Miracle-dz/UniFAR-FTUs huggingface dataset:
Valproic Acid Combined with Zoledronate Enhance γδ T Cell-Mediated Cytotoxicity against Osteosarcoma Cells via the Accumulation of Mevalonate Pathway Intermediates

The long-term survival of osteosarcoma has remained unchanged in the last several decades. Immunotherapy is proved to be a promising therapeutic strategy against osteosarcoma, especially for those with metastasis. Our previous study explored the sensibilization of zoledronate (ZOL) in γδ T cell-mediated cytotoxicity against osteosarcoma, but we have not yet elucidated the specific mechanism. Besides, high concentration is required to achieve these effects, whereas plasma ZOL concentration declines rapidly in the circulation. Valproic acid (VPA), a histone deacetylase inhibitor commonly used as the antiepileptic drug, has attracted much attention due to its synergistic antitumor efficacy with chemotherapy or immunotherapy. Here, we demonstrated that VPA combined with ZOL revealed the synergistic effect in enhancing antitumor efficacy of γδ T cells against osteosarcoma cells. This enhancement was mainly TCR-mediated and largely dependent on granule exocytose pathway. Of note, our findings indicated that ZOL sensitized osteosarcoma cells to γδ T cells by increasing the accumulation of the mevalonate pathway intermediates, which could be facilitated by VPA. We also found that this combination had similar effects on primary osteosarcoma cells. All the results suggested that VPA combined with ZOL could reduce the dose required to achieve a significant antitumor effect of γδ T cells, promoting it to be a novel therapy against osteosarcoma.
Accounting for Uncertainty in Gene Tree Estimation: Summary-Coalescent Species Tree Inference in a Challenging Radiation of Australian Lizards

Accurate gene tree inference is an important aspect of species tree estimation in a summary-coalescent framework. Yet, in empirical studies, inferred gene trees differ in accuracy due to stochastic variation in phylogenetic signal between targeted loci. Empiricists should therefore examine the consistency of species tree inference, while accounting for the observed heterogeneity in gene tree resolution of phylogenomic datasets. Here, we assess the impact of gene tree estimation error on summary-coalescent species tree inference by screening ~2000 exonic loci based on gene tree resolution prior to phylogenetic inference. We focus on a phylogenetically challenging radiation of Australian lizards (genus Cryptoblepharus, Scincidae) and explore effects on topology and support. We identify a well-supported topology based on all loci and find that a relatively small number of high-resolution gene trees can be sufficient to converge on the same topology. Adding gene trees with decreasing resolution produced a generally consistent topology, and increased confidence for specific bipartitions that were poorly supported when using a small number of informative loci. This corroborates coalescent-based simulation studies that have highlighted the need for a large number of loci to confidently resolve challenging relationships and refutes the notion that low-resolution gene trees introduce phylogenetic noise. Further, our study also highlights the value of quantifying changes in nodal support across locus subsets of increasing size (but decreasing gene tree resolution). Such detailed analyses can reveal anomalous fluctuations in support at some nodes, suggesting the possibility of model violation. By characterizing the heterogeneity in phylogenetic signal among loci, we can account for uncertainty in gene tree estimation and assess its effect on the consistency of the species tree estimate. We suggest that the evaluation of gene tree resolution should be incorporated in the analysis of empirical phylogenomic datasets. This will ultimately increase our confidence in species tree estimation using summary-coalescent methods and enable us to exploit genomic data for phylogenetic inference.
The miR-644a/CTBP1/p53 axis suppresses drug resistance by simultaneous inhibition of cell survival and epithelial-mesenchymal transition in breast cancer

Tumor cells develop drug resistance which leads to recurrence and distant metastasis. MicroRNAs are key regulators of tumor pathogenesis; however, little is known whether they can sensitize cells and block metastasis simultaneously. Here, we report miR-644a as a novel inhibitor of both cell survival and EMT whereby acting as pleiotropic therapy-sensitizer in breast cancer. We showed that both miR-644a expression and its gene signature are associated with tumor progression and distant metastasis-free survival. Mechanistically, miR-644a directly targets the transcriptional co-repressor C-Terminal Binding Protein 1 (CTBP1) whose knock-outs by the CRISPR-Cas9 system inhibit tumor growth, metastasis, and drug resistance, mimicking the phenotypes induced by miR-644a. Furthermore, downregulation of CTBP1 by miR-644a upregulates wild type- or mutant-p53 which acts as a ‘molecular switch’ between G1-arrest and apoptosis by inducing cyclin-dependent kinase inhibitor 1 (p21, CDKN1A, CIP1) or pro-apoptotic phorbol-12-myristate-13-acetate-induced protein 1 (Noxa, PMAIP1), respectively. Interestingly, an increase in mutant-p53 by either overexpression of miR-644a or downregulation of CTBP1 was enough to shift this balance in favor of apoptosis through upregulation of Noxa. Notably, p53-mutant patients, but not p53-wild type ones, with high CTBP1 have a shorter survival suggesting that CTBP1 could be a potential prognostic factor for breast cancer patients with p53 mutations. Overall, re-activation of the miR-644a/CTBP1/p53 axis may represent a new strategy for overcoming both therapy resistance and metastasis.
Before Name-Calling: Dynamics and Triggers of Ad Hominem Fallacies in Web Argumentation

Arguing without committing a fallacy is one of the main requirements of an ideal debate. But even when debating rules are strictly enforced and fallacious arguments punished, arguers often lapse into attacking the opponent by an ad hominem argument. As existing research lacks solid empirical investigation of the typology of ad hominem arguments as well as their potential causes, this paper fills this gap by (1) performing several large-scale annotation studies, (2) experimenting with various neural architectures and validating our working hypotheses, such as controversy or reasonableness, and (3) providing linguistic insights into triggers of ad hominem using explainable neural network architectures.
Protective effects of carnosine on dehydroascorbate-induced structural alteration and opacity of lens crystallins: important implications of carnosine pleiotropic functions to combat cataractogenesis

The high level of dehydroascorbic acid (DHA) in the lenticular tissue is an important risk factor for the development of age-related cataracts. In this study, the effects of DHA on structure and function of lens crystallins were studied in the presence of carnosine using gel mobility shift assay, different spectroscopic techniques, and lens culture analysis. The DHA-induced unfolding and aggregation of lens proteins were largely prevented by this endogenous dipeptide. The ability of carnosine to preserve native protein structure upon exposure to DHA suggests the essential role of this dipeptide in prevention of the senile cataract development. Although the DHA-modified α-crystallin was characterized by altered chaperone activity, functionality of this protein was significantly restored in the presence of carnosine. The increased proteolytic instability of DHA-modified lens proteins was also attenuated in the presence of carnosine. Furthermore, the assessment of lens culture suggested that DHA can induce significant lens opacity which can be prevented by carnosine. These observations can be explained by the pleiotropic functions of this endogenous and pharmaceutical compound, notably by its anti-glycation and anti-aggregation properties. In summary, our study suggests that carnosine may have therapeutic potential in preventing senile cataracts linked with the increased lenticular DHA generation, particularly under pathological conditions associated with the oxidative stress.
Leydig cells contribute to the inhibition of spermatogonial differentiation after irradiation of the rat

Irradiation with 6 Gy produces a complete block of spermatogonial differentiation in LBNF1 rats that would be permanent without treatment. Subsequent suppression of gonadotropins and testosterone (T) restores differentiation to the spermatocyte stage; however, this process requires 6 weeks. We evaluated the role of Leydig cells (LCs) in maintenance of the block in spermatogonial differentiation after exposure to radiation by specifically eliminating functional LCs with ethane dimethane sulfonate (EDS). EDS (but not another alkylating agent), given at 10 weeks after irradiation, induced spermatogonial differentiation in 24% of seminiferous tubules 2 weeks later. However, differentiation became blocked again at 4 weeks as LCs recovered. When EDS was followed by treatment with GnRH antagonist and flutamide, sustained spermatogonial differentiation was induced in >70% of tubules within 2 weeks. When EDS was followed by GnRH antagonist plus exogenous T, which also inhibits LC recovery but restores follicle stimulating hormone (FSH) levels, the spermatogonial differentiation was again rapid but transient. These results confirm that the factors that block spermatogonial differentiation are indirectly regulated by T, and probably FSH, and that adult and possibly immature LCs contribute to the production of such inhibitory factors. We tested whether insulin‐like 3 (INSL3), a LC‐produced protein whose expression correlated with the block in spermatogonial differentiation, was indeed responsible for the block by injecting synthetic INSL3 into the testes and knocking down its expression in vivo with siRNA. Neither treatment had any effect on spermatogonial differentiation. The Leydig cell products that contribute to the inhibition of spermatogonial differentiation in irradiated rats remain to be elucidated.
Lactobacillus plantarum lipoteichoic acid inhibits biofilm formation of Streptococcus mutans

Dental caries is a biofilm-dependent oral disease and Streptococcus mutans is the known primary etiologic agent of dental caries that initiates biofilm formation on tooth surfaces. Although some Lactobacillus strains inhibit biofilm formation of oral pathogenic bacteria, the molecular mechanisms by which lactobacilli inhibit bacterial biofilm formation are not clearly understood. In this study, we demonstrated that Lactobacillus plantarum lipoteichoic acid (Lp.LTA) inhibited the biofilm formation of S. mutans on polystyrene plates, hydroxyapatite discs, and dentin slices without affecting the bacterial growth. Lp.LTA interferes with sucrose decomposition of S. mutans required for the production of exopolysaccharide, which is a main component of biofilm. Lp.LTA also attenuated the biding of fluorescein isothiocyanate-conjugated dextran to S. mutans, which is known to have a high affinity to exopolysaccharide on S. mutans. Dealanylated Lp.LTA did not inhibit biofilm formation of S. mutans implying that D-alanine moieties in the Lp.LTA structure were crucial for inhibition. Collectively, these results suggest that Lp.LTA attenuates S. mutans biofilm formation and could be used to develop effective anticaries agents.
Current mathematical models for cancer drug discovery

ABSTRACT Introduction: Pharmacometric models represent the most comprehensive approaches for extracting, summarizing and integrating information obtained in the often sparse, limited, and less-than-optimally designed experiments performed in the early phases of oncology drug discovery. Whilst empirical methodologies may be enough for screening and ranking candidate drugs, modeling approaches are needed for optimizing and making economically viable the learn-confirm cycles within an oncology research program and anticipating the dose regimens to be investigated in the subsequent clinical development. Areas covered: Papers appearing in the literature of approximately the last decade reporting modeling approaches applicable to anticancer drug discovery have been listed and commented. Papers were selected based on the interest in the proposed methodology or in its application. Expert opinion: The number of modeling approaches used in the discovery of anticancer drugs is consistently increasing and new models are developed based on the current directions of research of new candidate drugs. These approaches have contributed to a better understanding of new oncological targets and have allowed for the exploitation of the relatively sparse information generated by preclinical experiments. In addition, they are used in translational approaches for guiding and supporting the choice of dosing regimens in early clinical development.
Glass Capillary Tube Feeding: A Method for Infecting Nymphal Ixodes scapularis (Acari: Ixodidae) with The Lyme Disease Spirochete Borrelia burgdorferi

Abstract We evaluated an artificial capillary feeding method to infect nymphal Ixodes scapularis (Say) ticks with Borrelia burgdorferi, the causative agent of Lyme disease. Thirty to 70% of the nymphs were infected after feeding for 2.5 h from glass capillary tubes filled with a solution of spirochetes. Capillary infection was stable and persisted in the nymphs for at least 10 d after feeding. Capillary feeding also maintained natural vector competence patterns because I. scapularis ticks acquired infection unlike Dermacentor variablis (Say), which did not become infected. Capillary infected I. scapularis nymphs were capable of transmitting the infection to naive mice although not as efficiently as naturally infected nymphs. The capillary infection method is convenient and is a better alternative to syringe inoculation as a means of infecting animals with B. burgdorferi.
Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions*

Background: The role of FGFR4 in glucose and energy metabolism is not well defined. Results: FGFR4-deficient mice display improved glucose metabolism and insulin sensitivity under high fat conditions. Conclusion: These improvements are mediated in part by bile acid actions and induction of endocrine hormones. Significance: FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes. The role of fibroblast growth factor receptor 4 (FGFR4) in regulating bile acid synthesis has been well defined; however, its reported role on glucose and energy metabolism remains unresolved. Here, we show that FGFR4 deficiency in mice leads to improvement in glucose metabolism, insulin sensitivity, and reduction in body weight under high fat conditions. Mechanism of action studies in FGFR4-deficient mice suggest that the effects are mediated in part by increased plasma levels of adiponectin and the endocrine FGF factors FGF21 and FGF15, the latter of which increase in response to an elevated bile acid pool. Direct actions of increased bile acids on bile acid receptors, and other potential indirect mechanisms, may also contribute to the observed metabolic changes. The results described herein suggest that FGFR4 antagonists alone, or in combination with other agents, could serve as a novel treatment for diabetes.
A New Metre for Cheap, Quick, Reliable and Simple Thermal Transmittance (U-Value) Measurements in Buildings

This paper deals with the thermal transmittance measurement focused on buildings and specifically in building energy retrofitting. Today, if many thermal transmittance measurements in a short time are needed, the current devices, based on the measurement of the heat flow through the wall, cannot carry out them, except if a great amount of devices are used at once along with intensive and tedious post-processing and analysis work. In this paper, from well-known physical laws, authors develop a methodology based on three temperatures measurements, which is implemented by a novel thermal transmittance metre. The paper shows its development step by step. As a result the developed device is modular, scalable, and fully wireless; it is capable of taking as many measurements at once as user needs. The developed system is compared working together on a same test to the currently used one based on heat flow. The results show that the developed metre allows carrying out thermal transmittance measurements in buildings in a cheap, quick, reliable and simple way.
Thiamethoxam honey bee colony feeding study: Linking effects at the level of the individual to those at the colony level

Neonicotinoid insecticides have been used globally on a wide range of crops through seed treatment as well as soil and foliar applications and have been increasingly studied in relation to the potential risk to bees because of their detection in pollen and nectar of bee‐attractive crops. The present article reports the results of laboratory studies (10‐d adult and 22‐d larval toxicity studies assessing the chronic toxicity of thiamethoxam to adult honey bees and larvae, respectively) and a colony feeding study, with 6 wk of exposure in an area with limited alternative forage, to provide a prewintering colony‐level endpoint. The endpoints following exposure of individuals in the laboratory (10‐d adult chronic no‐observed‐effect concentration [NOEC] for mortality 117 μg thiamethoxam/kg sucrose solution, 141 μg thiamethoxam/L sucrose solution; 22‐d larval chronic NOEC 102 μg thiamethoxam/kg diet) are compared with those generated at the colony level, which incorporates sublethal effects (no‐observed‐adverse‐effect concentration [NOAEC] 50 μg thiamethoxam/L sucrose solution, 43 μg thiamethoxam/kg sucrose solution). The data for sucrose‐fed honey bee colonies support the lack of effects identified in previous colony‐level field studies with thiamethoxam. However, unlike these field studies demonstrating no effects, colony feeding study data also provide a threshold level of exposure likely to result in adverse effects on the colony in the absence of alternative forage, and a basis by which to evaluate the potential risk of thiamethoxam residues detected in pollen, nectar, or water following treatment of bee‐attractive crops. Environ Toxicol Chem 2018;37:816–828. © 2017 SETAC
Characterization of Inner Retinal Spots With Inverted Reflectivity on En Face Optical Coherence Tomography in Diabetic Retinopathy.

PURPOSE The purpose of this study was to characterize inner retinal spots with inverted reflectivity on en face images of swept-source optical coherence tomography (SS-OCT) in diabetic retinopathy (DR). METHODS We retrospectively reviewed seventy-five eyes of 75 patients with DR (15 eyes with individual grades of DR severity). We obtained three-dimensional images (6 × 6 mm) centered on the fovea, followed by the generation of en face images. We investigated the morphologic characteristics of spots with inverted reflectivity, which had lower reflectivity than the surrounding areas in the nerve fiber layer (NFL) and higher reflectivity in the ganglion cell layer (GCL). RESULTS Thirty-seven of 45 eyes (82.2%) with moderate nonproliferative diabetic retinopathy (NPDR) or more severe grades were accompanied with well-defined spots with inverted reflectivity, whereas 30 eyes with no apparent retinopathy or mild NPDR had no such lesions. These spots had various shapes in the NFL and GCL on en face OCT images; the mean area was 0.126 ± 0.052 mm2 at the NFL level. In all 75 eyes, 153 of 184 spots (83.2%) were localized in the NFL and GCL, whereas 31 spots (16.8%) extended to retinal layers deeper than the GCL. One-hundred sixty-nine spots (91.8%) were not visible on color fundus photographs, and 15 spots (8.2%) were accompanied by whitish-yellow lesions in the corresponding areas. In 45 eyes for which fluorescein angiography images were obtained, mild hypofluorescence was seen in 156 spots (84.8%) and focal nonperfused areas in 17 spots (9.2%). CONCLUSIONS En face images of SS-OCT showed spots with inverted reflectivity in the NFL and GCL in DR.
Functional assessment of knee joint position sense following anterior cruciate ligament reconstruction

Context: The anterior cruciate ligament (ACL) has both mechanical and proprioceptive (sensory) functions. Knee-joint proprioception has been assessed using either reproduction of position or threshold to detect passive motion in non-weight-bearing positions. It has been suggested that a more functional and dynamic/active assessment of proprioception might clarify the effects of injury and reconstruction on the proprioceptive function of ACL at the knee joint. Objective: To assess knee joint position sense (JPS) following ACL reconstruction in functional positions. Subjects: Twelve male patients who had undergone ACL reconstruction and 12 male healthy control subjects participated in the study. Methods and main outcome measures: JPS was evaluated by reproduction of the angles in weight-bearing position with limb movement into flexion and extension. The dominant knee of healthy subjects and both (reconstructed and uninjured) knees of the patients were tested. Absolute angular error was used as a dependent variable. Results: There was no significant difference between the operated and uninjured knees of patients or between patients and healthy controls (p⩾0.05). These results were measured during two tasks of limb movement into flexion and extension. Conclusion: We found no evidence of impaired JPS in weight-bearing positions in subjects with ACL reconstruction at a mean follow-up of 11 months after surgery compared with subjects with healthy knees.
Influence of Floating-Mass Transducer Coupling Efficiency for Active Middle-Ear Implants on Speech Recognition.

OBJECTIVE The efficiency of vibroplasty (coupler-floating mass transducer [FMT] assembly) can be monitored by direct stimulation of the inner ear through the active middle-ear implant system and comparison of the vibroplasty in vivo threshold and the postoperative bone-conduction pure-tone threshold. The aim of this study was to compare the vibroplasty in vivo threshold with the postoperative speech recognition in patients with a high preoperative maximum word recognition score. STUDY DESIGN Retrospective cohort study of German-speaking patients implanted with a vibrating ossicular prosthesis (VORP) 502 or VORP 503 and high preoperative maximum word recognition score between the years of 2011 and 2015. SETTING Multicenter study of four German centers. PATIENTS Twenty-three active middle-ear implant users. INTERVENTION Rehabilitative. MAIN OUTCOME MEASURES Bone-conduction pure-tone and vibroplasty thresholds, postoperative aided word recognition score (WRS) at 65 dB SPL (sound pressure level) and preoperative maximum WRS with Freiburg monosyllabic words. RESULTS The mean postoperative aided WRS at 65 dB SPL was 82%. An increasing difference between vibroplasty thresholds and bone-conduction thresholds was associated with a higher discrepancy between the unaided maximum WRS and the postoperative aided WRS. Only if this difference was less than 20 dB, an articulation index of 0.5 (WRS = 75%) or more was achieved. CONCLUSIONS Audiological outcome after vibroplasty depends on the coupling efficiency reflected by the vibroplasty threshold.