Miracle-dz/UniFAR-FTUs huggingface dataset:
FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells

Fibroblast growth factor 9 (FGF9) promotes cancer progression; however, its role in cell proliferation related to tumorigenesis remains elusive. We investigated how FGF9 affected MA‐10 mouse Leydig tumor cell proliferation and found that FGF9 significantly induced cell proliferation by activating ERK1/2 and retinoblastoma (Rb) phosphorylations within 15 minutes. Subsequently, the expressions of E2F1 and the cell cycle regulators: cyclin D1, cyclin E1 and cyclin‐dependent kinase 4 (CDK4) in G1 phase and cyclin A1, CDK2 and CDK1 in S‐G2/M phases were increased at 12 hours after FGF9 treatment; and cyclin B1 in G2/M phases were induced at 24 hours after FGF9 stimulation, whereas the phosphorylations of p53, p21 and p27 were not affected by FGF9. Moreover, FGF9‐induced effects were inhibited by MEK inhibitor PD98059, indicating FGF9 activated the Rb/E2F pathway to accelerate MA‐10 cell proliferation by activating ERK1/2. Immunoprecipitation assay and ChIP‐quantitative PCR results showed that FGF9‐induced Rb phosphorylation led to the dissociation of Rb‐E2F1 complexes and thereby enhanced the transactivations of E2F1 target genes, Cyclin D1, Cyclin E1 and Cyclin A1. Silencing of FGF receptor 2 (FGFR2) using lentiviral shRNA inhibited FGF9‐induced ERK1/2 phosphorylation and cell proliferation, indicating that FGFR2 is the obligate receptor for FGF9 to bind and activate the signaling pathway in MA‐10 cells. Furthermore, in a severe combined immunodeficiency mouse xenograft model, FGF9 significantly promoted MA‐10 tumor growth, a consequence of increased cell proliferation and decreased apoptosis. Conclusively, FGF9 interacts with FGFR2 to activate ERK1/2, Rb/E2F1 and cell cycle pathways to induce MA‐10 cell proliferation in vitro and tumor growth in vivo.
Insonation of Systemically Delivered Cisplatin-Loaded Microbubbles Significantly Attenuates Nephrotoxicity of Chemotherapy in Experimental Models of Head and Neck Cancer

The use of cisplatin (CDDP), the most common chemotherapy drug for head and neck cancer, is limited by its undesirable side effects, especially nephrotoxicity. We investigated ultrasound microbubbles (USMB) as a tool to increase the local intra-tumoral CDDP level while decreasing systemic CDDP cytotoxicity. We allowed CDDP to interact with human serum albumin and then sonicated the resulting CDDP‒albumin complex to generate CDDP-loaded MBs (CDDP-MBs). We then established a head-and-neck tumor-bearing mouse model by implanting FaDu-fLuc/GFP cells into severe combined immunodeficiency mice and used IVIS® bioluminescence imaging to determine the tumor xenograft formation and size. Twice weekly (until Day 33), we administered CDDP only, CDDP + MBs + US, CDDP-MBs, or CDDP-MBs + US intravenously by tail-vein injection. The US treatment was administered at the tumor site immediately after injection. The in vivo systemic distribution of CDDP indicated that the kidney was the most vulnerable organ, followed by the liver, and then the inner ear. However, CDDP uptake into the kidney and liver was significantly decreased in both the CDDP-MBs and CDDP-MBs + US groups, suggesting that MB binding significantly reduced the systemic toxicity of CDDP. The CDDP-MBs + US treatment reduced the tumor size as effectively as conventional CDDP-only chemotherapy. Therefore, the combination of CDDP-MBs with ultrasound is effective and significantly attenuates CDDP-associated nephrotoxicity, indicating a promising clinical potential for this approach.
Denuclearizing North Korea: A verified, phased approach

The process must reflect existing levels of trust at each stage At the June 2018 Singapore Summit, North Korea agreed to the goal of “complete denuclearization” in exchange for “security guarantees” by the United States, including an end to enmity (1). Like earlier efforts in the 1990s and 2000s, the current round of diplomacy may well fail because of the challenges of balancing North Korean insistence on the primacy of building trust and cooperation with U.S. demands for progress on denuclearization. Any successful attempt to balance these priorities will have to resolve the thorny question of verification. Here, we propose a phased approach for verified denuclearization that relies on technical measures and tools to allow for the scope, pace, and intrusiveness of denuclearization to reflect progress in political confidence building. More broadly, successfully bridging the goals of denuclearization and political security for North Korea could inform judgments by the international community about how to approach verified disarmament for other states that currently have nuclear weapons.
Dietary antioxidants, but not courtship effort, affect oxidative balance in the testes and muscles of crickets

ABSTRACT Recent interest has focused on the role of reactive oxygen species (ROS) as universal constraints in life-history evolution. Empirical studies have examined the oxidative costs of reproduction for females, with little work conducted on males. The male germline is thought to be particularly susceptible to oxidative damage because the testes, and the sperm themselves, can be prolific producers of ROS. We tested the hypothesis that protection of the male germline from oxidative damage represents a cost of reproduction for males. We fed male crickets, Teleogryllus oceanicus, with one of two experimental diets in which we manipulated the availability of dietary antioxidants, and we induced variation in their expenditure on courtship effort by manipulating access to females. We measured the total antioxidant capacity, levels of ROS production and the amount of oxidative damage to proteins in both testis and thoracic muscle tissues. Dietary antioxidants contributed to positive oxidative balance in both tissue types. Although the testes had greater antioxidant defences than muscle tissue, they also produced considerably higher levels of ROS and sustained higher levels of oxidative damage. Courtship effort had no impact on any measure of oxidative balance. Our data confirm that the male germline is especially susceptible to oxidative stress and that dietary antioxidants can alleviate this oxidative cost of reproduction. Summary: Dietary antioxidants protect the male germline from oxidative damage, and may play an important role in the life-history cost of reproduction for males.
Sequential management of tibial fractures using a temporary unicortical external fixator

Introduction: The development of damage control orthopedics (DCO) procedures has led to the development of temporary unicortical external fixators (TUEFs) intended to limit deep infectious complications and facilitate early conversion to internal fixation. Methods: A retrospective study was conducted in two French military trauma centers, including on patients being treated for tibial fractures with a TUEF (UNYCO® − Orthofix®) followed by an early conversion to intramedullary nailing. Results: Eleven patients with an average age of 41 were included between September 2015 and June 2017. A total of 12 TUEFs were implanted for one closed fracture and 11 open fractures, including one type I, eight types II, and two Gustilo types IIIB. The indication of DCO was related to hemodynamic instability in three cases, to the severity of soft tissue lesions in eight cases, and to the context of treatment in one case. The conversion to IM nailing was made after an average of 7.6 days. No significant loss of reduction was observed until internal osteosynthesis, which was performed with “fixator in place” in ten cases. The coverage of Gustilo type III injuries was performed by free flap transfers at the same time as IM nailing. All the patients were reviewed with an average follow-up of 16.5 months. Bone union was achieved in all cases. Two IM nailing dynamizations were carried out, but no bone grafting was required. Two cases of pandiaphysitis were observed and treated without functional complications. Discussion: Despite a limited number of patients, this study demonstrates the reliability of the TUEF to maintain the reduction of tibial fractures and facilitate early conversion to IM nailing. Unicortical fixation does not prevent septic complications related to the severity of soft tissue injuries.
Membrane-wrapped nanoparticles probe divergent roles of GM3 and phosphatidylserine in lipid-mediated viral entry pathways

Significance Membrane-wrapped noble metal nanoparticles provide a synthetic platform to investigate lipid-mediated, glycoprotein-independent virus–cell interactions. Different from membrane-wrapped virus-like particles (VLPs), these artificial virus nanoparticles (AVNs) are not derived from cellular systems and can contain organic or inorganic cores optimized for imaging or delivery purposes. A particular advantage is the rational control over the AVN membrane composition, which can be complex or undefined in VLP. This work shows that monosialodihexosylganglioside-presenting AVNs accumulate in virus-containing compartments (VCCs) that represent assembly sites for HIV-1. VCCs provide evasion for HIV-1 from the immune system as well as antiviral therapeutics. The ability to target VCCs with AVNs provides opportunities for eradicating a putative reservoir of HIV-1 persistence. Gold nanoparticles (NPs) wrapped in a membrane can be utilized as artificial virus nanoparticles (AVNs) that combine the large nonblinking or bleaching optical cross-section of the NP core with the biological surface properties and functionalities provided by a self-assembled lipid membrane. We used these hybrid nanomaterials to test the roles of monosialodihexosylganglioside (GM3) and phosphatidylserine (PS) for a lipid-mediated targeting of virus-containing compartments (VCCs) in macrophages. GM3-presenting AVNs bind to CD169 (Siglec-1)–expressing macrophages, but inclusion of PS in the GM3-containing AVN membrane decreases binding. Molecular dynamics simulations of the AVN membrane and experimental binding studies of CD169 to GM3-presenting AVNs reveal Na+-mediated interactions between GM3 and PS as a potential cause of the antagonistic action on binding by the two negatively charged lipids. GM3-functionalized AVNs with no or low PS content localize to tetherin+, CD9+ VCC in a membrane composition-depending fashion, but increasing amounts of PS in the AVN membrane redirect the NP to lysosomal compartments. Interestingly, this compartmentalization is highly GM3 specific. Even AVNs presenting the related monosialotetrahexosylganglioside (GM1) fail to achieve an accumulation in VCC. AVN localization to VCC was observed for AVN with gold NP core but not for liposomes, suggesting that NP sequestration into VCC has additional requirements beyond ligand (GM3)–receptor (CD169) recognition that are related to the physical properties of the NP core. Our results confirm AVN as a scalable platform for elucidating the mechanisms of lipid-mediated viral entry pathways and for selective intracellular targeting.
Potential Consequences of High-Dose Infusion of Ketamine for Refractory Status Epilepticus: Case Reports and Systematic Literature Review

Our goal was to provide comprehensive data on the effectiveness of ketamine in refractory status epilepticus (RSE) and to describe the potential consequences of long-term ketamine infusion. Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, blocks excitatory pathways contributing to ongoing seizure. While ketamine use is standard in anaesthetic induction, no definitive protocol exists for its use in RSE, and little is known about its adverse effects in long-term, high-dose administration. We present two cases of RSE that responded rapidly to ketamine infusion, both with fatal outcomes secondary to metabolic acidosis and cardiovascular collapse. We performed a systematic review of the application and consequences of ketamine use in RSE. PubMed, Ovid, MEDLINE and PMC were searched for articles describing ketamine treatment for RSE according to a predetermined search strategy and inclusion criteria. The systematic review revealed wide discrepancies in ketamine dosing (infusion maintenance dose range 0.0075–10.5 mg/kg/hour), but good outcomes in medically managed RSE (75% of studies reported moderate or complete seizure control in adults, 62.5% in paediatrics). Additionally, literature review elucidated a potentially causal relationship between prolonged ketamine infusion and both cardiovascular and metabolic dysregulation. Ketamine is effective in RSE by antagonising excitotoxic NMDA receptors. However, there is high variability in ketamine dosing and scarce data on its safety in long-term infusion. Metabolic acidosis and haemodynamic instability associated with the use of long-term, high-dose ketamine infusions must be of concern to clinicians administering ketamine to critically ill patients.
Push-Out Bond Strength and SEM Evaluation in Roots Filled with Two Different Techniques Using New and Conventional Sealers

The aim of this study was to evaluate the influence of calcium-silicate-based sealer (Endosequence-BC-Sealer) in roots, filled with thermo-plasticized injectable technique aided by Calamus-Flow-Delivery-System, on bond strength to radicular dentin, in comparison with conventional epoxy-resin-based sealer (AH-Plus) along with cold-lateral-compaction technique. Root canals of mandibular-premolar teeth (n = 80) were instrumented using Protaper Universal rotary files and were randomly divided into four experimental groups (n = 20) as follows: (1) AH-Plus + cold-lateral-compaction technique; (2) Endosequence-BC-Sealer + cold-lateral-compaction technique; (3) AH-Plus + thermo-plasticized injectable technique; and (4) Endosequence-BC-Sealer + thermo-plasticized injectable technique. Horizontal disc shaped samples from each group (n = 60/group) were obtained and push-out bond strength testing was performed at a cross-head speed of 0.5 mm/min. Data were analyzed statistically using nonparametric Kruskal-Wallis analysis and Mann-Whitney test (p < 0.001). The statistical analysis revealed a significant difference amongst the groups (p < 0.001). The highest bond strength values were found in group 1 compared with all the other experimental groups (p < 0.001), whereas the lowest bond strength values were found in group 4 (p < 0.001). It was concluded that thermo-plasticized injectable technique with Calamus-Flow-Delivery-System lowered the bond strengths of the sealers, especially Endosequence-BC-Sealer. Therefore, this technique is not recommended to calcium-silicate-based sealers. Further studies are needed to confirm the findings of this study.
A Memory-Network Based Solution for Multivariate Time-Series Forecasting

Multivariate time series forecasting is extensively studied throughout the years with ubiquitous applications in areas such as finance, traffic, environment, etc. Still, concerns have been raised on traditional methods for incapable of modeling complex patterns or dependencies lying in real word data. To address such concerns, various deep learning models, mainly Recurrent Neural Network (RNN) based methods, are proposed. Nevertheless, capturing extremely long-term patterns while effectively incorporating information from other variables remains a challenge for time-series forecasting. Furthermore, lack-of-explainability remains one serious drawback for deep neural network models. Inspired by Memory Network proposed for solving the question-answering task, we propose a deep learning based model named Memory Time-series network (MTNet) for time series forecasting. MTNet consists of a large memory component, three separate encoders, and an autoregressive component to train jointly. Additionally, the attention mechanism designed enable MTNet to be highly interpretable. We can easily tell which part of the historic data is referenced the most.
Inhaled corticosteroids in COPD: friend or foe?

The efficacy, safety and positioning of inhaled corticosteroids (ICS) in the treatment of patients with chronic obstructive pulmonary disease (COPD) is much debated, since it can result in clear clinical benefits in some patients (“friend”) but can be ineffective or even associated with undesired side effects, e.g. pneumonia, in others (“foe”). After critically reviewing the evidence for and against ICS treatment in patients with COPD, we propose that: 1) ICS should not be used as a single, stand-alone therapy in COPD; 2) patients most likely to benefit from the addition of ICS to long-acting bronchodilators include those with history of multiple or severe exacerbations despite appropriate maintenance bronchodilator use, particularly if blood eosinophils are >300 cells·µL−1, and those with a history of and/or concomitant asthma; and 3) the risk of pneumonia in COPD patients using ICS is higher in those with older age, lower body mass index (BMI), greater overall fragility, receiving higher ICS doses and those with blood eosinophils <100 cells·µL−1. All these factors must be carefully considered and balanced in any individual COPD patient before adding ICS to her/his maintenance bronchodilator treatment. Further research is needed to clarify some of these issues and firmly establish these recommendations. The use of inhaled corticosteroids in patients with COPD must be personalised http://ow.ly/ZyFI30lDfUR
Diet as a hot topic in psychiatry: a population‐scale study of nutritional intake and inflammatory potential in severe mental illness

ically useful (95%). There has been significant concern that introducing a diagnosis of prolonged grief would increase the likelihood that clinicians will medicalize or pathologize grief. We found, however, that mental health providers who received information about PGD were no more likely to pathologize normative grief than those who did not receive this information in advance of evaluating standardized patients. Furthermore, clinicians who correctly diagnosed PGD were shown to be less likely to recommend antidepressants for individuals they accurately diagnosed with PGD andmore likely to recommend psychotherapies that have direct relevance to PGD symptoms, such as disbelief (emotion-focused therapy), loss of meaning (existential therapy), and persistent suffering (acceptance and commitment therapy). This may reflect clinicians’ perception that PGD is less biologically based than, for example, MDD. Although, like the DSM, the PGD tutorial did not offer treatment recommendations, it did describe risk factors that were psychological in nature,whichmayhave affected the recommendationsmade. This study also suggests the clinical value of using straightforward diagnostic criteria to distinguish pathological grief from other clinical presentations. The proposed PGD criteria are highly specific, which should reduce the risk of pathologizing normative grief reactions. At the same time, they are sufficiently sensitive to capture those in need. Under-recognition of PGD and misclassifying it as another diagnosis is likely to lead to suboptimal treatment. PGD improves when specific interventions, such as those recommended by the study participants, target unique pathological grief symptoms. The misdiagnosis of PGD as MDD or PTSD may promote the use of inappropriate interventions. Although this study was limited by a relatively small sample size and by the biases inherent in those who chose to participate, it demonstrates that PGD is perceived and shown to be clinically useful. We therefore believe that educating clinicians about PGD is likely to improve their ability to distinguish normal from pathological grief; to enhance communication between clinicians, patients, and their families; and to assist in the delivery of effective treatments for PGD. Wendy G. Lichtenthal, Paul K. Maciejewski, Caraline Craig Demirjian, Kailey E. Roberts, Michael B. First, DavidW. Kissane, Robert A. Neimeyer,William Breitbart, Elizabeth Slivjak, Greta Jankauskaite, Stephanie Napolitano, Andreas Maercker, Holly G. Prigerson Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medicine, New York, NY, USA; Monash University, Clayton, VIC, Australia; University of Memphis, Memphis, TN, USA; Columbia University Medical Center, New York, NY, USA; University of Zurich, Zurich, Switzerland
Rural Versus Urban Patients: Benchmarking the Outcomes of Patients with Acute Myocardial Infarction in Shanxi, China from 2013 to 2017

Rural-urban disparity in China attracts special international attention in view of the imbalance of economic development between rural and urban areas. However, few studies used patient level data to explore the disparity of health outcomes between rural and urban patients. This study aims to evaluate the trend of health outcomes between rural and urban patients hospitalized with acute myocardial infarction (AMI) in China. Using an electronic medical records (EMRs) database in Shanxi, China, we identified 87,219 AMI patients hospitalized between 2013 and 2017. We used multivariable binary logistic regressions and two-part models to estimate the association between region of origin (rural/urban) and two outcomes, in-hospital mortality and out-of-pocket (OOP) expenses. Rural patients were associated with lower in-hospital mortality and the adjusted Odds Ratios (ORs) were 0.173, 0.34, 0.605, 0.522, 0.556 (p-values < 0.001) from 2013 to 2017, respectively. For the OOP expenses, rural patients were experiencing increasing risk of having OOP expenses, with the ORs of 0.159, 0.573, 1.278, 1.281, 1.65. The coefficients for the log-linear models in the five years were 0.075 (p = 0.352), 0.61, 0.565, 0.439, 0.46 (p-values < 0.001). Policy makers in China should notice and narrow the gap of health outcomes between rural and urban patients.
Head-mounted sensors reveal visual attention of free-flying homing pigeons

ABSTRACT Gaze behavior offers valuable insights into attention and cognition. However, technological limitations have prevented the examination of animals' gaze behavior in natural, information-rich contexts; for example, during navigation through complex environments. Therefore, we developed a lightweight custom-made logger equipped with an inertial measurement unit (IMU) and GPS to simultaneously track the head movements and flight trajectories of free-flying homing pigeons. Pigeons have a limited range of eye movement, and their eye moves in coordination with their head in a saccadic manner (similar to primate eye saccades). This allows head movement to act as a proxy for visual scanning behavior. Our IMU sensor recorded the 3D movement of the birds' heads in high resolution, allowing us to reliably detect distinct saccade signals. The birds moved their head far more than necessary for maneuvering flight, suggesting that they actively scanned the environment. This movement was predominantly horizontal (yaw) and sideways (roll), allowing them to scan the environment with their lateral visual field. They decreased their head movement when they flew solo over prominent landmarks (major roads and a railway line) and also when they flew in pairs (especially when flying side by side, with the partner maintained in their lateral visual field). Thus, a decrease in head movement indicates a change in birds' focus of attention. We conclude that pigeons use their head gaze in a task-related manner and that tracking flying birds' head movement is a promising method for examining their visual attention during natural tasks. Highlighted Article: A lightweight custom-made logger equipped with an inertial measurement unit (IMU) and GPS revealed head-gaze movement during homing flights in pigeons.