreover, MST1/2 may affect immune communication by influencing the release of cytokines, including TNFα, CXCL10, and IL-1ra. Comparative analyses of the single- and double-knockout macrophages revealed that MST1 and MST2 differentially regulate TNFα release and expression of the immune transcription factor MAF, indicating that the two homologous Hippo kinases individually play a unique role in innate immunity. Notably, both MST1 and MST2 can promote apoptotic cell death in macrophages upon stimulation. Lastly, we demonstrate that the Hippo kinases are critical factors in mammalian macrophages and single-cell amoebae to restrict infection by Legionella pneumophila, Escherichia coli, and Pseudomonas aeruginosa. Together, these results uncover non-canonical inflammatory Hippo signaling in macrophages and the evolutionarily conserved role of the Hippo kinases in the anti-microbial defense of eukaryotic hosts.IMPORTANCEIdentifying host factors involved in susceptibility to infection is fundamental for understanding host-pathogen interactions. Clinically, individuals with mutations in the MST1 gene which encodes one of the Hippo kinases experience recurrent infection. However, the impact of the Hippo kinases on innate immunity remains largely undetermined. This study uses mammalian macrophages and free-living amoebae with single- and double-knockout in the Hippo kinase genes and reveals that the Hippo kinases are the evolutionarily conserved determinants of host defense against microbes. In macrophages, the Hippo kinases MST1 and MST2 control immune activities at multiple levels, including gene expression, immune cell communication, and programmed cell death. Importantly, these activities controlled by MST1 and MST2 in macrophages are independent of the canonical Hippo cascade that is known to limit tissue growth and tumor formation. Together, these findings unveil a unique inflammatory Hippo signaling pathway that plays an essential role in innate immunity.

Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib’s angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.

Abstract Aims/Introduction Fatty acid desaturase (FADS) genetic polymorphisms are strongly correlated with the risk of dyslipidemia and cardiovascular disease. In this study, we examined the impact of FADS1 and FADS2 genetic variants on plasma lipid status, and assessed interactions between FADS genetic polymorphisms and plasma n‐3/n‐6 fatty acids regarding lipid status within a population of 816 Taiwanese patients with type 2 diabetes. Materials and Methods Selected tag single‐nucleotide polymorphisms (FADS1 rs174546 [T/C]; FADS2 rs174602 [A/G] and rs2072114 [A/G]) were genotyped (n = 816). Results The distribution of genotypes were compared with reports publicly available in the Genome Aggregation Database for East Asian populations (https://gnomad.broadinstitute.org). In the subgroup of patients not taking lipid‐lowering medications (n = 192), we observed that the G allele of FADS2 rs174602 was statistically significantly correlated with lower low‐density lipoprotein cholesterol (LDL‐C) concentrations (P = 0.001), whereas the G allele of rs2072114 was marginally associated with LDL‐C concentrations (P = 0.091). Using a general linear model adjusted for confounding factors, statistically significant interactions (P = 0.016) between single‐nucleotide polymorphisms in rs2072114 and a low alpha‐linolenic acid (18:3n‐3)/linoleic acid (18:2n‐6) ratio; the G allele correlated with lower LDL‐C levels among individuals with a low alpha‐linolenic acid/linoleic acid ratio. Interaction between rs174602 single‐nucleotide polymorphisms and low alpha‐linolenic acid/linoleic acid values on LDL‐C was only marginally significant (P = 0.063). Conclusions Our results show the role of n‐3/n‐6 dietary polyunsaturated fatty acids in modifying the effects of genetic susceptibility on lipoprotein concentrations in patients with type 2 diabetes. Our findings highlight the potential of interventions with dietary polyunsaturated fatty acids regarding developing individualized prevention strategies for type 2 diabetes presenting with co‐occurring dyslipidemia and cardiovascular diseases.

Tidying up objects poses a complex challenge for service robots, particularly when it involves scheduling operations that require real-time action for achieving optimal results. This paper presents a decision system aimed at selecting priority locations to address the problem of robots searching for miscellaneous items in indoor environments. Initially, three datasets with varying complexities are generated using real environmental data, and the environmental information is integrated into feature matrices. Subsequently, the rule base of the fuzzy inference system is trained and optimized using an equilibrium optimizer, and its performance is compared with other commonly used algorithms. The feature matrices and the optimized rule base are then incorporated into the fuzzy inference system, leveraging the traveling salesman problem to determine the optimal sequence for visiting locations. The accuracy and efficiency of the proposed method are validated through physical implementation tests using analog data. Finally, the system is applied and evaluated in real-world scenarios to validate its effectiveness. The video of experiment is available at https://youtu.be/rjMDgopM-9M.

Objective: While many studies agree that the fetal birth weight is higher after frozen embryo transfer (FET), few studies have explored the difference in fetal weight change during such pregnancies. This cohort study was to identify the difference in fetal birth weight and gestational age at birth between singletons born following fresh ET and those born following FET. Materials and methods: This was a hospital-based cohort study using clinical data from the Kaohsiung Chang Gung Memorial Hospital Obstetric and Neonatal Database from January 1, 2007, to December 1, 2018. A sample of 784 eligible women who had singleton pregnancies and live-born deliveries after 428 fresh ET or 356 FET between January 2007 and December 2018. Results: Compared with those in the fresh ET group, singletons in the FET group had higher birth weight (3137 g [2880–3441 g] vs. 3060 g [2710–3340 g], p

Abstract Introduction Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti‐GCa effects in experimental models, are currently being investigated. Method The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5‐fluracil were applied onto AGS, SC‐M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web‐based GCa cohort for Ar expression association with prognosis was performed. Result The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5‐FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer‐suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor‐suppressing index (TSI) score of 90% over a 6‐week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements.

AIM: To study the effects of the specific simulated luminous environment on the visual performance of people with different vision, so as to provide an experimental basis for revising pilots' vision standards. METHODS: A controlled randomized trial was conducted. Twenty-four volunteers were recruited and divided into four groups(1.0/1.0, 0.8/0.8, 0.6/0.6 and 0.4/0.4, decimal vision)according to right/left eye visual acuity, with six subjects in each group. Each subject was tested for static distant vision, kinetic visual acuity, color vision, depth perception error and visual search time under the simulated luminous environments of sunlight, twilight, and on-cloud, respectively, to compare changes in the impact of distinctive luminous surroundings on the visual performance indicators of human beings with different vision.RESULTS: There were main effect differences in static distant vision, kinetic visual acuity, color error, depth perception error and visual search time under different light environments(all P

Background: The presence of only morphologically poor embryos (MPEs) on day3 is common in autologous in vitro fertilization (IVF), particularly among p Tel: 886-7-7317123 Ext. 8916. Fax: 886-7-7322915.atients who have advanced maternal age or are poor responders. However, there are limited data regarding the disposition of embryos from patients who only produced MPEs on day3. The present study was designed to investigate the possible benefits of extended culturing MPEs. Try to detect whether the extended culture (day4 or day5 culture) can improve the live birth rate per cycle? Methods: This retrospective, observational, single-center, cohort study examined 224 IVF/intracytoplasmic sperm injection (ICSI) cycles between January 2010 and June 2015, in which women only produced MPEs on day3. A total of 544 MPEs were analyzed. The defines a day3 embryo as an MPE if it fails to develop to eight cells, blastomeres of equal size, and less than 20% cytoplasmic fragments. Of the 224 cycles, 89 (39.7%) underwent fresh embryo transfer on day3, and 135 (60.3%) underwent extended culture. Of the 135 extended cultures, 54 cycles (40.0%) experienced day4, or day5 embryo transfer, 16 cycles (11.9%) had all embryos frozen, and 65 cycles (48.1%) had total embryo arrest. Results: Analysis of patient baseline demographic data, cycle characteristics, and cycle outcomes for day3 transfer group and extended culture group indicated that a higher body mass index in the day3 transfer group was the only significant difference (p = 0.006). Both fresh transfer groups had low live birth rates (LBRs) (4.5% vs. 7.4% p = 0.46). After extended culture, 65 cycles (48.1%) were cancelled because the embryos exhibited developmental arrest and 70 cycles (51.9%) grew to day4 or day5. Thirteen frozen embryo transfer (FET) cycles and 22 frozen blastocysts derived from MPEs were thawed. There were more high-quality embryos (p

Background: Previous studies have demonstrated that high levels of estradiol (E2) impair blastocyst implantation through effects on the endometrium; however, whether high E2 directly affects blastocysts is not well established. The present study sought to clarify the direct impacts of high E2 levels on blastocysts in vitro. Methods: ICR virgin albino mice were used. Using an in-vitro 8-day blastocyst culture model, immunofluorescence staining for the estrogen receptor (ER), blastocyst outgrowth assays, differential staining and TUNEL assays of blastocysts, and embryo transfer, we investigated the main outcomes of exposure to different E2 concentrations (10−7 to 10−4 M) in vitro and in vivo. Results: ERα and ERβ expression were detected in pre-implantation stage embryos. In vitro exposure of blastocysts to 10−4 M E2 for 24 h followed by 7 days culture in the absence of E2 caused severe inhibition of implantation and post-implantation development. The late adverse effects of E2 on post-implantation development still occurred at concentrations of 10−7 to 10−5 M. In addition, blastocyst proliferation was reduced and apoptotic cells were increased following exposure to 10−4 M E2. Using an in vivo embryo-transfer model, we also showed that treatment with high E2 resulted in fewer implantation sites (38% vs. 72% in control) and greater resorption of implanted blastocysts (81% vs. 38% in control). Conclusion: Exposure to high E2 concentrations in vitro is deleterious to blastocyst implantation and early post-implantation development, mainly owing to direct impacts of E2 on implanting blastocysts. In clinical assisted reproductive technique (ART), high serum E2 concentrations not only affects the endometrium, but also affects blastocysts directly at the period of implantation.

A quartz oscillator has a stable frequency that can be tuned by applying a voltage across the quartz crystal. This study applied a triboelectric generator (TEG) as mechanical stimuli on the input voltage of a remote transmitter in a transmitter-to-receiver system. The intermodulation (IM) frequencies were chosen instead of the transmitter frequencies because the IM signals are generally significant. This study first examined the rectified electric voltage from contact-separation and single-electrode mode TEGs. The series connection TEG, stored capacitor, and passive voltage regulator (zener diode) determine the quality of the direct current voltage. The increase in the input voltage via mechanical stimuli on the transmitter was proved to deliver a signal where the IM frequencies increase with the stimuli in the system.

This study provides a complete Selective Compliance Assembly Robot Arm (SCARA) wafer inspection system. This system mainly includes two phases. In the first phase, a SCARA manipulator acts as an inspection application platform, and a depth camera is used to position the position vector of an inspection point and a cassette together with a single-axis visual frame so that SCARA can automatically perform calibration in the working area. In the second phase, the wafer ready for inspection is optimized for procedure sorting to perform all detection items in the shortest time when SCARA is in the process of inspection. This study has solved the problem of calibrating positions of a manipulator and a working area with consumption of manpower in a traditional wafer inspection field in such a way that the manipulator can complete a predetermined task with the economic benefits of the inspection center without colliding with the working area. In addition, optimized scheduling reduces the time for the manipulator to complete all inspection tasks to allow more wafers to be inspected per unit time. Finally, the relative positions of all inspection points are automatically calculated by the manipulator by placing SCARA in a field not calibrated by the inspection points. The predefined wafer inspection scheduling is sent to the system for optimization calculation, and the experimental results are presented by SCARA.

The aging global population is increasingly affected by osteoporosis (OP), which is one of the most significant threats to the elderly. Moreover, its prevention and treatment situations have become increasingly severe. Therefore, it is imperative to develop alternatives or complementary drugs for preventing and treating osteoporosis. Kidney tonifying traditional Chinese medicine (KTTCM) has been used for the treatment of osteoporosis for a long time. Pharmacological studies have shown that kidney tonifying traditional Chinese medicine can promote osteoblasts, inhibit osteoclasts, and regulate the level of estrogen and plays vital roles in stimulating osteogenesis, restraining adipogenesis of marrow mesenchymal stem cells (MSCs), regulating the metabolism of calcium and phosphorus, and inhibiting oxidative stress. These effects are mediated by OPG/RANKL/RANK, BMP/Smads, MAPKs, and Wnt/β-catenin systems. To develop a safe, synergistic, effective, and homogenized TCM formula with robust scientific evidence to provide faster and more economical alternatives, the anti-osteoporosis ingredients and pharmacological mechanisms of kidney tonifying traditional Chinese medicine are recapitulated from the perspective of molecular and cell biology, and the safety and toxicity of kidney tonifying traditional Chinese medicine have also been reviewed in this paper.

Abstract Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.

Background: This study aims to investigate the antimicrobial ability and mechanism analysis of Lactobacillus species against carbapenemase-producing Enterobacteriaceae (CPE). Methods: Five Lactobacillus spp. strains and 18 CPE clinical isolates were collected. Their anti-CPE effects were assessed by agar well diffusion and broth microdilution assay, as well as time-kill test. Finally, the specific anti-CPE mechanism, especially for the effect of organic acids was determined using broth microdilution method. Results: All of five Lactobacilli isolates displayed the potent activity against most CPE isolates with mean zones of inhibition ranging 10.2–21.1 mm. The anti-CPE activity was not affected by heating, catalase, and proteinase treatment. Under the concentration of 50% LUC0180 cell-free supernatant (CFS), lactic acid, and mix acid could totally inhibit the growth of carbapenem-resistant Klebsiella pneumoniae (CPE0011), and acetic acid could inhibit 67.8%. In contrast, succinic acid and citric acid could not inhibit the growth of CPE0011. While we decreased the concentration to 25%, only lactic acid and mix acid displayed 100% inhibition. In contrast, succinic acid, citric acid and acetic acid did not show any inhibitory effect. Conclusions: Lactobacillus strains exhibit potent anti-CPE activity, and lactic acid produced by Lactobacillus strains is the major antimicrobial mechanism.

The clinical use of mifepristone for medical abortions has been established in 1987 in France and since 2000 in the United States. Mifepristone has a limited medical period that lasts n = 3, mifepristone n = 3). When we performed a gene set enrichment analysis, our data indicated that mifepristone treatment considerably altered the cellular pathways of embryos in terms of viability, proliferation, and development. The data indicated that mifepristone was involved in hallmark gene sets of protein secretion, mTORC1, fatty acid metabolism, IL-2-STAT5 signaling, adipogenesis, peroxisome, glycolysis, E2F targets, and heme metabolism. The data further revealed that mifepristone interfered with normal embryonic development. In sum, our data suggest that continuing a pregnancy after mifepristone treatment fails is inappropriate and infeasible. The results of our study reveal a high risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Background/Purpose: Endometriosis (EM) is linked to cardiovascular disease (CVD). However, whether this finding can be applied to the Taiwanese population remained unanswered. To investigate the association between EM and major adverse cardiovascular and cerebrovascular events (MACCE) and the therapeutic effect on the risk of MACCE in Asian women with EM. A retrospective population-based cohort study was performed. Methods: A total of 17 543 patients with EM aged between 18 and 50 years were identified from a general population of 1 million Taiwanese after excluding diagnoses of major CVD and cerebrovascular accident (CVA) prior to EM. The comparison group (n = 70 172) without EM was selected by matching the study cohort with age, sex, and income and urbanization levels in a 4:1 ratio. Results: During a median follow-up period of 9.2 years, Taiwanese women with EM had a significantly higher frequency of comorbidities, medical and surgical treatment, and MACCE than did their non-EM counterparts (2.76% vs 2.18%, P

Abstract Background Pregnant women have high serum concentrations of sex steroid hormones, which are major regulators of paracrine and autocrine responses for many maternal and placental functions. The main purpose of this study was to compare patients with preeclampsia and patients with uncomplicated pregnancies in terms of serum steroid hormones (estradiol [E2], progesterone [P4], dehydroepiandrosterone sulfate [DHEAS], and testosterone [T]) throughout pregnancy and the levels of cord blood and placental steroid receptors during the third trimester. Methods Quantitative real-time reverse transcription PCR, western blotting, and immunohistochemistry were used to determine the levels of steroid hormones in the serum and cord blood and the placental levels of estrogen receptor-α (ERα), ERβ, androgen receptor (AR), and progesterone receptor (PR). Results There were 45 women in the uncomplicated pregnancy group and 30 women in the preeclampsia group. Serum levels of T were greater and serum levels of E2 were reduced in the preeclampsia group, but the two groups had similar levels of P4 and DHEAS during the third trimester. Cord blood had a decreased level of DHEAS in the preeclampsia group, but the two groups had similar levels of P4, E2, and T. The two groups had similar placental mRNA levels of ERα, ERβ, AR, and PR, but the preeclampsia group had a higher level of ERβ protein and a lower level of ERα protein. Immunohistochemistry indicated that the preeclampsia group had a greater level of ERβ in the nucleus and cytoplasm of syncytiotrophoblasts and stromal cells. Conclusions Women with preeclampsia had lower levels of steroid hormones, estrogen, and ERα but higher levels of T and ERβ. These molecules may have roles in the pathogenesis of preeclampsia.

Polycystic ovary syndrome (PCOS) is the most common reproductive disease affecting the hormone and metabolic status of women. Its associated symptoms are diverse among the patients, including hyperandrogenism, insulin resistance, anovulation, infertility, obesity, hirsutism, acne, and more. In addition, PCOS can potentially increase the risk of dysmenorrhea, endometriosis, endometrioma, and irritable bowel syndrome, which are highly related to pelvic pain and sexual difficulty. However, little known is whether PCOS exacerbates other chronic bodily pain or contributes to hyperalgesia. Health-related quality of Life (HRQoL) reflects the life satisfaction and quality derived by an individual from mental, physical, emotional, and social activities under specific conditions. In this study, we reviewed pain perception from HRQoL of PCOS patients (SF-36). The review data evidently indicated that pain perception is significantly more prevalent in patients with PCOS than in healthy controls, and obesity and infertile status could be the rationales associated with pain development. Nevertheless, underlying causes remain undetermined due to the limited information from SF-36. Furthermore, we reviewed pathophysiologic factors to pain development or exacerbation, such as the deregulation of inflammation levels, adipokines, and insulin resistance. Although current evidence of pain perception and pathophysiologic risk factors are solid in PCOS, patients’ pain perception is often ignored in clinical settings. Clinicians should note the perception and treatment of pain in PCOS patients. The correlation or causality between pain and PCOS warrants further clinical examination and basic studies, thereby providing new insights into this topic in the context of clinical diagnosis and health care.

Electric light has been widely adopted in numerous applications, including signage, display, and illumination. Enhancing its efficiency and quality has been the focal point until now. Long exposure to intensive blue-light-enriched white light is, however, likely to cause health concerns, such as retina damage and melatonin suppression. A good light should hence be redefined as, at least, human-friendly, besides energy-saving and high-quality. Here, we demonstrate a novel design approach toward a good light based on the state-of-the-art solid-state lighting technologies. Taking the typical phosphor converted white-light-emitting diode (LED) for lighting, for example, a 2000 K orange-white emission with a black-body-radiation chromaticity can be 5 times safer than the 5000 K pure-white counterpart from a retina-protection perspective and 3.9 times safer from an MLT-secretion perspective. Further tuning its chromaticity from black-body-radiation- to sunlight-style, the 2000 K LED can be made 303% safer in terms of maximum retina permissible exposure limit or 100% better in terms of melatonin suppression sensitivity. Moreover, its corresponding efficacy limit can be increased from 270 to 285 lm/W, while keeping light quality constant at 91, in terms of natural light spectrum resemblance index. The same approach can be extended to organic LED as well as the design of a good light for display, wherein pure-white emission with a color temperature around 6000 K is suggested to replace the bluish-white backlight to safeguard human health.

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism.

Abstract Background The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear. Methods HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo. Results We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells. Conclusions The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b–mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.

Objective: Transvaginal oocyte retrieval has become the common method for infertility couples undergoing artificial reproductive technology. Although it was considered to be safe, rare complications including urinary bladder injury were reported. Case report: We described two cases of bladder injury with refractory blood clots after oocyte retrieval, for whom conservative treatment failed. Diagnostic cystoscopy was performed and an Ellik evacuator was used for clot dissolution successfully. Conclusion: Urinary bladder injury with clots retention is a rare complication following ovary puncture. When tenacious clots become organized, the removal with traditional bladder irrigation may be difficult. We introduce Ellik evacuator as an effective and reliable procedure for evacuating tenacious clots in the urinary bladder. Keywords: Transvaginal oocyte retrieval (TVOR), Bladder injury, Hematuria, Tenacious clot, Ellik

Abstract Background Morulas with delayed growth sometimes coexist with blastocysts. There is still limited evidence regarding the optimal disposal of surplus morulas. With the advancement of vitrification, the freezing-thawing technique has been widely applied to zygotes with 2 pronuclei, as well as embryos at the cleavage and blastocyst stages. The freezing of morulas, however, has rarely been discussed. The purpose of this study was to investigate whether these poor-quality and slow-growing morulas are worthy of cryopreservation. Methods This is a retrospective, observational, proof-of-concept study. A total of 1033 day 5/6 surplus morulas were cryopreserved from January 2015 to December 2018. The study included 167 women undergoing 180 frozen embryo transfer cycles. After the morulas underwent freezing-thawing procedures, their development was monitored for an additional day. The primary outcome was the blastocyst formation rate. Secondary outcomes were clinical pregnancy rate, live birth rate and abortion rate. Results A total of 347 surplus morulas were thawed. All studied morulas showed delayed compaction (day 5, n = 329; day 6, n = 18) and were graded as having low (M1, n = 54), medium (M2, n = 138) or high (M3, n = 155) fragmentation. The post-thaw survival rate was 79.3%. After 1 day in extended culture, the blastocyst formation rate was 66.6%, and the top-quality blastocyst formation rate was 23.6%. The day 5 morulas graded as M1, M2, and M3 had blastocyst formation rates of 88.9, 74.0, and 52.8% (p

Glioma is the most common primary malignant brain tumor with a poor prognosis. Immune checkpoint inhibitors have been of great interest in investigation of glioma treatments. Here, we report single-cell transcriptomic analyses of two tumor areas from an oligodendroglioma taken from a patient who had multiple tumor recurrences, following several chemotherapies and radiation treatments. The patient subsequently received nivolumab and was considered have disease progression based on conventional diagnostic imaging after two cycles of treatment. He underwent a debulking surgical resection and pathological diagnosis was recurrent disease. During the surgery, tumor tissues were also collected from the enhancing and non-enhancing areas for a scRNAseq analysis to investigate the tumor microenvironment of these radiographically divergent areas. The scRNAseq analysis reveals a plethora of immune cells, suggesting that the increased mass observed on MRI may be partially a result of immune cell infiltration. The patient continued to receive immunotherapy after a short course of palliative radiation and remained free of disease progression for at least 12 months after the last surgery, suggesting a sustained response to immunotherapy. The scRNAseq analysis indicated that the radiological progression was in large part due to immune cell infiltrate and continued immunotherapy led to a positive clinical outcome in a patient who would have otherwise been admitted to hospice care with halting of immunotherapy. Our study demonstrates the potential of scRNAseq analyses in understanding the tumor microenvironment, which may assist the clinical decision-making process for challenging glioma cases following immunotherapy.

Attention mechanism has been extensively used in video captioning tasks, which enables further development of deeper visual understanding. However, most existing video captioning methods apply the attention mechanism on the frame level, which only model the temporal structure and generated words, but ignore the region-level spatial information that provides accurate visual features corresponding to the semantic content. In this paper, we propose a fine-grained spatial-temporal attention model (FSTA), and the spatial information of objects appearing in the video will be our main concern. In the proposed FSTA, we achieve the spatial-hard attention at a fine-grained region level of objects through the mask pooling module and compute the temporal soft attention by using a two-layer LSTM network with attention mechanism to generate sentences. We test the proposed model on two benchmark datasets, namely, MSVD and MSR-VTT. The results indicate that our proposed FSTA model can achieve competitive performance against the state of the arts on both datasets.

In this paper, we discover an operation method that can effectively decrease the forming voltage in resistance random access memory (RRAM). Forming voltage can be reduced by either increasing the rising time of the forming-waveform or by increasing the temperature in the forming process. However, the resulting electronic RRAM characteristics after each of these methods differ. While increasing the rising time causes greater damage to the switching layer due to longer accumulation of charge, increasing temperature in the forming process does not. The high temperature-formed RRAM excels in retention and endurance tests, proving an effective means to decrease forming voltage.

Mifepristone (RU-486), a synthetic steroid with potent antiprogestogen and anti-glucocorticoid properties, has been widely used in clinical practice. Its effect on the endometrium, ovary, and fallopian tube has been well reported in many human and animal studies. However, its direct impact on post-implantation embryos remains underexplored. Additionally, some women choose to keep their pregnancy after mifepristone treatment fails. Thus, the potential risk remains controversial. Hence, this study investigated the direct effects of mifepristone on the development of mice blastocysts in vitro in terms of implantation and post-implantation. We detected the level of progesterone (P4) associated with ovulation in vivo. The presence of progesterone receptors (PRs) in blastocysts and post-implantation embryos was also evaluated. Cultured embryos were treated directly with mifepristone. We further examined embryonic implantation and post-implantation of blastocysts in vitro to evaluate the direct effects of mifepristone on embryos by the assessment of embryonic outgrowth and differential cell staining. In the oviduct lumen, the P4 level dramatically increased at 48 h and slightly decreased at 72 and 96 h following ovulation. PR was expressed in blastocysts not only in the preimplantation stage but also in the early post-implantation period. In the evaluation of developmental stages, mifepristone significantly reduced the successful ratio of developing into the late egg cylinder and the early somite stage. In addition, it further decreased the cell number of the embryos’ inner cell mass and trophectoderm. We herein provide evidence that mifepristone affects blastocyst viability directly and inhibits post-implantation embryo development in vitro. Furthermore, our data reveal a potential risk of fetus fatality and developmental problems when pregnancies are continued after mifepristone treatment fails.

Objective: Clinical prognosis appears to be varied in females with poor ovarian response (POR), and poor responders defined by the Bologna criteria might not be sufficiently homogeneous. The aim of this study was to determine the major predictor of reproductive outcomes in extremely low oocyte retrieval cycles. Materials and Methods: A cohort of fresh in vitro fertilization/intracytoplasmic sperm injection cycles (n = 858) was analyzed from January 2001 to September 2014. Females from whom zero, one, two, or three oocytes were retrieved following ovarian stimulation were examined. Univariate analyses were performed to determine the association of pregnancy rate with potential confounding variables. Multiple logistic regression analysis was subsequently performed to identify factors that affected the occurrence of pregnancy. Results: The clinical pregnancy rate was higher in women aged < 40 years, long protocol, and high embryo score in univariate analysis. After adjusting for confounding factors in multivariate analysis, the maternal age [odds ratio (OR) = 0.91], primary or secondary infertility (OR = 1.99), number of matured oocytes retrieved (OR = 0.64), and score of embryos transferred (OR = 1.39) were significantly associated with the clinical pregnancy rate per cycle and per transfer. In the age subgroup analysis, POR females aged < 35 years significantly demonstrated the highest number of matured oocytes, embryo scores, and clinical pregnancy rates compared with POR females aged 35–40 years and ≥ 40 years. Conclusion: This study highlights the predictive value of maternal age and embryo quality on the probability of pregnancy in females with extremely low oocyte retrieval cycles. Young females with few eggs collected can still achieve acceptable pregnancy probability as long as they have good-quality embryos. Future randomized control trials for POR using the Bologna criteria should first stratify patients into different age groups.

We present an approach to jointly detect mitotic events spatially and temporally in time-lapse phase contrast microscopy images. In particular, we combine a convolutional neural network (CNN) and a long short-term memory (LSTM) network to detect mitotic events in patch sequences. The CNN-LSTM network can be trained end-to-end to simultaneously learn convolutional features within each frame and temporal dynamics between frames, without hand-crafted visual or temporal feature design. Owing to the LSTM layer, this approach is able to detect mitotic events in patch sequences of variable length, as well as making use of longer context information among frames in the sequences. To the best of our knowledge, this is the first work to detect mitosis using deep learning in both spatial and temporal domains. Experiments have shown that the CNN-LSTM network can be trained efficiently, and we evaluate this design by applying the network to original raw microscopy image sequences to locate mitotic events both spatially and temporally. The data with which we validate the proposed method include C3H10 mesenchymal and C2C12 myoblastic stem cell populations. Our approach achieved the F score of 98.72% on the C2C12 data set, and the F score of 96.5% on the C3H10 data set. The results on both data sets outperform the traditional graph modelbased approaches by a large margin, both in terms of detection accuracy and frame localization accuracy. Furthermore, we have developed a framework to aid humans in annotating mitosis with high efficiency and accuracy in raw phase contrast microscopy images based on the joint detection results using the proposed method. Under this framework, expert level annotations can be obtained in raw phase contrast microscopy image sequences, and the annotations have shown to further improve the training performance of the CNN-LSTM network.

In the original publication of this article [1], labelling within Fig. 7a was incorrect. The updated figure is shown below, with ‘DMT1’ now corrected to read ‘DNMT1’.

Adult stem cell therapy for the treatment of tendon injuries is a growing area of research. This study is aimed to investigate the efficacy of human adipose-derived stem cell (hADSC) injection on the tendon during its healing process in a rat model of rotator cuff injury. hADSCs were injected 3 days after collagenase-induced rotator cuff injuries in experimental groups, while the control group received saline as a placebo. Histological and biomechanical analyses were performed 7, 14, 21, and 28 days after collagenase injection. Compared to the control group, it was found that inflammatory cells were significantly decreased in the hADSC-treated group after collagenase injection for 7 and 14 days. In the hADSC-injected group, the fiber arrangement and tendon organization had also been improved. On the seventh day after collagenase injection, the load to failure of the hADSC-injected group (15.87 ± 2.20 N) was notably higher than that of the saline-injected group (11.20 ± 1.35 N). It is suggested that the tensile strength of the supraspinatus tendon was significantly enhanced. Local administration of hADSCs might have the possibility to restore the tensile strength and attenuate the progression of tendinitis. Taken together, these findings demonstrate that the recovery processes in damaged tendons can be facilitated architecturally and functionally after hADSC injection.

A novel avian influenza A (H7N9) virus causes severe human infections and was first identified in March 2013 in China. The H7N9 virus has exhibited two epidemiological peaks of infection, occurring in week 15 of 2013 and week 5 of 2014. Taiwan, which is geographically adjacent to China, faces a large risk of being affected by this virus. Through extensive surveillance, launched in April 2013, four laboratory-confirmed H7N9 cases imported from China have been identified in Taiwan. The H7N9 virus isolated from imported case 1 in May 2013 (during the first wave) was found to be closest genetically to a virus from wild birds and differed from the prototype virus, A/Anhui/1/2013, in the MP gene. The other three imported cases were detected in December 2013 and April 2014 (during the second wave). The viruses isolated from cases 2 and 4 were similar in the compositions of their 6 internal genes and distinct from A/Anhui/1/2013 in the PB2 and MP genes, whereas the virus isolated from case 3 exhibited a novel reassortment that has not been identified previously and was different from A/Anhui/1/2013 in the PB2, PA and MP genes. The four imported H7N9 viruses share similar antigenicity with A/Anhui/1/2013, and their HA and NA genes grouped together in their respective phylogenies. In contrast with the HA and NA genes, which exhibited a smaller degree of diversity, the internal genes were heterogeneous and provided potential distinctions between transmission sources in terms of both geography and hosts. It is important to strengthen surveillance of influenza and to share viral genetic data in real-time for reducing the threat of rapid and continuing evolution of H7N9 viruses.

Discovering visual dynamics during human actions is a challenging task for human action recognition. To deal with this problem, we theoretically propose the multi-task conditional random fields model and explore its application on human action recognition. For visual representation, we propose the part-induced spatiotemporal action unit sequence to represent each action sample with multiple partwise sequential feature subspaces. For model learning, we propose the multi-task conditional random fields (MTCRFs) model to discover the sequence-specific structure and the sequence-shared relationship. Specifically, the multi-chain graph structure and the corresponding probabilistic model are designed to represent the interaction among multiple part-induced action unit sequences. Moreover we propose the model learning and inference methods to discover temporal context within individual action unit sequence and the latent correlation among different body parts. Extensive experiments are implemented to demonstrate the superiority of the proposed method on two popular RGB human action datasets, KTH & TJU, and the depth dataset in MSR Daily Activity 3D.

The title compound, C10H14O5, is an intermediate in our study of the asymmetric synthesis of α-hydroxyalkanoic acids. The structure consists of 1,4-dioxaspiro[4,5]decane skeleton formed when the cyclohexylidene group binds to both of the hydroxyl groups of carboxylic groups of the starting malic acid. The six-membered ring adopts a chair conformation.