Advancing Transformer's Capabilities in Commonsense Reasoning

Recent advances in general purpose pre-trained language models have shown great potential in commonsense reasoning. However, current works still perform poorly on standard commonsense reasoning benchmarks including the Com2Sense Dataset. We argue that this is due to a disconnect with current cutting-edge machine learning methods. In this work, we aim to bridge the gap by introducing current ML-based methods to improve general purpose pre-trained language models in the task of commonsense reasoning. Specifically, we experiment with and systematically evaluate methods including knowledge transfer, model ensemble, and introducing an additional pairwise contrastive objective. Our best model outperforms the strongest previous works by ~15\% absolute gains in Pairwise Accuracy and ~8.7\% absolute gains in Standard Accuracy

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Aim of this study was the site-specific conjugation of an epidermal growth factor (EGF)-polyethylene glycol (PEG) chain by click chemistry onto a poly(amido amine) (PAMAM) dendron, as a key step toward defined multifunctional carriers for targeted gene delivery. For this purpose, at first propargyl amine cored PAMAM dendrons with ester ends were synthesized. The chain terminal ester groups were then modified by oligoamines with different secondary amino densities. The oligoamine-modified PAMAM dendrons were well biocompatible, as demonstrated in cytotoxicity assays. Among the different oligoamine-modified dendrons, PAMAM-pentaethylenehexamine (PEHA) dendron polyplexes displayed the best gene transfer ability. Conjugation of PAMAM-PEHA dendron with PEG spacer was conducted via click reaction, which was performed before amidation with PEHA. The resultant PEG-PAMAM-PEHA copolymer was then coupled with EGF ligand. pDNA transfections in HuH-7 hepatocellular carcinoma cells showed a 10-fold higher efficiency with the polyplexes containing conjugated EGF as compared to the ligand-free ones, demonstrating the concept of ligand targeting. Overall gene transfer efficiencies, however, were moderate, suggesting that additional measures for overcoming subsequent intracellular bottlenecks in delivery have to be taken

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood–brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS

Study on the Static and Dynamic Fracturing Properties of Marble after Being Damaged Dynamically

A split Hopkinson pressure bar (SHPB) system was first used to perform the cyclic impact loading tests on notched semicircular bend (NSCB) marble specimens. Then, static and dynamic three-point bending tests were conducted on these dynamically damaged specimens, respectively. In the cyclic impact loading tests, the dynamic elastic modulus decreases gradually as the impact number increases, but dynamic cumulative damage exhibits a growing trend. In the static and dynamic three-point bending tests, when dynamic cumulative damage is less than 0.345, the dynamic fracture toughness values are larger than the static fracture toughness values, but the experimental data exhibit the opposite results when dynamic cumulative damage ranges from 0.345 to 0.369. Through the quantitative analysis of fracture surface morphologies, the roughness and area of the fracture surfaces increase with an increasing dynamic cumulative damage. Under the same dynamic cumulative damage of the specimens, both the roughness and area of the surfaces fractured by static three-point bending are larger than those fractured by dynamic three-point bending

Optimizing Management of the Qinling–Daba Mountain Area Based on Multi-Scale Ecosystem Service Supply and Demand

Accurately identifying the supply and demand of ecosystem services at multiple scales and determining the factors that influence the supply–demand relationship are crucial for guiding the sustainable management and restoration of regional ecosystem services. In view of this, we quantified the supply and demand of five ecosystem services at multiple scales in the Qinling–Daba Mountain area based on spatial and statistical data, exploring the relationships between the supply and demand for ecosystem services at multiple scales and examining the mechanisms by which factors like natural and human activities affect the evolution of the supply and demand patterns of these services. The results show that (1) there was no risk associated with supply and demand of ESs in the Qinling–Daba Mountain area, and numerous ESs were in excess. The impact of ES supply and demand became increasingly clear as the spatial scale was increased. (2) Under multiple spatial scales, the relationship between the supply and demand of ESs will change. At the mesoscale, the relationship between ES supply and demand was the most significant, whereas at the macroscale, the relationship between ES demands was the most significant. (3) Cultivated land, grass land, and forest land are the key land use categories in regional ecosystem service hotspots, providing richer ecosystem service functions for the region. (4) Precipitation and NDVI are the main elements determining the supply of ecosystem services. While GDP and population density have a significant impact on the demand for ecosystem services, natural causes are primarily responsible for trade-offs in ecosystem services. This study aims to evaluate the supply–demand relationship and driving factors of multiple scale in the Qinling–Daba Mountains, providing a scientific basis for the sustainable management of ecosystems in the region

Oncogenic HPV-induced high expression of ESM1 predicts poor prognosis and regulates aerobic glycolysis in cervical cancer

Summary: The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory mechanisms in relation to cervical cancer remain insufficiently understood. Through bioinformatics analysis, we revealed that ESM1 was highly expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and correlated with dismal clinicopathological features. The activation of ESM1 is facilitated by the presence of oncogenic HPV E6 and E7. HPV E6 and E7 enhance the expression of ESM1 by diminishing the levels of miR-205-5p, which specifically targets the 3′ untranslated region of ESM1 mRNA. In addition, we demonstrated that ESM1 facilitates aerobic glycolysis of cervical cancer cells via the Akt/mTOR pathway. Suppression of ESM1 led to a reduction in the expression of HIF-1α and multiple glycolytic enzymes. Taken together, our findings provide insights into the mechanisms by which HPV infections regulate oncogenes, thereby contributing to cervical carcinogenesis

Additional file 1 of Serum lipidomic study of long-chain fatty acids in psoriasis patients prior to and after anti-IL-17A monoclonal antibody treatment by quantitative GC‒MS analysis with in situ extraction

Additional file 1: Table S1. Qualitative and quantitative ions of 14 LCFAs in SIM mode. Table S2. Concentrations (μM) of LCFAs in serum samples of healthy individuals and psoriasis patients receiving pretherapy and posttreatment with anti-IL-17A mAb. Table S3. Concentrations (μM) of LCFAs in serum samples of IMQ-treat WT and Tcrd-/- mice. Fig. S1. LCFAs derivatization method optimization. To achieve optimal efficiency, 30 μL LCFAs should be heated in the 500 μL 15% BF3-CH3OH solution (a-c) at 40°C for 30 minutes (d, e). Dichloromethane was also recommended as a superior extraction solvent (f). *P <0.05, **P <0.01, ***P <0.001, ****P <0.0001. Fig. S2. Correlation analysis of serum ω-6 (a) and ω-3 (b) PUFAs with PASI scores in psoriasis patients. Fig. S3. LCFAs were conducted on ROC curve analysis. AUC values of 10 LCFAs in the PSV/HC (a) and W8/PSV (b) comparisons