Multi-Omics Reveals the Role of Osteopontin/Secreted Phosphoprotein 1 in Regulating Ovarian Aging.

Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is located on chromosome 4q22.1. This multifunctional secreted acidic glycoprotein is expressed intracellularly and extracellularly in various tissues, where it interacts with regulatory proteins and pro-inflammatory immune chemokines, contributing to the pathogenesis of multiple diseases. Nevertheless, the intricate genetic connections between SPP1 and ovarian aging remain largely unexplored. This study aims to bridge this knowledge gap by delving into ovarian aging and its associations with SPP1 using multi-omics data analysis. Our findings indicate that SPP1 is a potential gene related to ovarian aging. To comprehend the role of SPP1, we conducted spatial transcriptomic analyses on young and aged female mouse ovaries, revealing a significant decline in SPP1 expression in the aging group compared to the young group. Similarly, a significantly low level of SPP1 was found in the 73-year-old sample. Additionally, in-depth single-cell RNA-sequencing analysis identified associations between SPP1 and ITGAV, ITGB1, CD44, MMP3, and FN1. Notably, co-expression analysis highlighted a strong correlation between SPP1 and ITGB1. In summary, this study pioneers the identification of SPP1 as a gene implicated in ovarian aging. Further research into the role of SPP1 has the potential to advance precision medicine and improve treatment strategies for ovarian aging-related conditions.

Gestalt neurons and emergent properties in visual perception: A novel concept for the transformation from local to global processing.

Gestalten in visual perception are defined by emergent properties of the whole, which cannot be predicted from the sum of its parts; rather, they arise by virtue of inherent principles, the Laws of Seeing. This review attempts to assign neurophysiological correlates to select emergent properties in motion and contour perception and proposes parallels to the processing of local versus global attributes by classical versus contextual receptive fields. The aim is to identify Gestalt neurons in the visual system to account for the Laws of Seeing in causal terms and to explain "Why do things look as they do" (Koffka, 1935, p. 76).

Female Human Papillomavirus Infection Associated with Increased Risk of Ectopic Pregnancy: Early Evidence from Taiwan Population-Based Cohort Study.

BACKGROUND: This is an investigation of the human papillomavirus (HPV) infection and its correlation with the risk of ectopic pregnancy (EP). METHODS: The cohort study includes 11,239 patients with newly diagnosed HPV infections between 2000 and 2012, and by using computer-generated random numbers, patients who do not have HPV infections are selected randomly as the comparison cohort. The HPV infection cohort is matched to comparison individuals at a 1:10 ratio by age and index year. All individuals included in the study were followed up to the point they developed EP, pulled-out from the insurance program, lost to follow-up, or until the end of 2013. A Cox proportional-hazards regression analysis was used to analyze the risk of EP with the hazard ratios (HRs) and 95% confidence intervals (CIs) between the HPV and control cohort. RESULTS: The adjusted hazard ratio (aHR) of EP for HPV patients relative to controls is 1.70 (95% CI = 1.04, 2.78), indicating a positive correlation between EP and HPV in the 13-year follow-up period, after adjusting for age and relevant comorbidities. The sensitivity analyses yield similar results. CONCLUSIONS: A history of HPV infection is a potential risk factor associated with the development of subsequent EP in Taiwanese individuals, especially those diagnosed with an HPV infection within 3 years.

Emotional sensitivity predicts internship performance of medical students enrolled under different admission screening protocols.

BACKGROUND AND PURPOSE: People with heightened emotional sensitivity can perceive better how others feel. Students admitted to medical school by interviews for assessing pre-set personal qualities, such as emotional sensitivity, may be more likely to meet patients' satisfaction in the future. We tested whether a student enrolled by passing the interview would have more emotional sensitivity than those by taking an exam. We also investigated what impact the enrolment protocols might have on students' internship performance. METHODS: Participants were first- and second-year medical students and assigned into the interviewed group or examined group according to the entrance protocols. Two emotion-related tasks and one control task were adopted. Subsequently, the performance evaluation of clinical work from students' advisors about these two groups of participants were collected after they finished the internship training at the hospital. CONCLUSIONS: Students selected through the pre-programmed interview which is based on personal qualities showed greater emotional sensitivity than those selected by the exam. Those students with better emotional sensitivity also performed better when they were in the internship training. Emotional sensitivity is a valid index to predict students' future performance and could be used in the selection protocol for medical students.

Female Human Papillomavirus Infection Associated with Increased Risk of Infertility: A Nationwide Population-Based Cohort Study.

OBJECTIVE: This study investigated whether women with a history of human papillomavirus (HPV) infection have an increased risk of infertility. MATERIAL AND METHODS: All patients with an HPV infection (n = 11,198) in Taiwan's National Health Insurance Research Database (2000-2012) were propensity score matched with control subjects (n = 11,198) without an HPV infection by age, sex, index year, and relevant co-morbidities. Both groups were tracked until a diagnosis of infertility was recorded. The Chi-square test was used to analyze the distribution of demographic characteristics in the HPV group and non-HPV group. A Cox proportional hazards regression was used to estimate the hazard ratios (HRs) for the development of infertility, adjusting for age, sex, and co-morbidities. The Kaplan-Meier method was used to plot the cumulative incidence curves. We also performed negative controls to test for possible unmeasured confounding. RESULTS: The HPV cohort had a higher risk of infertility. The adjusted HR (aHR) was found to be 1.39 (95% CI = 1.19-1.63) after adjusting for demographic characteristics and relevant co-morbidities. In the age subgroup analysis, patients with an HPV infection had an increased risk of infertility compared to the non-HPV cohort in the group aged 26 to 35 years (aHR, 1.53; 95% CI = 1.24-1.88). As we used propensity score matching to treat measurable confounders and negative controls to access unmeasured confounders, the findings of the study are robust. CONCLUSIONS: Among females of reproductive age, HPV infection is a potential risk factor that predisposes individuals to subsequent infertility.

Time-Dependent Squamous Cell Carcinoma Antigen in Prediction of Relapse and Death of Patients With Cervical Cancer.

OBJECTIVE: The aim of the study was to develop a methodology to identify the best use of a longitudinally measured biomarker in relevance to prognosis. MATERIALS AND METHODS: Data of squamous cell carcinoma antigen (SCC-Ag) from 770 patients with cervical squamous cell carcinoma (SCC) were used. The pretreatment, nadir, and time-dependent SCC-Ag values were analyzed in relevance to disease relapse and death with univariate and multivariate analysis side by side with a variety of available clinicopathologic factors. The predictive power of the significant variates was evaluated by C-index with 5-fold cross validation. RESULTS: The pretreatment, nadir, and time-dependent SCC-Ag were all significant risk factors for both relapse and death in the univariate analysis (p < .05), and the time-dependent SCC-Ag had the highest C-index in both events. The nadir and time-dependent SCC-Ag were both independently significant in response to relapse with International Federation of Gynecology and Obstetrics (FIGO) stage as the covariate, and the latter had a higher C-index (0.745). Only the time-dependent SCC-Ag was independently significant together with FIGO stage in response to death with the C-index at 0.844. CONCLUSIONS: Increases in the serum level of SCC-Ag in cervical SCC patients suggest a higher risk of both relapse and death. The best use of serial SCC-Ag measurements is to include the time-dependent value in prognostic assessment with FIGO stage also accounted for. Cervical SCC patients should be followed up on their levels of SCC-Ag, and prognostic evaluation should be updated with recent measurements.

Maternal pregnancy-induced hypertension increases the subsequent risk of transient tachypnea of the newborn: A nationwide population-based cohort study.

OBJECTIVE: To determine the association between pregnancy-induced hypertension (PIH) and transient tachypnea of the newborn (TTN) and to identify the predictive risk factors. MATERIALS AND METHODS: Pregnant women with a newly diagnosed PIH (between 2000 and 2013) from the Taiwan National Health Insurance Research Database (NHIRD) were compared with a matched (with respect to age and year of delivery) cohort of pregnant women without PIH. The occurrence of TTN was evaluated in both cohorts. RESULTS: Among the 23.3 million individuals registered in the NHIRD, 29,013 patients with PIH and 116,052 matched controls were identified. According to a multivariate analysis, PIH (odds ratio [OR] = 1.85, 95% confidence interval [CI] = 1.69-2.03, p < 0.0001), age ≥ 30 years (OR = 1.38, 95% CI = 1.26-1.51, p < 0.0001), primiparity (OR = 1.37, 95% CI = 1.24-1.5, p < 0.0001), preterm birth (OR = 3.4, 95% CI = 3.09-3.75, p < 0.0001), multiple births (OR = 2.54, 95% CI = 2.24-2.89, p < 0.0001), and cesarean section (OR = 1.71, 95% CI = 1.56-1.88, p < 0.0001) were independent risk factors for the development of TTN. CONCLUSION: Women with PIH have an increased risk of having infants who develop TTN compared with those without PIH. Additionally, age ≥30 years, primiparity, preterm birth, multiple births, and cesarean section were independent risk factors for the development of TTN.

Impact of putamen stroke on task context updating: Evidence from P300 brain waves.

According to the context updating theory, the oddball P300 component indexes brain activities underlying revision of the mental representation induced by incoming stimuli. It involves an attention-driven comparison process that evaluates the representation of the previous event in working memory. Delayed latencies have been reported for various types of stroke such as unilateral thalamic stroke. We investigated memory updating effects in patients with putamen stroke. Two groups of patients with putamen and thalamic stroke were recruited along with two control groups of young and old healthy participants. Auditory and visual P300 were elicited respectively in a two-stimulus oddball paradigm. The auditory P300 peak latencies were significantly longer in patients with a putamen lesion than in the aged and young control groups and the same pattern was found in the thalamus-lesioned patient. The delayed auditory P300 component in both patient groups but neither control group suggests impairment of memory updating in patients with putamen stroke comparable with thalamic stroke. Our study illustrates the important role of subcortical structures subserved in context updating.

Degraded Impairment of Emotion Recognition in Parkinson's Disease Extends from Negative to Positive Emotions.

Because of dopaminergic neurodegeneration, patients with Parkinson's disease (PD) show impairment in the recognition of negative facial expressions. In the present study, we aimed to determine whether PD patients with more advanced motor problems would show a much greater deficit in recognition of emotional facial expressions than a control group and whether impairment of emotion recognition would extend to positive emotions. Twenty-nine PD patients and 29 age-matched healthy controls were recruited. Participants were asked to discriminate emotions in Experiment 1 and identify gender in Experiment 2. In Experiment 1, PD patients demonstrated a recognition deficit for negative (sadness and anger) and positive faces. Further analysis showed that only PD patients with high motor dysfunction performed poorly in recognition of happy faces. In Experiment 2, PD patients showed an intact ability for gender identification, and the results eliminated possible abilities in the functions measured in Experiment 2 as alternative explanations for the results of Experiment 1. We concluded that patients' ability to recognize emotions deteriorated as the disease progressed. Recognition of negative emotions was impaired first, and then the impairment extended to positive emotions.

Safety and mutagenicity evaluation of red mold dioscorea fermented from Monascus purpureus NTU 568.

Monascus-fermented products, including red mold rice and red mold dioscorea, have been developed as functional foods with many health benefits. We performed safety and mutagenic evaluations on red mold dioscorea powder (RMDP) fermented from Monascus purpureus NTU 568. The results of Ames test using Salmonella typhimurium strains TA97a, TA98, TA100, TA102, and TA1535 showed that RMDP (⩽5 mg/plate) was not mutagenic. The mammalian chromosomal aberration test showed that the number of Chinese hamster ovary cells with abnormal chromosomes was <3% after RMDP treatment (maximum concentration: 5 mg/mL). Imprinting control region mice were used to estimate the genotoxicity of RMDP. Compared with the control, high-dose RMDP administration (2000 mg/kg) did not show significant differences in the number of reticulocytes or the occurrence of micronucleated reticulocytes. A 28-day oral toxicity assay in Sprague-Dawley rats was performed to investigate the no observed adverse effect level of RMDP. Compared with the control, high-dose RMDP administration (2000 mg/kg) caused no toxicological responses such as mortality, variation in body weight, or toxicopathologic lesions. Thus, RMDP from M. purpureus NTU 568 shows no significant mutagenic or toxic effects.

Predicting raters' transparency judgments of English and Chinese morphological constituents using latent semantic analysis.

The morphological constituents of English compounds (e.g., "butter" and "fly" for "butterfly") and two-character Chinese compounds may differ in meaning from the whole word. Subjective differences and ambiguity of transparency make judgments difficult, and a computational alternative based on a general model might be a way to average across subjective differences. In the present study, we propose two approaches based on latent semantic analysis (Landauer & Dumais in Psychological Review 104:211-240, 1997): Model 1 compares the semantic similarity between a compound word and each of its constituents, and Model 2 derives the dominant meaning of a constituent from a clustering analysis of morphological family members (e.g., "butterfingers" or "buttermilk" for "butter"). The proposed models successfully predicted participants' transparency ratings, and we recommend that experimenters use Model 1 for English compounds and Model 2 for Chinese compounds, on the basis of differences in raters' morphological processing in the different writing systems. The dominance of lexical meaning, semantic transparency, and the average similarity between all pairs within a morphological family are provided, and practical applications for future studies are discussed.

Anti-inflammatory properties of yellow and orange pigments from Monascus purpureus NTU 568.

The Monascus species has been used in foods for thousands of years in China. In this study, 10 azaphilone pigments, including four yellow and six orange pigments, were isolated from the fermented rice and dioscorea of Monascus purpureus NTU 568. By employing lipopolysaccharide (LPS)-stimulated murine macrophage RAW 264.7 cells, we determined the inhibitory activities of these pigments on nitric oxide (NO) production. As a result, four orange pigments, monaphilols A-D, showed the highest activities (IC50 = 1.0-3.8 µM), compared with the other two orange pigments, monascorubrin (IC50 > 40 µM) and rubropunctatin (IC50 = 21.2 µM), and the four yellow pigments ankaflavin (IC50 = 21.8 µM), monascin (IC50 = 29.1 µM), monaphilone A (IC50 = 19.3 µM), and monaphilone B (IC50 = 22.6 µM). Using Western blot and ELISA kits, we found that treatments with 30 µM of the yellow pigments and 5 µM of the orange pigments could down-regulate the protein expression of inducible nitric oxide synthase (iNOS) and suppress the production of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). We also used two animal experiments to evaluate the anti-inflammatory effects of these pigments. In a 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema model, eight of these pigments (0.5 mg/ear) could prevent ear edema against TPA administrations on the ears of BALB/c mice. In an LPS-injection mice model, several of these pigments (10 mg/kg) could inhibit the NO, TNF-α, IL-1ß, and IL-6 levels in the plasma of BALB/c mice. As concluded from the in vitro and in vivo studies, six azaphilonoid pigments, namely, ankaflavin, monaphilone A, and monaphilols A-D, showed high potential to be developed into chemopreventive foods or drugs against inflammation-associated diseases.

Protective effect of deferricoprogen isolated from Monascus purpureus NTU 568 on citrinin-induced apoptosis in HEK-293 cells.

Monascus species have traditionally been used in Asian food, with rice as their fermentation substrate. Red mold rice (RMR) contains citrinin, a nephrotoxic agent capable of exerting oxidative stress and cellular apoptosis. We investigated the components in RMR that could minimize the adverse effects of citrinin. Combining chemical separations and bioactivity assays, we identified an antioxidative component called deferricoprogen (DFC) in the fermented rice of Monascus purpureus NTU 568. The DFC structure was confirmed by nuclear magnetic resonance (NMR) and mass spectra analysis. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging activity of DFC was similar to that of vitamin E. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometric analysis showed the effect of DFC and citrinin on cell viability and cell cycle. DFC was found to be protective against the cytotoxicity and cell death induced by citrinin on human embryonic kidney (HEK-293) cells. DFC also demonstrated anti-apoptotic property in preventing citrinin-induced apoptosis.

Induction of apoptosis in human breast adenocarcinoma cells MCF-7 by monapurpyridine A, a new azaphilone derivative from Monascus purpureus NTU 568.

A new azaphilonidal derivative, monapurpyridine A (MPA), has recently been isolated from the fermented products of Monascus purpureus NTU 568. The structure of MPA was elucidated by nuclear magnetic resonance (1H-NMR, 13C-NMR, COSY, HMQC, and HMBC) and other spectroscopic analyses. Biological evaluation revealed that MPA could induce cell death in human breast adenocarcinoma cells MCF-7, and it has no significant toxicity to normal mammary epithelial cells M10. The MTT assay and flow cytometric analysis were employed to investigate cell viability and cell cycle influenced by MPA. Moreover, we used Western blot and caspase activity assay to demonstrate the activation of caspase-3, -8 and -9 resulted from MPA. All evidence supported that MPA was suitable for developing into a chemotherapeutic or chemopreventive agent against breast cancer.

New bioactive orange pigments with yellow fluorescence from Monascus-fermented dioscorea.

Red mold dioscorea (RMD) is a fermented product of Monascus purpureus NTU 568 using dioscorea as culture substrate. To investigate the bioactive components of RMD, six orange pigments including four new azaphilones with yellow fluorescence, monapilol A-D (1-4), and known monascorubrin (5) and rubropunctatin (6) were isolated and characterized. Structural elucidation of new isolates was based on nuclear magnetic resonance ((1)H NMR, (13)C NMR, COSY, HMQC, and HMBC) and other spectroscopic analyses. The structures of monapilols (1-4) were similar to those of monascorubrin (5) and rubropunctatin (6); however, the hydroxyl group (8-OH) in compounds 1-4 substituted for the C-8 carbonyl in compounds 5 and 6. Biological evaluation indicated that compounds 1-4 inhibited nitric oxide (NO) production on lipopolysaccharide-stimulated RAW 264.7 cells. Compounds 1-4 also exhibited antiproliferative activities against human laryngeal carcinoma (HEp-2) and human colon adenocarinoma (WiDr).

Anti-tumor and anti-inflammatory properties of ankaflavin and monaphilone A from monascus purpureus NTU 568.

An azaphilonidal derivative monaphilone A (MA) was recently isolated from the fermented products of Monascus purpureus NTU 568 by our laboratory. We report here the exploration of apoptosis-related and anti-inflammatory properties of MA and ankaflavin (AK) by some experiments about inducing death of human laryngeal carcinoma cell line HEp-2 and reducing inflammatory responses on murine macrophage RAW 264.7 cells. We employed a ssDNA enzyme-linked immunosorbent assay (ELISA) kit to investigate the nuclear changes of early apoptosis induced by AK and MA on HEp-2 cells and used a western blot and an enzyme activity assay to demonstrate the activation of caspase-3, caspase-8, and caspase-9 by MA and AK. Our studies revealed that AK and MA may decrease lipopolysaccharide (LPS)-induced inflammatory responses, including nitrite productions and expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in RAW 264.7 cells. All evidence support that azaphilonidal derivatives from M. purpureus NTU 568, such as AK and MA, are suitable for the development of chemotherapy or chemopreventive agents.