Molecular docking has become an increasingly important tool for drug discovery. In this review, we present a brief introduction of the available molecular docking methods, and their development and ...applications in drug discovery. The relevant basic theories, including sampling algorithms and scoring functions, are summarized. The differences in and performance of available docking software are also discussed. Flexible receptor molecular docking approaches, especially those including backbone flexibility in receptors, are a challenge for available docking methods. A recently developed Local Move Monte Carlo (LMMC) based approach is introduced as a potential solution to flexible receptor docking problems. Three application examples of molecular docking approaches for drug discovery are provided.
The deposition of aggregated human islet amyloid polypeptide (hIAPP) in the pancreas, that has been associated with β-cell dysfunction, is one of the common pathological features of patients with ...type 2 diabetes (T2D). Therefore, hIAPP aggregation inhibitors hold a promising therapeutic schedule for T2D. Chitosan oligosaccharides (COS) have been reported to exhibit a potential antidiabetic effect, but the function of COS on hIAPP amyloid formation remains elusive. Here, we show that COS inhibited the aggregation of hIAPP and disassembled preformed hIAPP fibrils in a dose-dependent manner by thioflavin T fluorescence assay, circular dichroism spectroscopy, and transmission electron microscope. Furthermore, COS protected mouse β-cells from cytotoxicity of amyloidogenic hIAPP, as well as apoptosis and cycle arrest. There was no direct binding of COS and hIAPP, as revealed by surface plasmon resonance analysis. In addition, both chitin-oligosaccharide and the acetylated monosaccharide of COS and glucosamine had no inhibition effect on hIAPP amyloid formation. It is presumed that, mechanistically, COS regulate hIAPP amyloid formation relating to the positive charge and degree of polymerization. These findings highlight the potential role of COS as inhibitors of hIAPP amyloid formation and provide a new insight into the mechanism of COS against diabetes.
In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2, no specific and effective drugs for treating this disease have been reported until today. ...Angiotensin-converting enzyme 2 (ACE2), a receptor of SARS-CoV-2, mediates the virus infection by binding to spike protein. Although ACE2 is expressed in the lung, kidney, and intestine, its expressing levels are rather low, especially in the lung. Considering the great infectivity of COVID-19, we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection. Here, we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein. The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody, Meplazumab, inhibits SARS-CoV-2 amplification. Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells, which can be neutralized by CD147 extracellular fragment. Viral loads are detectable in the lungs of human CD147 (hCD147) mice infected with SARS-CoV-2, but not in those of virus-infected wild type mice. Interestingly, virions are observed in lymphocytes of lung tissue from a COVID-19 patient. Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dose-dependent manner, which is specifically inhibited by Meplazumab. Furthermore, CD147 mediates virus entering host cells by endocytosis. Together, our study reveals a novel virus entry route, CD147-spike protein, which provides an important target for developing specific and effective drug against COVID-19.
Artificial intelligence (AI) has invaded our daily lives, and in the last decade, there have been very promising applications of AI in the field of medicine, including medical imaging,
in vitro
...diagnosis, intelligent rehabilitation, and prognosis. Breast cancer is one of the common malignant tumors in women and seriously threatens women’s physical and mental health. Early screening for breast cancer
via
mammography, ultrasound and magnetic resonance imaging (MRI) can significantly improve the prognosis of patients. AI has shown excellent performance in image recognition tasks and has been widely studied in breast cancer screening. This paper introduces the background of AI and its application in breast medical imaging (mammography, ultrasound and MRI), such as in the identification, segmentation and classification of lesions; breast density assessment; and breast cancer risk assessment. In addition, we also discuss the challenges and future perspectives of the application of AI in medical imaging of the breast.
Ticks are important vectors of zoonotic diseases and play a major role in the circulation and transmission of many rickettsial species. The aim of this study was to investigate the carriage of ...Candidatus Rickettsia tarasevichiae (CRT) in a total of 1168 ticks collected in Inner Mongolia to elucidate the potential public health risk of this pathogen, provide a basis for infectious disease prevention, control and prediction and contribute diagnostic ideas for clinical diseases that present with fever in populations exposed to ticks. A total of four tick species, Haemaphysalis concinna (n = 21), Dermacentor nuttalli (n = 122), Hyalomma marginatum (n = 148), and Ixodes persulcatus (n = 877), were collected at nine sampling sites in Inner Mongolia, China, and identified by morphological and molecular biological methods. Reverse transcription PCR targeting the 16S ribosomal RNA (rrs), gltA, groEL, ompB and Sca4 genes was used to detect CRT DNA. Sequencing was used for pathogen species confirmation. The molecular epidemiological analysis showed that three species of ticks were infected with CRT, and the overall positive rate was as high as 42%. The positive rate of I. persulcatus collected in Hinggan League city was up to 96%, and that of I. persulcatus collected in Hulun Buir city was 50%. The pool positive rates of D. nuttalli and H. marginatum collected in Bayan Nur city and H. concinna collected in Hulun Buir city were 0%, 28% and 40%, respectively. This study revealed the high prevalence of CRT infection in ticks from Inner Mongolia and the first confirmation of CRT detected in H. marginatum in China. The wide host range and high infection rate in Inner Mongolia may dramatically increase the exposure of CRT to humans and other vertebrates. The role of H. marginatum in the transmission of rickettsiosis and its potential risk to public health should be further considered.
The dual-affinity nitrate transceptor NITRATE TRANSPORTER1.1 (NRT1.1) has two modes of transport and signaling, governed by Thr-101 (T101) phosphorylation. NRT1.1 regulates lateral root (LR) ...development by modulating nitrate-dependent basipetal auxin export and nitrate-mediated signal transduction. Here, using the Arabidopsis (
) NRT1.1
phosphomimetic and NRT1.1
nonphosphorylatable mutants, we found that the phosphorylation state of NRT1.1 plays a key role in NRT1.1 function during LR development. Single-particle tracking revealed that phosphorylation affected NRT1.1 spatiotemporal dynamics. The phosphomimetic NRT1.1
form showed fast lateral mobility and membrane partitioning that facilitated auxin flux under low-nitrate conditions. By contrast, nonphosphorylatable NRT1.1
showed low lateral mobility and oligomerized at the plasma membrane (PM), where it induced endocytosis via the clathrin-mediated endocytosis and microdomain-mediated endocytosis pathways under high-nitrate conditions. These behaviors promoted LR development by suppressing NRT1.1-controlled auxin transport on the PM and stimulating Ca
-ARABIDOPSIS NITRATE REGULATED1 signaling from the endosome.
Estrogen receptor β (ERβ) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERβ is overexpressed in ...papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERβ decreases stemness-related factors expression, diminishes ALDH
cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERβ and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERβ expression. ERβ depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERβ is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERβ expression. Collectively, our findings reveal that ERβ-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.
The identification of CN– in water, seeds, and biological systems has, because of its high toxicity, attracted the increasing attention of many chemical industry researchers. In the work, a novel ...highly selective and reversible sensor, MMY, was shown to recognize CN– effectively. The color and fluorescent changes verified the interaction of MMY with CN–, and the fluorescence lifetime of MMY was also changed upon addition of CN–. A mode of interaction of MMY with CN– based on the results of various experiments was speculated. The LOD of MMY toward CN– was 9.4 × 10–10 M, lower than the concentration of CN– deemed acceptable by the WHO (World Health Organization) and the U.S. EPA (United States Environmental Protection Agency). MMY showed good reversibility and reusability for detecting CN–. In addition, test slips and silica plates were both earned by ourselves, which were able to recognize CN– qualitatively. Additionally, MMY could recognize CN– in tap water quantitatively with the use of a smartphone APP. Interestingly, MMY was also used to detect CN– in seeds. It was valid to image CN– in Caenorhabditis elegans and mice with a vivid “turn-on” fluorescence. MMY thus can circulate in the bloodstream.
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