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One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable activity. Traditional drug development typically begins with target selection, but the correlation between targets and disease remains to be further investigated, and drugs designed based on targets may not always have the desired drug efficacy. The emergence of machine learning provides a powerful tool to overcome the challenge. Herein, a machine learning‐based strategy is developed for de novo generation of novel compounds with drug efficacy termed DTLS (Deep Transfer Learning‐based Strategy) by using dataset of disease‐direct‐related activity as input. DTLS is applied in two kinds of disease: colorectal cancer (CRC) and Alzheimer's disease (AD). In each case, novel compound is discovered and identified in in vitro and in vivo disease models. Their mechanism of actionis further explored. The experimental results reveal that DTLS can not only realize the generation and identification of novel compounds with drug efficacy but also has the advantage of identifying compounds by focusing on protein targets to facilitate the mechanism study. This work highlights the significant impact of machine learning on the design of novel compounds with drug efficacy, which provides a powerful new approach to drug discovery. [ABSTRACT FROM AUTHOR]

Objective: To explore role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in idiopathic membranous nephropathy (IMN) and its possible mechanism of activation. Methods: A total of 135 patients with no adrenal corticosteroid and immunosuppressive therapy who were diagnosed with IMN by renal biopsy were collected, and 10 patients with renal tuberculosis and renal tumors who underwent nephrectomy were selected as control group. Immunohistochemical was used to detect NLRP3, tumor necrosis factor receptor-related factor 6 (TRAF6), Caspase-1, NF-κB p65, MAPK signaling pathway-related proteins, including phosphorylated ERK1/2 (p-ERK1/2), phosphorylated p38 (p-p38), phosphorylated JNK (p-JNK) expressions. Blood and 24-hour urine of IMN patients were collected, and 24-hour urine protein quantification, serum creatinine, creatinine clearance rate, blood urea nitrogen and other general clinical data were were analyzed, correlation between urine protein and NLRP3, Caspase-1, IL-1β, TNF- α, NLRP3 and TRAF6 were analyzed, respectively. Results: Compared with control group, 24-hour urine protein and serum creatinine of IMN patients were significantly increased (both P<0.05), and protein expressions of NLRP3 and Caspase-1 in kidney tissues of IMN patients were significantly increased (both P<0.05), among which renal tissue of stage II IMN patients had the highest protein expressions of NLRP3 and Caspase-1, IL-1β and TNF- α expressions were enhanced (both P<0.05), and IL-1β and TNF-α protein expressions in renal tissue of stage II IMN patients were the strongest, protein expressions of NF-κB p65, p-ERK1/2, p-p38 and p-JNK were significantly increased (all P<0.05) . 24-hour urinary protein of IMN patients was positively correlated with expression of NLRP3 protein in kidney tissues (r=0.689, P<0.01), positively correlated with Caspase-1 protein (r=0.614, P<0.000 1), positively correlated with IL-1β (r=0.708, P<0.000 1), positively correlated with TNF-α (r=0.594, P<0.01) . Conclusion: TRAF6 induces ERK1/2, p38 and JNK signaling pathways to stimulate activation of NLRP3 inflammasome through activation of NF-κB, which promotes occurrence of IMN and production of large amounts of urine protein. [ABSTRACT FROM AUTHOR]

The mechanical properties of the cell membrane play an important role in electroporation. This paper studied the influence of the mechanical properties of the cell membrane on the transition energy of electroporation through both modeling and experiments. An electromechanical coupling model of a single pore on the cell membrane was established in COMSOL, and the effect of elastic strain energy on the formation of pores was analyzed. Additionally, to compare the transition energy barrier of pores for different elastic properties of the cell membrane, electroporation experiments were carried out at different temperatures. The simulation showed that the elastic strain energy of the cell membrane increased the transition energy barrier of the pores. The experiments also showed that the transition energy barrier was larger when the elasticity of the cell membrane is intact, which was in good agreement quantitatively with the simulation results. We demonstrated that the mechanical properties of the cell membrane hinder the pore formation, which may be due to the increase of the transition energy barrier. We analyzed the possible mechanism of the effect of cell membrane mechanical properties on electroporation and found the contribution of cell membrane mechanical properties to electroporation during the delivery of exogenous substances, which can provide guidance for improving therapies in electrochemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Total hip arthroplasty (THA) is often associated with moderate to severe pain. The present study compared the efficacy of circum-psoas block (CPB) with supra-inguinal fascia iliaca block (SIFIB) for postoperative analgesia in patients undergoing THA.Patients and Methods: In this randomized trial, sixty-four patients undergoing THA were allocated randomly to the CPB group or SIFIB group with 40 mL of 0.3% ropivacaine. The primary outcome was dynamic pain score at 6 h postoperatively. Secondary outcomes included dynamic pain scores at 12, 24 and 48 h; static pain scores; sensory and motor block; opioid consumption; time to first opioid request; length of hospital stay; patient satisfaction; and adverse events.Results: CPB patients showed significantly lower dynamic pain scores at 6 (3.11 ± 0.66 vs 4.47 ± 0.74, respectively; P = 0.000), 12 (2.52 ± 0.73 vs 3.53 ± 0.85, respectively; P = 0.000) and 24 h (2.30 ± 0.57 vs 2.87 ± 0.71, respectively; P = 0.001) after surgery, as well as lower static pain scores at 6 and 12h (P = 0.001 and P = 0.033 respectively) than SIFIB patients. Lower opioid consumption was observed in the CPB group at 24 and 48 h (P = 0.000, both) than in the SIFIB group. Patients in the CPB group reported improved quadriceps strength at 6 and 12 h (P = 0.000, both), as well as better muscle strength of hip flexion at 6, 12 and 24 h (P = 0.000, P = 0.000 and P = 0.025 respectively). Compared with SIFIB, CPB was associated with increased sensory block coverage at 6, 12 and 24 h (P = 0.000, P = 0.000, and P =0.022, respectively).Conclusion: CPB has a greater potential to alleviate postoperative pain and improve recovery in THA patients than SIFIB. [ABSTRACT FROM AUTHOR]