Miracle-dz/UniFAR-FTUs huggingface dataset:
Indolethylamine-N-Methyltransferase Inhibits Proliferation and Promotes Apoptosis of Human Prostate Cancer Cells: A Mechanistic Exploration

Indolethylamine-N-methyltransferase (INMT) is a methyltransferase downregulated in lung cancer, meningioma, and prostate cancer; however, its role and mechanism in prostate cancer remain unclear. By analyzing The Cancer Genome Atlas (TCGA)-PRAD, we found that the expression of INMT in prostate cancer was lower than that of adjacent non-cancerous prostate tissues and was significantly correlated with lymph node metastasis Gleason score, PSA expression, and survival. Combined with the GSE46602 cohorts for pathway enrichment analysis, we found that INMT was involved in regulating the MAPK, TGFβ, and Wnt signaling pathways. After overexpression of INMT in prostate cancer cell lines 22Rv1 and PC-3, we found an effect of INMT on these tumor signal pathways; overexpression of INMT inhibited the proliferation of prostate cancer cells and promoted apoptosis. Using the ESTIMATE algorithm, we found that with the increase of INMT expression, immune and stromal scores in the tumor microenvironment increased, immune response intensity increased, and tumor purity decreased. The difference in INMT expression affected the proportion of several immune cells. According to PRISM and CTRP2.0, the potential therapeutic agents associated with the INMT expression subgroup in TCGA were predicted. The area under the curve (AUC) values of 26 compounds positively correlated with the expression of INMT, while the AUC values of 14 compounds were negatively correlated with the expression of INMT. These findings suggest that INMT may affect prostate cancer’s occurrence, development, and drug sensitivity via various tumor signaling pathways and tumor microenvironments.
Sedentary Behavior in Childhood, Lower Arterial Compliance and Decreased Endothelial Function-Cross Sectional Data From a German School Cohort

Background Endothelial function by flow-mediated dilatation assesses early markers of atherosclerotic progression. Greater amounts of physical activity and physical fitness in children are associated with cardiovascular health benefits. We aimed to explore factors, influencing endothelial function and arterial compliance in a cohort of healthy school children. Methods The 94 participants (41 girls, 53 boys) in the study were young, healthy children from a German school cohort. Anthropometric data, body composition and blood pressure were assessed. Blood was drawn (8 h overnight fast), assessing total cholesterol, high density lipoprotein and low density lipoprotein and triglycerides. Endothelial function was diagnosed by flow-mediated dilatation with ultrasonography (ALOKA/Hitachi, Prosound alpha 6). Tracking gates were set on the intima in B-mode. The waveform of diameter changes over the cardiac cycle was displayed in real time using the FMD-mode of the eTRACKING system. Changes in arterial diameter at baseline, ischaemia and vasodilatation were measured. A symptom limited pulmonary exercise test on a bicycle ergometer was performed to test cardiorespiratory fitness. Physical activity was assessed using GT3x accelerometers (Actigraph, USA), over 4 days (including 1 week-end day), with a minimum wear-time duration of 10 h. Results The median age was 12.2 years (11.8–12.8). Children were normal weight, blood lipid profiles (cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride) were in normal range. Baseline measurements during the diagnostics of endothelial function revealed higher arterial compliance of the brachial artery in boys. Boys' cardiorespiratory fitness was higher than compared to girls. Boys met the recommendations of 60 min moderate to vigorous activity, whereas girls were significantly less active and did not meet current recommendations. More time spent in sedentary activity was the main predictor for lower arterial compliance (adjusted for age and sex), accounting for 14% of the variance. No significant model revealed, analyzing the influencing factors such as anthropometric data, blood lipids, physical activity and fitness on endothelial function. Conclusion This is the first study on endothelial function in association to objectively measured physical activity and cardiorespiratory fitness in healthy school children in Germany. The study highlights the importance of reducing time spent being sedentary to maintain endothelial health.
Comparison of Physiological and Perceptional Responses to 5-m Forward, Forward-Backward, and Lateral Shuttle Running

Purpose The aim of this study was to investigate the physiological and perceptional responses to forward, forward-backward, and lateral shuttle running. Methods Twenty-four eligible male subjects performed a maximal oxygen uptake (VO2max) test and three directional modes (i.e., forward, forward-backward, and lateral) of 5-m shuttle running at the speed of 6 km⋅h–1 for 5 min on separate days. Heart rate (HR) and oxygen uptake (VO2) were continuously measured during the whole tests. Rating of perceived exertion (RPE) was inquired and recorded immediately after the test. Capillary blood samples were collected from the earlobe during the recovery to determine the peak value of blood lactate concentration ([La–]peak). Results Running directional mode had significant effects on HR (F = 72.761, P < 0.001, η2p = 0.760), %HRmax (F = 75.896, P < 0.001, η2p = 0.767), VO2 (F = 110.320, P < 0.001, η2p = 0.827), %VO2max (F = 108.883, P < 0.001, η2p = 0.826), [La–]peak (F = 55.529, P < 0.001, η2p = 0.707), and RPE (F = 26.268, P < 0.001, η2p = 0.533). All variables were significantly different between conditions (P ≤ 0.026), with the variables highest in lateral shuttle running and lowest in forward shuttle running. The effect sizes indicated large magnitude in the differences of all variables between conditions (ES = 0.86–2.83, large) except the difference of RPE between forward and forward-backward shuttle running (ES = 0.62, moderate). Conclusion These findings suggest that the physiological and perceptional responses in shuttle running at the same speed depend on the directional mode, with the responses highest in lateral shuttle running, and lowest in forward shuttle running.
Cortical Inhibition State-Dependent iTBS Induced Neural Plasticity

Background Intermittent theta burst stimulation (iTBS) is an effective stimulus for long-term potentiation (LTP)-like plasticity. However, iTBS-induced effects varied greatly between individuals. Ample evidence suggested that an initial decrease in local γ-aminobutyric acid (GABA) or enhancement in N-methyl-D-aspartate (NMDA) facilitation neurotransmission is of vital importance for allowing LTP-like plasticity to occur. Therefore, we aimed to investigate whether the individual level of GABA or NMDA receptor-mediated activity before stimulation is correlated with the after-effect in cortical excitability induced by iTBS. Methods Fifteen healthy volunteers were recruited for the present study. We measured short-interval intracortical inhibitory (SICI), long-interval intracortical inhibitory (LICI), and intracortical facilitation (ICF), which index GABAA receptor-, GABAB receptor-, and glutamate receptor-mediated activity, respectively, in the cortex before conducting iTBS. After iTBS intervention, the changes of motor-evoked potential (MEP) amplitude were taken as a measure for cortical excitability in response to iTBS protocol. Results There was a significant negative correlation between the amount of SICI measured before iTBS and the after-effect of iTBS-induced LTP-like plasticity at the time points of 5, 10, and 15 min after inducing iTBS. A multiple linear regression model indicated that SICI was a good predictor of the after-effect in cortical excitability induced by iTBS at 5, 10, and 15 min following stimulation. Conclusion The present study found that GABAA receptor-mediated activity measured before stimulation is negatively correlated with the after-effect of cortical excitability induced by iTBS. SICI, as the index of GABAA receptor-mediated activity measured before stimulation, might be a good predictor of iTBS-induced LTP-like plasticity for a period lasting 15 min following stimulation.
Identification of Genetic Networks Reveals Complex Associations and Risk Trajectory Linking Mild Cognitive Impairment to Alzheimer’s Disease

Amnestic mild cognitive impairment (aMCI) and sporadic Alzheimer’s disease (AD) are multifactorial conditions resulting from a complex crosstalk among multiple molecular and biological processes. The present study investigates the association of variants localized in genes and miRNAs with aMCI and AD, which may represent susceptibility, prognostic biomarkers or multi-target treatment options for such conditions. We included 371 patients (217 aMCI and 154 AD) and 503 healthy controls, which were genotyped for a panel of 120 single nucleotide polymorphisms (SNPs) and, subsequently, analyzed by statistical, bioinformatics and machine-learning approaches. As a result, 21 SNPs were associated with aMCI and 13 SNPs with sporadic AD. Interestingly, a set of variants shared between aMCI and AD displayed slightly higher Odd Ratios in AD with respect to aMCI, highlighting a specific risk trajectory linking aMCI to AD. Some of the associated genes and miRNAs were shown to interact within the signaling pathways of APP (Amyloid Precursor Protein), ACE2 (Angiotensin Converting Enzyme 2), miR-155 and PPARG (Peroxisome Proliferator Activated Receptor Gamma), which are known to contribute to neuroinflammation and neurodegeneration. Overall, results of this study increase insights concerning the genetic factors contributing to the neuroinflammatory and neurodegenerative mechanisms underlying aMCI and sporadic AD. They have to be exploited to develop personalized approaches based on the individual genetic make-up and multi-target treatments.
Chenodeoxycholic Acid Enhances the Effect of Sorafenib in Inhibiting HepG2 Cell Growth Through EGFR/Stat3 Pathway

Background Hepatocellular carcinoma (HCC) is a highly invasive disease with a high mortality rate. Our previous study found that Chenodeoxycholic acid (CDCA) as an endogenous metabolite can enhance the anti-tumor effect. Sorafenib has limited overall efficacy as a first-line agent in HCC, and combined with CDCA may improve its efficacy. Methods HepG2 cells and Balb/c nude mice were used respectively for in vitro and in vivo experiments. Flow cytometry, Western blotting, HE and immunohistochemical staining and immunofluorescence were used to study the effects of CDCA combined with sorafenib on HepG2 cell growth and apoptosis-related proteins. Magnetic bead coupling, protein profiling and magnetic bead immunoprecipitation were used to find the targets of CDCA action. The effect of CDCA on EGFR/Stat3 signaling pathway was further verified by knocking down Stat3 and EGFR. Finally, fluorescence confocal, and molecular docking were used to study the binding site of CDCA to EGFR. Results In this study, we found that CDCA enhanced the effect of sorafenib in inhibiting the proliferation, migration and invasion of HepG2 cells. Magnetic bead immunoprecipitation and protein profiling revealed that CDCA may enhance the effect of sorafenib by affecting the EGFR/Stat3 signaling pathway. Further results from in vitro and in vivo gene knockdown experiments, confocal experiments and molecular docking showed that CDCA enhances the efficacy of sorafenib by binding to the extracellular structural domain of EGFR. Conclusion This study reveals the mechanism that CDCA enhances the inhibitory effect of sorafenib on HepG2 cell growth in vitro and in vivo, providing a potential new combination strategy for the treatment of HCC.
Chronic Sleep Deprivation Blocks Voluntary Morphine Consumption but Not Conditioned Place Preference in Mice

The opioid epidemic remains a significant healthcare problem and is attributable to over 100,000 deaths per year. Poor sleep increases sensitivity to pain, impulsivity, inattention, and negative affect, all of which might perpetuate drug use. Opioid users have disrupted sleep during drug use and withdrawal and report poor sleep as a reason for relapse. However, preclinical studies investigating the relationship between sleep loss and substance use and the associated underlying neurobiological mechanisms of potential interactions are lacking. One of the most common forms of sleep loss in modern society is chronic short sleep (CSS) (<7 h/nightly for adults). Here, we used an established model of CSS to investigate the influence of disrupted sleep on opioid reward in male mice. The CSS paradigm did not increase corticosterone levels or depressive-like behavior after a single sleep deprivation session but did increase expression of Iba1, which typically reflects microglial activation, in the hypothalamus after 4 weeks of CSS. Rested control mice developed a morphine preference in a 2-bottle choice test, while mice exposed to CSS did not develop a morphine preference. Both groups demonstrated morphine conditioned place preference (mCPP), but there were no differences in conditioned preference between rested and CSS mice. Taken together, our results show that recovery sleep after chronic sleep disruption lessens voluntary opioid intake, without impacting conditioned reward associated with morphine.
Active Engagement, Protective Buffering, and Depressive Symptoms in Young-Midlife Couples Surviving Cancer: The Roles of Age and Sex

Objective Cancer researchers have found midlife couples to have poorer outcomes compared to older couples due to the off-time nature of the illness for them. It is unknown if young couples (aged 18–39), who are under-represented in cancer studies and overlooked for supportive programs, are at further risk. This study explored the moderating roles of survivor age and sex on the associations between active engagement and protective buffering and depressive symptoms in couples surviving cancer. Methods The exploratory study comprised 49 couples (aged 27–58) 1–3 years post-diagnosis. Multilevel modeling was used to explore the moderating roles of survivor age and sex, controlling for interdependent data. Results Approximately, 37% of survivors and 27% of partners met clinical criteria for further assessment of depression, with 50% of couples having at least one member meeting the criteria. Survivors and their partners did not significantly differ on depressive symptoms, active engagement, or protective buffering. Male survivors reported significantly higher levels of active engagement by their partners than female survivors and female survivors reported significantly higher levels of protective buffering by their partners than male survivors. We found some evidence to suggest that survivor age and sex may play moderating roles between active engagement and protective buffering and depressive symptoms. Older partners and female survivors appeared to experience more positive effects from engaging in positive dyadic behaviors than younger partners and male survivors. Conclusion Findings not only confirm the important role of dyadic behaviors for couples surviving cancer together, but also the important roles of survivor age and sex may play in whether such behaviors are associated with lower levels of depressive symptoms. Future research that examines these complex associations over time and across the adult life span in diverse populations is needed.
Directed Evolution Pipeline for the Improvement of Orthogonal Translation Machinery for Genetic Code Expansion at Sense Codons

The expansion of the genetic code beyond a single type of noncanonical amino acid (ncAA) is hindered by inefficient machinery for reassigning the meaning of sense codons. A major obstacle to using directed evolution to improve the efficiency of sense codon reassignment is that fractional sense codon reassignments lead to heterogeneous mixtures of full-length proteins with either a ncAA or a natural amino acid incorporated in response to the targeted codon. In stop codon suppression systems, missed incorporations lead to truncated proteins; improvements in activity may be inferred from increased protein yields or the production of downstream reporters. In sense codon reassignment, the heterogeneous proteins produced greatly complicate the development of screens for variants of the orthogonal machinery with improved activity. We describe the use of a previously-reported fluorescence-based screen for sense codon reassignment as the first step in a directed evolution workflow to improve the incorporation of a ncAA in response to the Arg AGG sense codon. We first screened a library with diversity introduced into both the orthogonal Methanocaldococcus jannaschii tyrosyl tRNA anticodon loop and the cognate aminoacyl tRNA synthetase (aaRS) anticodon binding domain for variants that improved incorporation of tyrosine in response to the AGG codon. The most efficient variants produced fluorescent proteins at levels indistinguishable from the E. coli translation machinery decoding tyrosine codons. Mutations to the M. jannaschii aaRS that were found to improve tyrosine incorporation were transplanted onto a M. jannaschii aaRS evolved for the incorporation of para-azidophenylalanine. Improved ncAA incorporation was evident using fluorescence- and mass-based reporters. The described workflow is generalizable and should enable the rapid tailoring of orthogonal machinery capable of activating diverse ncAAs to any sense codon target. We evaluated the selection based improvements of the orthogonal pair in a host genomically engineered for reduced target codon competition. Using this particular system for evaluation of arginine AGG codon reassignment, however, E. coli strains with genomes engineered to remove competing tRNAs did not outperform a standard laboratory E. coli strain in sense codon reassignment.
The Influence of the Prolactins on the Development of the Uterus in Neonatal Mice

The endometrial gland is one of the most important components of the mammalian uterus. However, few studies have been conducted on the regulatory mechanisms of adenogenesis during the development of endometrium. In the present study, we detected the genes expression of 35 different prolactin family members (PRLs) together with the prolactin receptor (PRL-R) in the endometrium of neonatal mice along with the adenogenesis process, to address which prolactin-like genes play a key role during gland development in mice. We found that: (1) The expression of Prl1a1, Prl3d1, Prl5a1, Prl7a1, Prl7a2, Prl7d1, Prl8a6, Prl8a8, and Prl8a9 genes were significantly increased along with the development of uterine glands. Prl7c1 and Prl8a1 were observably up-regulated on Postnatal day 5 (PND5) when the uterine glandular bud invagination begins. Prl3a1, Prl3b1, and Prl7b1 suddenly increased significantly on PND9. But, Prl3c1 and Prl8a2 were markedly down-regulated on PND5 and the expression of Prl6a1 and Prlr were stable extremely. (2) After continuous injection of Progesterone (P4), a well-known method to suppress the endometrial adenogenesis, the expression of Prl1a1, Prl3d1, Prl5a1, Prl7a1, Prl7a2, Prl7d1, Prl8a6, Prl8a8, Prl8a9, and Prlr were suppressed on PND7. And on PND9, Prl1a1, Prl3d1, Prl8a6, Prl8a8, and Prl8a9 were significantly inhibited. (3) Further analysis of the epithelial and stroma showed that these PRLs were mainly expressed in the endometrial stroma of neonatal mice. Our results indicate that multiple PRLs are involved in uterine development and endometrial adenogenesis. Continued progesterone therapy may alter the expression pattern of these PRLs in endometrial stromal cells, thereby altering the interaction and communication between stroma and epithelium, and ultimately leading to complete suppression of endometrial adenogenesis.
Levistilide A Promotes Expansion of Human Umbilical Cord Blood Hematopoietic Stem Cells by Enhancing Antioxidant Activity

Several approaches to expand human hematopoietic stem cells (hHSCs) clinically along with retainable capability of multipotential differentiation have been reported, but only a few have advanced to evaluation in clinical trials, which limits the application of HSC-based therapy. Here we show a phthalide derivative, Levistilide A (LA), can serve as a promising molecule to expand functional human umbilical cord blood (UCB) HSCs ex vivo. An in-house screen identified LA out of nine natural products as an outstanding candidate for hHSCs expansion. Additionally, our data indicated that LA treatment not only increased the numbers of phenotype-defined HSCs, but also enhanced their colony formation ability. Xenotransplantation assays showed that LA treatment could maintain unaffected engraftment of hHSCs with multilineage differentiation capacity. Further experiments revealed that LA enhanced the antioxidant activity of hHSCs by reducing intracellular and mitochondrial reactive oxygen species (ROS) levels. The identification of LA provides a new strategy in solving the clinical issue of limited numbers of UCB HSCs.
Spatial Distribution, Temporal Changes, and Knowledge Gaps in Basking Shark (Cetorhinus maximus) Sightings in the California Current Ecosystem

Among the largest fish species, the basking shark (Cetorhinus maximus) is found circumglobally in temperate and tropical waters. Though historical documents have recorded their presence in the California Current Ecosystem (CCE), basking sharks are now only rarely observed in this part of their range. We compiled recent and historical data from systematic surveys (1962–1997) and other sources (1973–2018) to (i) examine temporal patterns of basking shark sightings in the CCE, and (ii) determine the spatial, temporal, and environmental drivers that have affected basking shark presence and distribution here for the last 50 years. We first calculated variation in basking shark sightings and school size over time. We then generated species distribution models using the systematic survey data and evaluated the performance of these models against the more recent non-systematic sightings data. The sightings records indicated that the number of shark sightings was variable across years, but the number and probability of sightings declined in the mid-1980s. The systematic survey data showed up to nearly 4,000 sharks sighted per year until the 1990s, after which there were no sightings reported. In parallel, there was more than a 50% decline in school size from the 1960s to the 1980s (57.2 to 24.0 individuals per group). During the subsequent decades in the non-systematic data (>1990), less than 60 sharks were sighted per year. There were no schools larger than 10 reported, and the mean school size in the last decade (2010s) was 3.53 individuals per group. Low sea surface temperature and high chlorophyll a concentration increased sightings probability, and prevailing climatic oscillations (El Nino-Southern Oscillation index, North Pacific Gyre Oscillation, Pacific Decadal Oscillation) were also correlated with basking shark presence. Lastly, we observed a significant shift in the seasonality of sightings, from the fall and spring during the systematic survey period to the summer months after the 2000s. We conclude by offering suggestions for future research and conservation efforts; specifically, coordinating the documentation of fisheries mortalities and sightings throughout the Pacific basin would facilitate more robust population estimates and identify sources of mortality. Additionally, monitoring shark fin markets and developing region-specific genetic markers would help ensure that convention on international trade in endangered species (CITES) regulations are being followed.