Miracle-dz/UniFAR-FTUs huggingface dataset:
Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia

Supplemental Digital Content is available in the text. Background: Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. Methods: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. Results: A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78–1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. Conclusions: Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn. com; Unique identifier ISRCTN16123934.
Assessment of relationships among clinicopathological characteristics, morphological computer tomography features, and tumor cell proliferation in stage I lung adenocarcinoma

Background Surgically resected stage I lung adenocarcinoma (ADC) has wide variation in prognosis. It is significant to identify high-risk patients and optimize therapeutic strategy. This study aimed to investigate the relationships among histological grade, serum tumor marker index (TMI), morphological computer tomography (CT) features, and a well-established prognosticator cell proliferation (Ki-67) in stage I ADC. Methods Preoperative CT was performed in 182 patients with stage I ADC confirmed by pathology. The Ki-67 expression was acquired by immunohistochemistry. TMI was the square root of standardized serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) values. Tumor shadow disappearance rate (TDR) and other morphological CT features were interpreted by two radiologists. Histological grade, TMI, CT features were statistically evaluated to explore the associations with Ki-67 expression. Results In univariate analysis, gender, smoking history, pack-year, histological grade, TNM stage (IA and IB), serum CEA and CYFRA 21-1 status, TMI status, as well as TDR, long-axis diameter, short-axis diameter, lobulation, spiculation, attenuation types, vacuolation, vascular invasion, vascular convergence, thickened bronchovascular bundles, pleural attachment and peripheral fibrosis were significantly associated with Ki-67 expression (all P<0.05). Solid-predominant ADC had the highest Ki-67 expression, followed by micropapillary, papillary and acinar-predominant ADC, while lepidic-predominant ADC had the lowest Ki-67 expression (P<0.001). TDR was negatively correlated with Ki-67 (r =−0.478, P<0.001). Multivariate logistic regression analysis revealed that gender, histological grade, TDR and attenuation types were independent factors associated with Ki-67 expression. Conclusions Ki-67 expression differed distinctly according to ADC histological subtypes. High Ki-67 expression is independently associated with male patients of stage I ADC with worse differentiation, lower TDR and solid tumors, which might be of prognostic value for poor prognosis in stage I ADC.
Azithromycin or Doxycycline for Asymptomatic Rectal Chlamydia trachomatis.

BACKGROUND Rectal chlamydia is a common bacterial sexually transmissible infection among men who have sex with men. Data from randomized, controlled trials are needed to guide treatment. METHODS In this double-blind trial conducted at five sexual health clinics in Australia, we randomly assigned men who have sex with men and who had asymptomatic rectal chlamydia to receive doxycycline (100 mg twice daily for 7 days) or azithromycin (1-g single dose). Asymptomatic chlamydia was selected as the trial focus because more than 85% of men with rectal chlamydia infection are asymptomatic, and clinical guidelines recommend a longer treatment course for symptomatic infection. The primary outcome was a negative nucleic acid amplification test for rectal chlamydia (microbiologic cure) at 4 weeks. RESULTS From August 2016 through August 2019, we enrolled 625 men (314 in the doxycycline group and 311 in the azithromycin group). Primary outcome data were available for 290 men (92.4%) in the doxycycline group and 297 (95.5%) in the azithromycin group. In the modified intention-to-treat population, a microbiologic cure occurred in 281 of 290 men (96.9%; 95% confidence interval [CI], 94.9 to 98.9) in the doxycycline group and in 227 of 297 (76.4%; 95% CI, 73.8 to 79.1) in the azithromycin group, for an adjusted risk difference of 19.9 percentage points (95% CI, 14.6 to 25.3; P<0.001). Adverse events that included nausea, diarrhea, and vomiting were reported in 98 men (33.8%) in the doxycycline group and in 134 (45.1%) in the azithromycin group (risk difference, -11.3 percentage points; 95% CI, -19.5 to -3.2). CONCLUSIONS A 7-day course of doxycycline was superior to single-dose azithromycin in the treatment of rectal chlamydia infection among men who have sex with men. (Funded by the National Health and Medical Research Council; RTS Australian New Zealand Clinical Trials Registry number, ACTRN12614001125617.).
New perspectives of quercetin and vitamin C effects on fibronectin-binding integrins and chemokine receptors in prostate cancer cell lines.

OBJECTIVES The aim of this study is to investigate the effect of two abundant dietary supplements, quercetin and vitamin C on some factors involved in metastasis and proliferation of prostate cancer, which are resistant to conventional chemotherapies in late stages. BACKGROUND Bone and brain are two common sites of metastases in prostate cancer, nevertheless the factors involved in their metastatic pathways are not well understood. METHODS The effect of quercetin (75µM) and vitamin C (100 µM) on CXCR4, CXCR7 chemokine receptors, α4, α5 and β1 integrins, ki-67 proliferation marker and Vascular endothelial growth factor, VEGF was evaluated using Quantitative Reverse Transcription PCR (RT-qPCR). RESULTS The effect of quercetin and vitamin C alone was different on PC3 and DU145 prostate cancer cell lines, but sequential combination reduced significantly the expression of CXCR and CXCR7 chemokine receptors, α4, α5 and β1 integrin subunits, VEGF and Ki-67 proliferation markers in PC3 and DU145 cell lines. CONCLUSION Our results indicated the beneficial effect of quercetin and vitamin C on prostate cancer cells with different metastatic sites and their differential response to the treatment which in turn may lead us to reach suitable therapeutic outcomes to combat cancer (Fig. 3, Ref. 36).
Review of treatment and therapeutic targets in brain arteriovenous malformation

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase (MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.
What factors motivate male and female Generation Z students to become engaged as peer teachers? A mixed‐method study among medical and dental students in the gross anatomy course

Peer‐teaching is widely established in anatomy teaching and offers well‐described advantages. Nevertheless, at Ulm University, Germany, a reduction in the number of peer teacher applicants for the dissection course was observed. This study examined factors related to the attractiveness of a position as a peer teacher for Generation Z students. Participants of the gross anatomy course were asked to evaluate factors influencing the attractiveness of a peer teacher position using a six‐point Likert scale. Additionally, open‐ended questions were analyzed qualitatively. Sex‐specific subgroup analysis was performed comparing students of low and high motivation to apply for a tutorship. Of the 374 students who participated in this study (response rate 53%), 38% stated that they were intending to apply as peer teachers. Data indicated that students displayed intrinsic motivation to apply for a tutorship because of the opportunity to improve their anatomy knowledge and/or their pleasure in teaching. In contrast, extrinsic factors like remuneration of the tutorship and its relevance for their curriculum vitae were least important. Anatomy educators underestimated the demotivating factor of the workload associated with the tutorship and encouraged students less frequently to apply than peer teachers. Only minor sex‐specific differences could be identified. Nevertheless, female students were encouraged less frequently to apply than their male peers. In summary, Generation Z students apply as peer teachers because they are enthusiastic about the task. To motivate students to commit to extracurricular activities like a tutorship, anatomy educators should actively encourage students—particularly females—more frequently to apply.
Linear Ubiquitination of RIPK1 on Lys612 Regulates Systemic Inflammation via Preventing Cell Death

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of the TNF-α–induced cell death program. The function of RIPK1 is tightly controlled by posttranslational modifications, including linear ubiquitin chain assembly complex–mediated linear ubiquitination. However, the physiological function and molecular mechanism by which linear ubiquitination of RIPK1 regulates TNF-α–induced intracellular signaling remain unclear. In this article, we identified Lys627 residue as a major linear ubiquitination site in human RIPK1 (or Lys612 in murine RIPK1) and generated Ripk1K612R/K612R mice, which spontaneously develop systemic inflammation triggered by sustained emergency hematopoiesis. Mechanistically, without affecting NF-κB activation, Ripk1K612R/K612R mutation enhances apoptosis and necroptosis activation and promotes TNF-α–induced cell death. The systemic inflammation and hematopoietic disorders in Ripk1K612R/K612R mice are completely abolished by deleting TNF receptor 1 or both RIPK3 and Caspase-8. These data suggest the critical role of TNF-α–induced cell death in the resulting phenotype in Ripk1K612R/K612R mice. Together, our results demonstrate that linear ubiquitination of RIPK1 on K612 is essential for limiting TNF-α–induced cell death to further prevent systemic inflammation. Visual Abstract Key Points RIPK1 can be linearly ubiquitinated by LUBAC at K612 (K627 in human). Ripk1K612R/K612R mice develop emergency hematopoiesis and systemic inflammation. Linear ubiquitination of RIPK1 restrains TNF-α–induced apoptosis and necroptosis.
A nomogram for predicting brain metastasis in patients with de novo stage IV breast cancer

Background Brain metastasis (BM) is a very serious event in patients with breast cancer. The aim of this study was to establish a nomogram to predict the risk of BM in patients with de novo stage IV breast cancer. Methods We gathered female patients diagnosed with de novo stage IV breast cancer between 2010 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. After randomly allocating the patients to the training set and verification set, we used univariate and multivariate logistic regression to analyze the relationship between BM and clinicopathological features. Finally, we developed a nomogram which was validated by the analysis of calibration curve and receiver operating characteristic curve. Results Of 7,154 patients with de novo stage IV breast cancer, 422 developed BM. Age, tumor size, subtype, and the degree of lung involvement were significantly correlated with BM. The nomogram had discriminatory ability with an area under curve (AUC) of 0.640 [95% confidence interval (CI): 0.607 to 0.673] in the training set, and 0.644 (95% CI: 0.595 to 0.693) in the validation set. Conclusions Our study developed a nomogram to predict BM for de novo stage IV breast cancer, thus helping clinicians to identify patients at high-risk of BM and implement early preventive interventions to improve their prognoses.
Multiscale modeling of tumor growth and angiogenesis: Evaluation of tumor-targeted therapy

The dynamics of tumor growth and associated events cover multiple time and spatial scales, generally including extracellular, cellular and intracellular modifications. The main goal of this study is to model the biological and physical behavior of tumor evolution in presence of normal healthy tissue, considering a variety of events involved in the process. These include hyper and hypoactivation of signaling pathways during tumor growth, vessels’ growth, intratumoral vascularization and competition of cancer cells with healthy host tissue. The work addresses two distinctive phases in tumor development—the avascular and vascular phases—and in each stage two cases are considered—with and without normal healthy cells. The tumor growth rate increases considerably as closed vessel loops (anastomoses) form around the tumor cells resulting from tumor induced vascularization. When taking into account the host tissue around the tumor, the results show that competition between normal cells and cancer cells leads to the formation of a hypoxic tumor core within a relatively short period of time. Moreover, a dense intratumoral vascular network is formed throughout the entire lesion as a sign of a high malignancy grade, which is consistent with reported experimental data for several types of solid carcinomas. In comparison with other mathematical models of tumor development, in this work we introduce a multiscale simulation that models the cellular interactions and cell behavior as a consequence of the activation of oncogenes and deactivation of gene signaling pathways within each cell. Simulating a therapy that blocks relevant signaling pathways results in the prevention of further tumor growth and leads to an expressive decrease in its size (82% in the simulation).
Observer-Based Adaptive Optimized Control for Stochastic Nonlinear Systems With Input and State Constraints

In this work, an adaptive neural network (NN) optimized output-feedback control problem is studied for a class of stochastic nonlinear systems with unknown nonlinear dynamics, input saturation, and state constraints. A nonlinear state observer is designed to estimate the unmeasured states, and the NNs are used to approximate the unknown nonlinear functions. Under the framework of the backstepping technique, the virtual and actual optimal controllers are developed by employing the actor–critic architecture. Meanwhile, the tan-type Barrier optimal performance index functions are developed to prevent the nonlinear systems from the state constraints, and all the states are confined within the preselected compact sets all the time. It is worth mentioning that the proposed optimized control is clearly simple since the reinforcement learning (RL) algorithm is derived based on the negative gradient of a simple positive function. Furthermore, the proposed optimal control strategy ensures that all the signals in the closed-loop system are bounded. Finally, a practical simulation example is carried out to further illustrate the effectiveness of the proposed optimal control method.
Role of lymphatic endothelial cells in the tumor microenvironment—a narrative review of recent advances

Background As lymphatic vessel is a major route for solid tumor metastasis, they are considered an essential part of tumor drainage conduits. Apart from forming the walls of lymphatic vessels, lymphatic endothelial cells (LECs) have been found to play multiple other roles in the tumor microenvironment, calling for a more in-depth review. We hope that this review may help researchers gain a detailed understanding of this fast-developing field and shed some light upon future research. Methods To achieve an informative review of recent advance, we carefully searched the Medline database for English literature that are openly published from the January 1995 to December 2020 and covered the topic of LEC or lymphangiogenesis in tumor progression and therapies. Two different authors independently examined the literature abstracts to exclude possible unqualified ones, and 310 papers with full texts were finally retrieved. Results In this paper, we discussed the structural and molecular basis of tumor-associated LECs, together with their roles in tumor metastasis and drug therapy. We then focused on their impacts on tumor cells, tumor stroma, and anti-tumor immunity, and the molecular and cellular mechanisms involved. Special emphasis on lung cancer and possible therapeutic targets based on LECs were also discussed. Conclusions LECs can play a much more complex role than simply forming conduits for tumor cell dissemination. Therapies targeting tumor-associated lymphatics for lung cancer and other tumors are promising, but more research is needed to clarify the mechanisms involved.
A study of the growth-time effect on graphene layer number based on a Cu-Ni bilayer catalyst system

The evolution of graphene-based electronic, optoelectronic, and sensing devices has grown at a fast pace in the recent decade, due to the rapid development of manufacturing technology for high-quality graphene. However, the absence of controllability of graphene thickness sets an additional barrier for device applications. Here, we demonstrate that the number of graphene layers can be well controlled by adjusting the Cu–Ni catalyst composition and the reaction time. The Cu–Ni bilayer catalysts are prepared by sputtering Ni and then Cu films on a SiO2/Si substrate with various film thicknesses. With the increase of the growth time, single-layer graphene would be formed on the Cu-rich catalysts, whereas bilayer to few-layer graphene can be obtained on the Ni-rich films. In addition, the formation of single-layer to bilayer graphene as a function of time is attributed to the synergic effect of Cu and Ni catalysts with 1 : 1 composition. The precise control of graphene layer number enables the further development of advanced electronics and sensors.
Predicting population genetic change in an autocorrelated random environment: Insights from a large automated experiment

Most natural environments exhibit a substantial component of random variation, with a degree of temporal autocorrelation that defines the color of environmental noise. Such environmental fluctuations cause random fluctuations in natural selection, affecting the predictability of evolution. But despite long-standing theoretical interest in population genetics in stochastic environments, there is a dearth of empirical estimation of underlying parameters of this theory. More importantly, it is still an open question whether evolution in fluctuating environments can be predicted indirectly using simpler measures, which combine environmental time series with population estimates in constant environments. Here we address these questions by using an automated experimental evolution approach. We used a liquid-handling robot to expose over a hundred lines of the micro-alga Dunaliella salina to randomly fluctuating salinity over a continuous range, with controlled mean, variance, and autocorrelation. We then tracked the frequencies of two competing strains through amplicon sequencing of nuclear and choloroplastic barcode sequences. We show that the magnitude of environmental fluctuations (determined by their variance), but also their predictability (determined by their autocorrelation), had large impacts on the average selection coefficient. The variance in frequency change, which quantifies randomness in population genetics, was substantially higher in a fluctuating environment. The reaction norm of selection coefficients against constant salinity yielded accurate predictions for the mean selection coefficient in a fluctuating environment. This selection reaction norm was in turn well predicted by environmental tolerance curves, with population growth rate against salinity. However, both the selection reaction norm and tolerance curves underestimated the variance in selection caused by random environmental fluctuations. Overall, our results provide exceptional insights into the prospects for understanding and predicting genetic evolution in randomly fluctuating environments.
SnRK1.1‐mediated resistance of Arabidopsis thaliana to clubroot disease is inhibited by the novel Plasmodiophora brassicae effector PBZF1

Abstract Plants have evolved a series of strategies to combat pathogen infection. Plant SnRK1 is probably involved in shifting carbon and energy use from growth‐associated processes to survival and defence upon pathogen attack, enhancing the resistance to many plant pathogens. The present study demonstrated that SnRK1.1 enhanced the resistance of Arabidopsis thaliana to clubroot disease caused by the plant‐pathogenic protozoan Plasmodiophora brassicae. Through a yeast two‐hybrid assay, glutathione S‐transferase pull‐down assay, and bimolecular fluorescence complementation assay, a P. brassicae RxLR effector, PBZF1, was shown to interact with SnRK1.1. Further expression level analysis of SnRK1.1‐regulated genes showed that PBZF1 inhibited the biological function of SnRK1.1 as indicated by the disequilibration of the expression level of SnRK1.1‐regulated genes in heterogeneous PBZF1‐expressing A. thaliana. Moreover, heterogeneous expression of PBZF1 in A. thaliana promoted plant susceptibility to clubroot disease. In addition, PBZF1 was found to be P. brassicae‐specific and conserved. This gene was significantly highly expressed in resting spores. Taken together, our results provide new insights into how the plant‐pathogenic protist P. brassicae employs an effector to overcome plant resistance, and they offer new insights into the genetic improvement of plant resistance against clubroot disease.