Search

Objective: The objective of this study was to investigate the protective mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) against LPS-ATP-induced pyroptosis in H9c2 cells., Methods: LPS and ATP were used to induce pyroptosis in the H9c2 cell, and the cells were divided into the control, model and LGZGD groups. LDH level was detected using a colorimetric assay. ELISA was used to detect the expressions of IL-1β. Flow cytometry was utilized to observe apoptosis, while Hoechst/PI staining was used to detect pyroptosis. Immunofluorescence was employed to observe the expression levels of NLRP3 in cardiomyocytes, and RT-PCR was used to detect NLRP3, Caspase-1, GSDMD, and ASC mRNA expression. The cells were separated into seven groups: control, model, LGZGD, MCC950, LGZGD+MCC950, Nigericin and LGZGD+Nigericin. The mRNA and protein expressions were determined by RT-PCR and Western blot., Results: LPS (10 μg/mL) for 12 h and ATP (8 mM) for 2 h were used as modeling condition. LGZGD demonstrated a significant reduction in LDH, and IL-1β levels (P<0.05, P<0.01). LGZGD dramatically reduced apoptosis rate, inhibited pyroptosis, decreased the fluorescence expressions of NLRP3, and reduced the mRNA expressions of NLRP3, ASC, Caspase-1, and GSDMD (P<0.01). Further mechanism studies showed that NLRP3, ASC, Caspase-1, and GSDMD decreased significantly when combined with NLRP3 inhibitor MCC950. Furthermore, LGZGD was able to effectively reverse the upregulation of protein and gene expression of Nigericin group (P<0.01)., Conclusion: LGZGD inhibits LPS-ATP-induced pyroptosis in H9c2 cell via the NLRP3/Caspase-1 signaling pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

The binding of nicotine (NCT) to acetylcholine-binding protein (AChBP) plays an important role in synaptic transmission and neurotransmitter regulation. However, effectively regulating their binding or dissociation processes remains a challenging problem. In this study, we employed all-atom molecular dynamics (MD) simulations to systematically investigate the impact of external terahertz (THz) waves on the binding kinetics between AChBP and NCT. We first identified the key residues (i.e., W143) and the key interactions (i.e., hydrogen bonding and cation-π interaction) in AChBP-NCT binding without THz waves. We then investigated the binding and dissociation of charged NCT with AChBP at three different frequencies (i.e., 13.02, 21.44, 42.55 THz). Importantly, the predominant vibrational modes at 13.02 THz can drive the rotation of the pentagonal ring on NCT. This leads to the disruption of hydrogen bonds between NCT and W143 and a reduced likelihood of forming cation-π interactions, resulting in the dissociation of NCT from AChBP. Additionally, we further investigated the influence of electric field intensities on the dissociation kinetics and found that when the electric field intensity exceeds a critical value (∼0.60 V/nm), the probability of ligand dissociation gradually rises as the intensity increases. In general, this study contributes to a better understanding of the effects of THz waves on protein-ligand interactions, which might also shed some light on potential applications in nicotine addiction treatment and therapeutic strategies for neurodegenerative diseases.

Human pharyngeal squamous cell carcinoma (HPSCC) is the most common malignancy in the head and neck region, characterized by high mortality and a propensity for metastasis. Fucoxanthin, a carotenoid isolated from brown algae, exhibits pharmacological properties associated with the suppression of tumor proliferation and metastasis. Nevertheless, its potential to inhibit HPSCC proliferation and metastasis has not been fully elucidated. This study represents the first exploration of the inhibitory effects of fucoxanthin on two human pharyngeal squamous carcinoma cell lines (FaDu and Detroit 562), as well as the mechanisms underlying those effects. The results showed dose-dependent decreases in the proliferation, migration, and invasion of HPSCC cells after fucoxanthin treatment. Further studies indicated that fucoxanthin caused a significant reduction in the expression levels of proteins in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, as well as the downstream proteins matrix metalloproteinase (MMP)-2 and MMP-9. Specific activators of PI3K/AKT reversed the effects of fucoxanthin on these proteins, as well as on cell proliferation and metastasis, in FaDu and Detroit 562 cells. Molecular docking assays confirmed that fucoxanthin strongly interacted with PI3K, AKT, mTOR, MMP-2, and MMP-9. Overall, fucoxanthin, a functional food component, is a potential therapeutic agent for HPSCC.

The size or the curvature of nanoparticles (NPs) plays an important role in regulating the composition of the protein corona. However, the molecular mechanisms of how curvature affects the interaction of NPs with serum proteins still remain elusive. In this study, we employ all-atom molecular dynamics simulations to investigate the interactions between two typical serum proteins and PEGylated Au NPs with three different surface curvatures (0, 0.1, and 0.5 nm -1 , respectively). The results show that for proteins with a regular shape, the binding strength between the serum protein and Au NPs decreases with increasing curvature. For irregularly shaped proteins with noticeable grooves, the binding strength between the protein and Au NPs does not change obviously with increasing curvature in the cases of smaller curvature. However, as the curvature continues to increase, Au NPs may act as ligands firmly adsorbed in the protein grooves, significantly enhancing the binding strength. Overall, our findings suggest that the impact of NP curvature on protein adsorption may be nonmonotonic, which may provide useful guidelines for better design of functionalized NPs in biomedical applications.

The effective isolation of rare target cells, such as circulating tumor cells, from whole blood is still challenging due to the lack of a capturing surface with strong target-binding affinity and non-target-cell resistance. Here we present a solution leveraging the flexibility of bacterial virus (phage) nanofibers with their sidewalls displaying target circulating tumor cell-specific aptamers and their ends tethered to magnetic beads. Such flexible phages, with low stiffness and Young's modulus, can twist and adapt to recognize the cell receptors, energetically enhancing target cell capturing and entropically discouraging non-target cells (white blood cells) adsorption. The magnetic beads with flexible phages can isolate and count target cells with significant increase in cell affinity and reduction in non-target cell absorption compared to magnetic beads having rigid phages. This differentiates breast cancer patients and healthy donors, with impressive area under the curve (0.991) at the optimal detection threshold (>4 target cells mL -1 ). Immunostaining of captured circulating tumor cells precisely determines breast cancer subtypes with a diagnostic accuracy of 91.07%. Our study reveals the power of viral mechanical attributes in designing surfaces with superior target binding and non-target anti-fouling., (© 2024. The Author(s).)

This study investigated the mechanism by which fucoxanthin acts as a novel ferroptosis inducer to inhibit tongue cancer. The MTT assay was used to detect the inhibitory effects of fucoxanthin on SCC-25 human tongue squamous carcinoma cells. The levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and total iron were measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to assess glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (Nrf2), Keap1, solute carrier family 7 member 11 (SLC7A11), transferrin receptor protein 1 (TFR1), p53, and heme oxygenase 1 (HO-1) expression. Molecular docking was performed to validate interactions. Compared with the control group, the activity of fucoxanthin-treated SCC-25 cells significantly decreased in a dose- and time-dependent manner. The levels of MMP, GSH, and SOD significantly decreased in fucoxanthin-treated SCC-25 cells; the levels of ROS, MDA, and total iron significantly increased. mRNA and protein expression levels of Keap1, GPX4, Nrf2, and HO-1 in fucoxanthin-treated cells were significantly decreased, whereas levels of TFR1 and p53 were significantly increased, in a concentration-dependent manner. Molecular docking analysis revealed that binding free energies of fucoxanthin with p53, SLC7A11, GPX4, Nrf2, Keap1, HO-1, and TFR1 were below -5 kcal/mol, primarily based on active site hydrogen bonding. Our findings suggest that fucoxanthin can induce ferroptosis in SCC-25 cells, highlighting its potential as a treatment for tongue cancer.

Understanding the dynamics of neurotransmitters is crucial for unraveling synaptic transmission mechanisms in neuroscience. In this study, we investigated the impact of terahertz (THz) waves on the aggregation of four common neurotransmitters through all-atom molecular dynamics (MD) simulations. The simulations revealed enhanced nicotine (NCT) aggregation under 11.05 and 21.44 THz, with a minimal effect at 42.55 THz. Structural analysis further indicated strengthened intermolecular interactions and weakened hydration effects under specific THz stimulation. In addition, enhanced aggregation was observed at stronger field strengths, particularly at 21.44 THz. Furthermore, similar investigations on epinephrine (EPI), 5-hydroxytryptamine (5-HT), and γ-aminobutyric acid (GABA) corroborated these findings. Notably, EPI showed increased aggregation at 19.05 THz, emphasizing the influence of vibrational modes on aggregation. However, 5-HT and GABA, with charged or hydrophilic functional groups, exhibited minimal aggregation under THz stimulation. The present study sheds some light on neurotransmitter responses to THz waves, offering implications for neuroscience and interdisciplinary applications.

The cellular uptake of nanoparticles (NPs) by biological cells is an important and fundamental process in drug delivery. Previous studies reveal that the physicochemical properties of nanoparticles as well as those of functionalized ligands can both critically affect the uptake behaviors. However, the effect of the conjugation strategy (i.e., the "bond" between the ligand and the NP) on the cellular uptake is overlooked and remains largely elusive. Here, by taking the broadly employed gold nanoparticle as an example, we comprehensively assessed the relationship between the conjugation strategy and uptake behaviors by introducing three ligands with the same functional terminal but different anchoring sites. As revealed by in vitro cell experiments and multiscale molecular simulations, the uptake efficiency of gold NPs was positively correlated with the strength of the "bond" and more specifically the ligand mobility on the NP surface. Moreover, we validated the results presented above by proposing a thermodynamic theory for the wrapping of NPs with mobile ligands. Further, we also showed that the endocytic pathway of NPs was highly dependent on ligand mobility. Overall, this study uncovered a vital role of conjugation strategy in the cellular uptake and may provide useful guidelines for tailoring the biobehaviors of nanoparticles.

Biomolecular condensates formed by multicomponent phase separation play crucial roles in diverse cellular processes. Accurate assessment of individual-molecule contributions to condensate formation and precise characterization of their spatial organization within condensates are crucial for understanding the underlying mechanism of phase separation. Using molecular dynamics simulations and graph theoretical analysis, we demonstrated quantitatively the significant roles of cation-π and π-π interactions mediated by aromatic residues and arginine in the formation of condensates in polypeptide systems. Our findings reveal temperature and chain length-dependent alterations in condensate network parameters, such as the number of condensate network layers, and changes in aggregation and connectivity. Notably, we observe a transition between assortativity and disassortativity in the condensate network. Moreover, polypeptides W, Y, F, and R consistently promote condensate formation, while the contributions of other charged and two polar polypeptides (Q and N) to condensate formation depend on temperature and chain length. Furthermore, polyadenosine and polyguanosine can establish stable connections with aromatic and R polypeptides, resulting in the reduced involvement of K, E, D, Q, and N in phase separation. Overall, this study provides a distinctive, precise, and quantitative approach to characterize the multicomponent phase separation., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The susceptibility of DNA nanomaterials to enzymatic degradation in biological environments is a significant obstacle limiting their broad applications in biomedicine. While DNA nanostructures exhibit some resistance to nuclease degradation, the underlying mechanism of this resistance remains elusive. In this study, the interaction of tetrahedral DNA nanostructures (TDNs) and double-stranded DNA (dsDNA) with DNase I is investigated using all-atom molecular dynamics simulations. Our results indicate that DNase I can effectively bind to all dsDNA molecules, and certain key residues strongly interact with the nucleic bases of DNA. However, the binding of DNase I to TDNs exhibits a non-monotonic behavior based on size; TDN15 and TDN26 interact weakly with DNase I (∼ - 75 kcal/mol), whereas TDN21 forms a strong binding with DNase I (∼ - 110 kcal/mol). Furthermore, the topological properties of the DNA nanostructures are analyzed, and an under-twisting (∼32°) of the DNA helix is observed in TDN15 and TDN26. Importantly, this under-twisting results in an increased width of the minor groove in TDN15 and TDN26, which primarily explains their reduced binding affinity to DNase I comparing to the dsDNA. Overall, this study demonstrated a novel mechanism for local structural control of DNA at the nanoscale by adjusting the twisting induced by length., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hong-Ming Ding reports financial support was provided by the National Natural Science Foundation of China. Yu-Qiang Ma reports financial support was provided by the National Natural Science Foundation of China., (Copyright © 2023. Published by Elsevier B.V.)

Neutral nanomaterials functionalized with PEG or similar molecules have been popularly employed as nanomedicines. Compared to positive counterparts that are capable of harnessing the well-known proton sponge effect to facilitate their escape from lysosomes, it is yet unclear how neutral substances got their entry into the cytosol. In this study, by taking PEGylated, neutral Au nanospheres as an example, we systematically investigated their time-dependent translocation postuptake. Specifically, we harnessed dissipative particle dynamics simulations to uncover how nanospheres bypass lysosomal entrapment, wherein a mechanism termed as "squeezing-out" mode was discovered. We next conducted a comprehensive investigation on how nanomaterials implicate lysosomes in terms of integrity and functionality. By using single-molecule imaging, specific preservation of PEG-terminated with targeting moieties in lysosomes supports the "squeezing-out" mode as the mechanism underlying the lysosomal escape of nanomaterials. All evidence points out that such a process is benign to lysosomes, wherein the escape of nanomaterials proceeds at the expense of targeting moieties loss. Furthermore, we proved that by fine-tuning of the efficacy of nanomaterials escaping from lysosomes, modulation of distinct pathways and metabolic machinery can be achieved readily, thereby offering us a simple and robust tool to implicate cells.

The fluorinated decorations have recently been widely used in many biomedical applications. However, the potential mechanism of the fluorination effect on the cellular delivery of nanoparticles (NPs) still remains elusive. In this work, we systemically explore the penetration of a perfluoro-octanethiol-coated gold NP (PF-Au NP) and, for comparison, an octanethiol-coated gold NP (OT-Au NP) across lipid bilayers. We also investigated the effect of these two types of NPs on the properties of lipid bilayers. Our findings indicate that the lipid type and the surface tension of the lipid bilayer significantly impact the penetration capabilities of the fluorinated gold NP. By examining the distribution of ligands on the surface of the two types of NPs in water and during the penetration process, we unveil their distinct penetration characteristics. Specifically, the PF-Au NP exhibits amphiphobic behavior (both hydrophobic and lipophobic), while the OT-Au NP exhibits solely hydrophobic characteristics. Finally, we observe that the penetration capabilities can be increased by adjusting the degree of fluorination of the ligands on the NP surface. Overall, this study provides useful physical insights into the unique properties of the fluorinated decorations in NP permeation.

As one of the most promising types of label-free nanopores has great potential for DNA sequencing via fast detection of different DNA bases. As one of the most promising types of label-free nanopores, two-dimensional nanopore materials have been developed over the past two decades. However, how to detect different DNA bases efficiently and accurately is still a challenging problem. In the present work, the translocation of four homogeneous DNA strands ( i.e. , poly(A) 20 , poly(C) 20 , poly(G) 20 , and poly(T) 20 ) through two-dimensional transition-metal carbide (MXene) membrane nanopores with different surface terminal groups is investigated via all-atom molecular dynamics simulations. Interestingly, it is found that the four types of bases can be distinguished by different ion currents and dwell times when they are transported through the Ti 3 C 2 (OH) 2 nanopore. This is mainly attributed to the different orientation and position distributions of the bases, the hydrogen bonding inside the MXene nanopore, and the interaction of the ssDNA with the nanopore. The present study enhances the understanding of the interaction between DNA strands and MXene nanopores with different functional groups, which may provide useful guidelines for the design of MXene-based devices for DNA sequencing in the future., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Amyloid-β (Aβ) and its assemblies play important roles in the pathogenesis of Alzheimer's disease (AD). Recent studies conducted by experimental and computational researchers have extensively explored the structure, assembly, and influence of biomolecules and cell membranes on Aβ. However, the impact of terahertz waves on the structures of Aβ monomers and aggregates remains largely unexplored. In this study, we systematically investigate the molecular mechanisms by which terahertz waves affect the structure of the Aβ42 monomer, dimer, and tetramer through all-atom molecular dynamics (MD) simulations. Our findings indicate that terahertz waves at a specific frequency (42.55 THz) can enhance intramolecular and intermolecular interactions in the Aβ42 monomer and dimer, respectively, by resonating with the symmetric stretching mode of the -COO - groups and the symmetric bending/stretching mode of -CH 3 groups. Consequently, the β-structure content of the Aβ42 monomer is greatly increased, and the binding energy between the monomers in the Aβ42 dimer is significantly enhanced. Additionally, our observations suggest that terahertz waves can mildly stabilize the structure of tetrameric protofibrils by enhancing the interactions among peripheral peptides. Furthermore, we also investigated the effect of the frequency of terahertz waves on the structure of Aβ42. The present study contributes to a better understanding of the impact of external fields on the biobehavior of Aβ42 peptides and may shed some light on the potential risks associated with electromagnetic field radiation.

Background: There is epidemiological evidence which suggests an association between 25-hydroxyvitamin D [25(OH)D] levels and bone and muscle function; however, it is unclear whether vitamin D supplementation has an added benefit beyond bone health. Here, we investigated the effects of vitamin D 3 supplementation (1 month) on physical performance in Chinese university students in winter., Methods: One hundred and seventeen eligible subjects with 25(OH)D (19.2 ± 7.8 ng/mL) were randomly assigned to either vitamin D 3 supplement ( N  = 56; 1000 IU/day) or the control ( N  = 61) group for 1 month. Pre- and post-measurements included: 1) serum levels of 25(OH)D; 2) musculoskeletal and pulmonary function [vertical jump height (VJH) and right handgrip strength (RHS), forced vital capacity (FVC), and forced expiratory volume at 1s (FEV 1 )]; 3) bone turnover markers [parathyroid hormone (PTH), n-terminal osteocalcin (N-MID), and calcium]; 4) hemoglobin-related parameters [hemoglobin (Hb), hematocrit (HCT), red blood cells (RBC), and red cell distribution width (RDW)]; 5) lipid parameters [total triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C)]; 6) Fatigue-related indicators [serum creatine kinase (CK), lactate dehydrogenase (LDH), and total testosterone (T)]. In addition, aerobic capacity was assessed by measuring maximal oxygen uptake (VO 2 max) at baseline., Results: During wintertime, supplementation with 1000 IU/d of vitamin D 3 significantly increased serum 25(OH)D levels (from 18.85 ± 7.04 to 26.98 ± 5.88 ng/mL, p  < 0.05), accompanied by a decrease of PTH ( p  < 0.05). However, vitamin D 3 supplementation did not significantly impact the physical performance, serum lipid parameters, and bone turnover markers of students. Furthermore, 25(OH)D was found to be positively correlated with VJH and negatively correlated with PTH and TC at the beginning and end of the study ( p  < 0.05). In addition, the multiple linear regression analysis showed that 25(OH)D combined with athletic, gender, height, weight, Hb, and FVC could account for 84.0% of the VO 2 max value., Conclusions: The study demonstrated that one-month of 1000 IU/d of vitamin D3 supplementation during the winter had beneficial effects on 25(OH)D status and PTH. However, vitamin D 3 intervention was not sufficient to improve physical performance. Furthermore, 25(OH)D levels combined with athletic, Hb and FVC could be a predictor of VO 2 max.

Recently, the asymmetric bifunctionalization of alkenes has received much attention. However, the development of enantioselective alkoxyalkenylation has posed a considerable challenge and has lagged largely behind. Herein, we report a new palladium-catalyzed enantioselective alkoxyalkenylation reaction, using a range of primary, secondary, and tertiary γ-hydroxy-alkenes with alkenyl halides. By employing newly identified Xu-Phos (Xu8 and Xu9) with a suitable side-arm adjacent to the PCy 2 motif, a series of allyl-substituted tetrahydrofurans were obtained in good yields with up to 95% ee. Besides (E)-alkenyl halides, (Z)-alkenyl halide was also examined and provided the corresponding (Z)-product as a single diastereomer, supporting a stereospecific oxidative addition and reductive elimination step. Moreover, deuterium labeling and VCD experiments were employed to determine a cis-oxypalladation mechanism. DFT calculations helped us gain deeper insight into the side-arm effect on the chiral ligand. Finally, the practicability of this method is further demonstrated through a gram-scale synthesis and versatile transformations of the products., (© 2023. The Author(s).)

Nanopore-based biomolecule detection has emerged as a promising and sought-after innovation, offering high throughput, rapidity, label-free analysis, and cost-effectiveness, with potential applications in personalized medicine. However, achieving efficient and tunable biomolecule capture into the nanopore remains a significant challenge. In this study, we employ all-atom molecular dynamics simulations to investigate the capture of double-stranded DNA (dsDNA) molecules into graphene nanopores with varying positive charges. We discover a non-monotonic relationship between the DNA capture rate and the charge of the graphene nanopore. Specifically, the capture rate initially decreases and then increases with an increase in nanopore charge. This behavior is primarily attributed to differences in the electrophoretic force, rather than the influence of electroosmosis or counterions. Furthermore, we also observe this non-monotonic trend in various ionic solutions, but not in ionless solutions. Our findings shed light on the design of novel DNA sequencing devices, offering valuable insights into enhancing biomolecule capture rates in nanopore-based sensing platforms.

Although numerous epidemiological studies investigated the association between dietary fat intakes or serum lipid levels and ovarian cancer risk, a consistent and explicit conclusion for specific dietary fats or serum lipids that increase the risk of ovarian cancer is not available. In this study, a systematic review and meta-analysis were conducted to assess the key dietary fats and serum lipids that increased the risk of ovarian cancer. Databases such as PubMed, Web of Science, and EMBASE were searched for observational studies. A total of 41 studies met the inclusion criteria, including 18 cohort and 23 case-control studies (109,507 patients with ovarian cancer and 2,558,182 control/non-ovarian cancer participants). Higher dietary intakes of total fat (RR = 1.19, 95% CI = 1.06-1.33, I 2 = 60.3%), cholesterol (RR = 1.14, 95% CI = 1.03-1.26, I 2 = 19.4%), saturated fat (RR = 1.13, 95% CI = 1.04-1.22, I 2 = 13.4%), and animal fat (RR = 1.21, 95% CI = 1.01-1.43, I 2 = 70.5%) were significantly associated with a higher risk of ovarian cancer. A higher level of serum triglycerides was accompanied by a higher risk of ovarian cancer (RR = 1.33, 95% CI = 1.02-1.72, I 2 = 89.3%). This meta-analysis indicated that a higher daily intake of total fat, saturated fat, animal fat, and cholesterol and higher levels of serum triglycerides were significantly associated with an increased risk of ovarian cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Ding, Deng, Chen, Li, He, Fu, Li, Jiang, Zhang and Li.)

The specific recognition of serum proteins by scavenger receptors is critical and fundamental in many biological processes. However, the underlying mechanism of scavenger receptor-serum protein interaction remains elusive. In this work, taking scavenger receptors class A1 (SR-A1) as an example, we systematically investigate its interaction with human serum albumin (HSA) at different states through a combination of molecular docking and all-atom molecular dynamics simulations. It is found that native HSA can moderately bind to collagen-like (CL) region or scavenger receptor cysteine-rich (SRCR) region, with both electrostatic (ELE) and van der Waals (VDW) interactions, playing important roles. After maleylation, the binding energy, particularly the ELE energy, between HSA and CL region is significantly enhanced, while the binding energy between HSA and SRCR region remains nearly unchanged. Additionally, we also observe that unfolding of the secondary structures in HSA leads to a larger contact surface area between denatured HSA and CL region, but has little impact on the HSA-SRCR region interaction. Therefore, similar to maleylated HSA, denatured HSA is also more likely to bind to the CL region of SR-A1., (© 2023 Wiley Periodicals LLC.)

Objective: Cisplatin (CDDP)-based chemotherapy is a first-line, drug regimen for muscle-invasive bladder cancer (BC) and metastatic bladder cancer. Clinically, resistance to CDDP restricts the clinical benefit of some bladder cancer patients. AT-rich interaction domain 1A (ARID1A) gene mutation occurs frequently in bladder cancer; however, the role of CDDP sensitivity in BC has not been studied., Methods: We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology. IC 50 determination, flow cytometry analysis of apoptosis, and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A. qRT-PCR, Western blotting, RNA interference, bioinformatic analysis, and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC., Results: It was found that ARID1A inactivation was associated with CDDP resistance in BC cells. Mechanically, loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3 (EIF4A3) through epigenetic regulation. Increased expression of EIF4A3 promoted the expression of hsa&#95;circ&#95;0008399 (circ0008399), a novel circular RNA (circRNA) identified in our previous study, which, to some extent, showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells. Importantly, EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP., Conclusion: Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3., (© 2023. Huazhong University of Science and Technology.)

Electroacupuncture may play a role in treatment of learning and memory impairment after ischemic stroke by regulating phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA)/cAMP response element binding protein (CREB) signaling pathway, nerve growth factor (NGF)/tyrosine kinase-A (TrkA) signaling pathway, Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, Notch signaling pathway, erythropoietin-producing hepatocyte (Eph)/ephrin signaling pathway. The interactions among these pathways should be further explored in treatment of learning and memory impairment after ischemic stroke.

The elaborate design of powerful Li-S binders with extended-functions like polysulfides adsorption/catalysis and Li + hopping/transferring in addition to robust adhesion-property has remained a challenge. Here, an in situ cathode-interweaving strategy based on metalloporphyrin based covalent-bonding organic polymer (M-COP, M = Mn, Ni, and Zn) binders is reported for the first time. Thus-produced functional binders possess excellent mechanical-strengths, polysulfides adsorption/catalysis, and Li + hopping/transferring ability. Specifically, the modulus of Mn-COP can reach up to ≈54.60 GPa (≈40 times higher than poly(vinylidene fluoride)) and the relative cell delivers a high initial-capacity (1027 mAh g -1 , 1 C and 913 mAh g -1 , 2 C), and excellent cycling-stability for >1000 cycles even at 4 C. The utilization-rate of sulfur can reach up to 81.8% and the electrodes based on these powerful binders can be easily scale-up fabricated (≈20 cm in a batch-experiment). Noteworthy, Mn-COP based cell delivers excellent capacities at a high sulfur-loading (8.6 mg cm -2 ) and low E/S ratio (5.8 µL mg -1 ). In addition, theoretical calculations reveal the vital roles of metalloporphyrin and thiourea-groups in enhancing the battery-performance., (© 2022 Wiley-VCH GmbH.)

Strategy that can design powerful photothermal-catalysts to achieve photothermal-effect assisted coupling-catalysis is much desired for the improvement of energy conversion efficiency and redox product value in CO 2 electroreduction system. Herein, a kind of bifunctional viologen-containing covalent organic framework (Ni-2CBpy 2+ -COF) has been prepared and successfully applied in photothermal-assisted co-electrolysis of CO 2 and methanol. Specifically, the FE CO (cathode) and FE HCOOH (anode) for Ni-2CBpy 2+ -COF can reach up to ≈100 % at 1.9 V with ≈31.5 % saved overall electricity-consumption when the anodic oxygen evolution reaction (OER) is replaced by methanol oxidation. The superior performance could be attributed to the cyclic diquats in Ni-2CBpy 2+ -COF that enhance the photothermal effect (ΔT=49.1 °C) to accelerate faster charge transfer between catalyst and immediate species as well as higher selectivity towards desired products as revealed by DFT calculations and characterizations., (© 2022 Wiley-VCH GmbH.)

Objective: To develop a nomogram model for the differential diagnosis of benign and malignant breast BI-RADS (Breast Imaging Reporting and Data System) category 4 nodules based on serum tumor specific protein 70 (SP70) and conventional laboratory indicators and validate its predictive efficacy. Methods: A case-control study design was used to retrospectively analyze the data of 429 female patients diagnosed with BI-RADS category 4 breast nodules by breast color doppler flow imaging at the First Affiliated Hospital of Nanjing Medical University from January 2021 to April 2022 with an age range of 16 to 91 years and a median age of 50 years, and the patients were divided into a training cohort (314 patients) and a validation cohort (115 patients) according to the inclusion time successively. Using postoperative pathological findings as the"gold standard", univariate and multivariate logistic regression analyses were used to identify the predictor variables used for the model. The nomogram, receiver operating characteristic (ROC) curves and calibration curves were drawn for the prediction model, and the discrimination and calibration of the model were evaluated using the consistency index (C-index) and calibration plots. Results: The postoperative pathological results showed that 286 (66.7%) were malignant nodules and 143 (33.3%) were benign nodules of 429 breast BI-RADS category 4 nodules. The serum SP70 ( OR =1.227,95% CI : 1.033-1.458, P =0.020), NLR ( OR =1.545,95% CI : 1.047-2.280, P =0.028), LDL-C ( OR =2.215, 95% CI : 1.354-3.622, P =0.002), GLU ( OR =2.050,95% CI :1.222-3.438, P =0.007), PT ( OR =1.383,95% CI : 1.046-1.828, P =0.023), nodule diameter ( OR =1.042, 95% CI : 1.008-1.076, P =0.015) and age ( OR =1.062,95% CI : 1.011-1.116, P =0.016) were independent risk factors which could be used to distinguish benign and malignant breast BI-RADS category 4 nodules ( P <0.05). The nomogram was plotted by the above seven independent variables, and the concordance index (C-index) for the training cohort and validation cohort were 0.842 (95% CI :0.786-0.898) and 0.787 (95% CI :0.687-0.886), respectively. The sensitivity and specificity of using this model to identify benign and malignant breast BI-RADS category 4 nodules in the training and validation cohort were 83.5%, 72.5% and 79.2%, 73.6%, respectively. The calibration curves showed good agreement between the predicted and actual values in the nomogram. Conclusions: This study combined serum SP70, conventional laboratory indicators and breast color doppler flow imaging to develop a nomogram model for the differential diagnosis of benign and malignant breast BI-RADS category 4 nodules. The model may have good predictive efficacy and may provide a basis for clinical treatment options, which is beneficial for guiding breast cancer screening and prevention.

The spread of coronavirus disease 2019 caused by SARS-CoV-2 and its variants has become a global health crisis. Although there were many attempts to use nanomaterials-based devices to fight against SARS-CoV-2, it still remains elusive as to how the nanomaterials interact with SARS-CoV-2 and affect its biofunctions. Here, taking the graphene nanosheet (GN) as the model nanomaterial, we investigate its interaction with the spike protein in both WT and Omicron by molecular simulations. In the closed state, the GN can insert into the region between the receptor binding domain (RBD) and the N-terminal domain (NTD) in both wild type (WT) and Omicron, which keeps the RBD in the down conformation. In the open state, the GN can hamper the binding of up RBD to ACE2 in WT, but it has little impact on up RBD and, even worse, stimulates the down-to-up transition of down RBDs in Omicron. Moreover, the GN can insert in the vicinity of the fusion peptide in both WT and Omicron and prevents the detachment of S1 from the whole spike protein. The present study reveals the effect of the SARS-CoV-2 variant on the nanomaterial-spike protein interaction, which informs prospective efforts to design functional nanomaterials against SARS-CoV-2.

Recent studies reported that adenosine triphosphate (ATP) could inhibit and enhance the phase separation in prion-like proteins. The molecular mechanism underlying such a puzzling phenomenon remains elusive. Here, taking the fused in sarcoma (FUS) solution as an example, we comprehensively reveal the underlying mechanism by which ATP regulates phase separation by combining the semiempirical quantum mechanical method, mean-field theory, and molecular simulation. At the microscopic level, ATP acts as a bivalent or trivalent binder; at the macroscopic level, the reentrant phase separation occurs in dilute FUS solutions, resulting from the ATP concentration-dependent binding ability under different conditions. The ATP concentration for dissolving the protein condensates is about 10 mM, agreeing with experimental results. Furthermore, from a dynamic point of view, the effect of ATP on phase separation is also nonmonotonic. This work provides a clear physical description of the microscopic interaction and macroscopic phase diagram of the ATP-modulated phase separation.

The selective photo-oxidation of biomass-derived 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) is important due to its substitute-role in polyester-fabrication. Here, a titanium-cluster based metal-covalent organic framework nanosheet has been synthesized through the covalent-coupling between Ti 6 -NH 2 and benzotrithiophene tricarbaldehyde (BTT). The integration of them endows the nanosheet with a visible-light-adsorption region, effective electron-hole separation-efficiency and suitable photo-oxidation ability. Specifically, its photo-selectivity for HMF-to-FDCA can be >95 % with ≈100 % conversion, which is more than 2, 5, and 10 times higher than MOF-901 (43 %), Ti 6 -NH 2 (19 %) and under-darkness (9 %), respectively. Notably, an O 2 -based mechanism is proposed and the vital roles of Ti 6 -NH 2 and BTT are verified by DFT calculations. This work might facilitate the exploration of porous-crystalline-catalysts for selective biomass-valorization., (© 2022 Wiley-VCH GmbH.)

Protein-ligand interactions are crucial in many biochemical processes and biomedical applications, yet accurately calculating the binding free energy of the interactions still remains challenging. In this work, we systematically investigate the performance of a generic force field GFN-FF and some semi-empirical quantum mechanical (SQM) methods (GFN n , n = 0, 1, 2) in terms of the accuracy of the calculated binding free energy. It is found that the performance of the GFN-FF method is quite good in a neutral-ligand system since the Pearson correlation coefficient ( r p ) is 0.70 and the mean absolute error (MAE) is 5.49 kcal mol -1 . However, it may fail in a charged-ligand system (the MAE is 18.98 kcal mol -1 ). Moreover, we also propose a cluster model ( i.e. , truncating the protein at a given cutoff) along with the SQM method in the GFN family. Importantly, the GFN2-xTB shows the best performance among the SQM methods (the MAE is 4.91 kcal mol -1 and 10.25 kcal mol -1 in the neutral-ligand and charged-ligand systems, respectively), much better than GFN-FF in the charged-ligand system. Notably, the computing cost of the GFN2-xTB in the appropriate cluster model is even lower than that of the GFN-FF (in the entire complex). The present study sheds some light on the potential power of the GFN family in the efficient calculation of the binding free energy in bio-systems.

Background: It has been established that the dipeptidyl peptidase-4 (DPP-4) inhibitor Diprotin A TFA can reduce vascular endothelial (VE)-cadherin disruption by inhibiting the increase in cleaved β-catenin in response to hypoxia, thereby protecting the vascular barrier of human umbilical vein endothelial cells. In this study, we sought to investigate the possible effect of Diprotin A TFA on the VE barrier after cerebral ischemic stroke in mice., Methods: C57BL/6J mice were divided into five groups, namely, (1) sham, (2) stroke, (3) stroke + dimethyl sulfoxide (DMSO), (4) stroke + Diprotin A TFA, and (5) stroke + Diprotin A TFA + XAV-939. First, the cerebral ischemia model was established by photothrombotic ischemia, followed by intraperitoneal injection with Diprotin A TFA and XAV-939 at doses of 70 μg/kg and 40 mg/kg 30 min once in the morning and once in the evening for 3 days. Immunofluorescence staining and Western blot methods were used to analyze the expression of vascular and blood-brain barrier (BBB)-associated molecular markers in the peri-infarct area., Results: Compared with the vehicle control group, we found that mice injected with Diprotin A TFA exhibited reduced cerebral infarction volume, increased vascular area and length around the brain injury, increased pericyte and basement membrane coverage, upregulated expression of BBB tight junction proteins, and improved their BBB permeability, whereas the group injected with both drug and inhibitor exhibited significantly aggravated vascular injury and BBB permeability., Conclusion: Diprotin A TFA can reduce VE-cadherin disruption by inhibiting ischemia-hypoxia-induced β-catenin cleavage to protect blood vessels., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Zhang, Ding, Wu, Cai, Wang and Geng.)

Accurate calculation of the binding free energies between a protein and a ligand is the primary objective of structure-based drug design, but it still remains a challenging problem. In this work, we apply the screening molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) method to calculate the binding affinity of protein-ligand interactions. Our results show that the performance of the screening MM/PBSA is better than that of the standard MM/PBSA, especially in a charged-ligand system. In addition, we also investigate the effect of the solute dielectric constant on the results, and find that the optimal solute dielectric constants are different between the neutral-ligand system and the charged-ligand system. Moreover, we also evaluate the effect of the atomic-charge methods on the performance of the screening MM/PBSA. The present study demonstrates that the screening MM/PBSA should be a reliable method for calculating binding energy of biosystems.

Strategies that enable simultaneous morphology-tuning and electroreduction performance boosting are much desired for the exploration of covalent organic frameworks in efficient CO 2 electroreduction. Herein, a kind of functionalizing exfoliation agent has been selected to simultaneously modify and exfoliate bulk COFs into functional nanosheets and investigate their CO 2 electroreduction performance. The obtained nanosheets (Cu-Tph-COF-Dct) with large-scale (≈1.0 μm) and ultrathin (≈3.8 nm) morphology enable a superior FE CH4 (≈80 %) (almost doubly enhanced than bare COF) with large current-density (-220.0 mA cm -2 ) at -0.9 V. The boosted performance can be ascribed to the immobilized functionalizing exfoliation agent (Dct groups) with integrated amino and triazine groups that strengthen CO 2 absorption/activation, stabilize intermediates and enrich the CO concentration around the Cu active sites as revealed by DFT calculations. The point-to-point functionalization strategy for modularly assembling Dct-functionalized COF catalyst for CO 2 electroreduction will open up the attractive possibility of developing COFs as efficient CO 2 RR electrocatalysts., (© 2021 Wiley-VCH GmbH.)

With the rapid development of nanotechnology, various DNA nanostructures have been synthesized and widely used in drug delivery. However, the underlying mechanisms of drug molecule loading into the DNA nanostructure are still elusive. In this work, we systematically investigate the interactions of a tetrahedral DNA nanostructure (TDN) with the anti-cancer drug doxorubicin (DOX) by combining molecular docking and all-atom molecular dynamics simulations. It is found that there are five possible binding modes in the single TDN-DOX interactions, namely the outside-corner mode, the inside-corner mode, the major-groove mode, the minor-groove mode, and the intercalation mode, where the van der Waals (VDW) interaction and the electrostatic (ELE) interaction dominate in the case of unionized DOX and ionized DOX, respectively. Moreover, with the increase of the DOX number, some of the interaction modes may disappear and the inside-corner mode is the most energy-favorable mode. The present study enhances the molecular understanding of the role of TDN as the drug carrier, which may provide a useful guideline for the future design of DNA nanostructures., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Objective: To investigate the auxiliary diagnostic value of seven tumor-associated autoantibodies (AABs) P53, PGP9.5, SOX2, GAGE7, GBU4-5, MAGEA1 and CAGE in early non-small cell lung cancer (NSCLC). Methods: The case-control study enrolled 195 patients with early NSCLC [71 males and 124 females, aged (55.70±11.78) years old], 114 patients with benign lung disease [44 males and 70 females, aged (52.85±12.31) years old] and 100 healthy subjects [39 males and 61 females, aged (53.62±9.97) years old] from the First Affiliate Hospital of Nanjing Medical University from June 2020 to December 2020. AABs were detected by enzyme-linked-immunosorbent serologic assay (ELISA), and carcinoembryonic antigen (CEA),cytokeratin 19-fragments (CYFRA21-1) and neuron specific enolase (NSE) were detected by electrochemiluminescence. The levels of AABs,CEA,CYFRA21-1 and NSE in the 3 groups were compared. Patients with benign lung diseases and healthy subjects were combined into the control group, and the positive rate of each indicator in the NSCLC group and the control group was compared. The diagnostic efficacy of single and combined tests for NSCLC were obtained using receiver operating characteristic (ROC) curves. Besides, the relationship between the levels of AABs, CEA, CYFRA21-1 and NSE and their clinicopathological features and preoperative imaging parameters in NSCLC patients was assessed. Results: The levels of SOX2 [0.70 (0.10, 2.40) U/mL] and GBU4-5 [1.30 (0.30, 8.90) U/mL] in NSCLC group were higher than those in benign disease group [SOX2: 0.50 (0.10, 1.60) U/mL, GBU4-5: 0.80 (0.10, 2.30) U/mL, Z values were 27.258 and 45.797; P values were all<0.05] and health control group [SOX2: 0.45 (0.10, 1.08) U/mL, GBU4-5: 0.75 (0.20, 1.78) U/mL, Z values were 32.551 and 40.456; P values were all<0.05], and there was no significant difference between benign disease group and health control group ( Z values were 5.293 and 5.340, P values were all>0.05). The levels of CEA [1.75 (1.08, 2.72) U/mL] and CYFRA21-1 [1.81 (1.41, 2.36) U/mL] in NSCLC group were higher than those in healthy control group [CEA: 1.22 (0.68, 1.81) U/mL, CYFRA21-1: 1.43 (1.14, 1.74) U/mL, Z values were 64.100 and 37.597; P values were all<0.05], but there was no significant difference between NSCLC group and benign group [CEA: 1.74 (1.01, 2.51) U/mL, CYFRA21-1: 1.82 (1.45, 2.46) U/mL, Z values were 7.275 and 10.621; P values were all>0.05]. The positive rates of P53, SOX2, GAGE7, GBU4-5 and CEA in NSCLC group were higher than those in the control group [P53: 10.3% vs 0.9%, SOX2: 11.3% vs 2.3%, GAGE7: 11.3% vs 0.5%, GBU4-5: 30.1% vs 5.6%, CEA: 9.7% vs 0.9%, χ 2 values were 17.420, 13.242, 22.485, 43.211, 16.255, respectively; P values were all<0.05]. The diagnostic efficiency of the combined detection of seven AABs was better than that of single detection. Seven AABs combined with CEA [area under curve (AUC): 0.732, sensitivity: 64.10%] and with CYFRA21-1 (AUC: 0.737, sensitivity: 58.97%) greatly improved the diagnostic efficiency and sensitivity of CEA (AUC: 0.583, sensitivity: 50.77%) and CYFRA21-1 (AUC: 0.552, sensitivity: 44.10%). The levels of SOX2 and CEA in NSCLC patients were correlated with the degree of tumor invasion ( H values were 6.436 and 14.071; P values were all<0.05); the levels of GAGE7 and CEA were correlated with the nodule density ( H values were 7.643 and 12.268; P values were all<0.05); and the levels of SOX2, GAGE7, CEA and CYFRA21-1 were all correlated with the nodule size ( H values were 10.837, 11.528, 31.835, 20.338; P values were all<0.05). Conclusion: The detection of AABs combined with CEA and CYFRA21-1 is helpful for the early auxiliary diagnosis of NSCLC, and plays an important role in prevention and screening for early lung cancer.

Peripheral nerve injuries occur as the result of sudden trauma and lead to reduced quality of life. The peripheral nervous system has an inherent capability to regenerate axons. However, peripheral nerve regeneration following injury is generally slow and incomplete that results in poor functional outcomes such as muscle atrophy. Although conventional surgical procedures for peripheral nerve injuries present many benefits, there are still several limitations including scarring, difficult accessibility to donor nerve, neuroma formation and a need to sacrifice the autologous nerve. For many years, other therapeutic approaches for peripheral nerve injuries have been explored, the most notable being the replacement of Schwann cells, the glial cells responsible for clearing out debris from the site of injury. Introducing cultured Schwann cells to the injured sites showed great benefits in promoting axonal regeneration and functional recovery. However, there are limited sources of Schwann cells for extraction and difficulties in culturing Schwann cells in vitro. Therefore, novel therapeutic avenues that offer maximum benefits for the treatment of peripheral nerve injuries should be investigated. This review focused on strategies using mesenchymal stem cells to promote peripheral nerve regeneration including exosomes of mesenchymal stem cells, nerve engineering using the nerve guidance conduits containing mesenchymal stem cells, and genetically engineered mesenchymal stem cells. We present the current progress of mesenchymal stem cell treatment of peripheral nerve injuries., Competing Interests: None

The unconjugated bilirubin (BR) may penetrate through the cell membrane and cause a severe cytotoxicity. However, the molecular mechanism underlying the penetration of BR into the cell membrane is still largely unknown. In this work, we systematically investigate the interaction of BR and a lipid bilayer under different conditions by using all-atom molecular dynamics simulations. It is found that BR at the Z , Z conformation can easily enter into the interior of the lipid bilayer due to its hydrophobicity. However, when BR transforms from the Z , Z conformation to the E,E conformation (after the blue-light emission), its penetration ability is greatly reduced (especially at its ionized state). This study may offer useful physical insights into the effect of phototherapy on the penetration behavior and the cytotoxicity of the unconjugated BR.

Sargassum fusiforme (S. fusiforme) has been used as an ingredient in Chinese herbal medicine for thousands of years. However, there are a limited number of studies concerning its therapeutic mechanism. High performance gel permeation chromatography (HPGPC) analysis showed that the average molecular weight of the S. fusiforme polysaccharide, SFPS 191212, is 43 kDa. SFPS 191212 is composed of mannose, rhamnose, galactose, xylose, glucose, and fucose (at a molar ratio: 2.1 : 2.9 : 1.8 : 15.5 : 4.6 : 62.5) with α- and β-configurations. The present research evaluated the anti-tumor potential of the S. fusiforme polysaccharide in human erythroleukemia (HEL) cells in vitro. To explore the SFPS 191212's apoptosis mechanism in HEL cells, transcriptome analysis was performed on HEL cells that were incubated with SFPS 191212. The inhibitory effect of SFPS 191212 on HEL cell growth was also analyzed. It was found that SFPS 191212 inhibited HEL cell proliferation, reduced cell viability in a concentration-dependent manner, and induced an insignificant toxic effect on normal human embryonic lung (MRC-5) cells. Compared with the control group, transcriptome analysis identified a total of 598 differentially expressed genes (DEGs), including 243 up-regulated genes and 355 down-regulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on all DEGs, and 900 GO terms and 52 pathways were found to be significantly enriched. Finally, 23 DEGs were randomly selected and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, SFPS 191212 down-regulated the PI3K/Akt signal transduction pathway. Our results provide a framework for understanding the effect of SFPS 191212 on cancer cells and can serve as a resource for delineating the anti-tumor mechanisms of S. fusiforme., (Copyright © 2021 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

The exploration of novel systems for the electrochemical CO 2 reduction reaction (CO 2 RR) for the production of hydrocarbons like CH 4 remains a giant challenge. Well-designed electrocatalysts with advantages like proton generation/transferring and intermediate-fixating for efficient CO 2 RR are much preferred yet largely unexplored. In this work, a kind of Cu-porphyrin-based large-scale (≈1.5 μm) and ultrathin nanosheet (≈5 nm) has been successfully applied in electrochemical CO 2 RR. It exhibits a superior FE CH 4 of 70 % with a high current density (-183.0 mA cm -2 ) at -1.6 V under rarely reported neutral conditions and maintains FE CH 4 >51 % over a wide potential range (-1.5 to -1.7 V) in a flow cell. The high performance can be attributed to the construction of numerous hydrogen-bonding networks through the integration of diaminotriazine with Cu-porphyrin, which is beneficial for proton migration and intermediate stabilization, as supported by DFT calculations. This work paves a new way in exploring hydrogen-bonding-based materials as efficient CO 2 RR catalysts., (© 2021 Wiley-VCH GmbH.)

The design of selective and efficient covalent organic frameworks (COFs) based electrocatalysts with tunable morphology for efficient CO 2 reduction reaction (CO 2 RR) to CH 4 is highly desirable. Here, two kinds of anthraquinone-based COFs (i.e., AAn-COF and OH-AAn-COF) with tunable 1D superstructures (e.g., nanofibers (NF) and hollow tubes (HT)) have been produced via Schiff-base condensation reaction. Interestingly, a rarely reported nanosheet-based self-template mechanism and a nanosheet-crimping mechanism have been demonstrated for the production of COF-based nanofibers and hollow tubes, respectively. Besides, the obtained COF-based superstructures can be post-modified with transition metals for efficient CO 2 RR. Specifically, AAn-COF-Cu (NF) and OH-AAn-COF-Cu (HT) exhibit superior faradaic-efficiency with CH 4 (FE CH4 ) of 77% (-128.1 mA cm -2 , -0.9 V) and 61% (-99.5 mA cm -2 , -1.0 V) in a flow-cell, respectively. Noteworthy, the achieved FE CH4 of AAn-COF-Cu (NF) (77%) the is highest one among reported crystalline COFs. This work provides a general methodology in exploring morphology-controlled COFs for electrocatalytic CO 2 RR., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2021 Science China Press. Published by Elsevier B.V. All rights reserved.)

The outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a worldwide public health crisis. When the SARS-CoV-2 enters the biological fluids in the human body, different types of biomolecules (in particular proteins) may adsorb on its surface and alter its infection ability. Although great efforts have recently been devoted to the interaction of specific antibodies with the SARS-CoV-2, it still remains largely unknown how the other serum proteins affect the infection of the SARS-CoV-2. In this work, we systematically investigate the interaction of serum proteins with the SARS-CoV-2 RBD by molecular docking and all-atom molecular dynamics simulations. It is found that non-specific immunoglobulins (Ig) indeed cannot effectively bind to the SARS-CoV-2 RBD while human serum albumin (HSA) may have some potential in blocking its infection (to ACE2). More importantly, we find that the RBD can cause significant structural changes in Apolipoprotein E (ApoE), by which SARS-CoV-2 may hijack the metabolic pathway of ApoE to facilitate its cell entry. The present study enhances the understanding of the role of protein corona in the bio-behaviors of SARS-CoV-2, which may aid the more precise and personalized treatment for COVID-19 infection in the clinic.

Accurate calculation of protein-protein binding free energy is of great importance in biological and medical science, yet it remains a hugely challenging problem. In this work, we develop a new strategy in which a screened electrostatic energy (i.e., adding an exponential damping factor to the Coulombic interaction energy) is used within the framework of the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. Our results show that the Pearson correlation coefficient in the modified MM/PBSA is over 0.70, which is much better than that in the standard MM/PBSA, especially in the Amber14SB force field. In particular, the performance of the standard MM/PBSA is very poor in a system where the proteins carry like charges. Moreover, we also calculated the mean absolute error (MAE) between the calculated and experimental Δ G values and found that the MAE in the modified MM/PBSA was indeed much smaller than that in the standard MM/PBSA. Furthermore, the effect of the dielectric constant of the proteins and the salt conditions on the results was also investigated. The present study highlights the potential power of the modified MM/PBSA for accurately predicting the binding energy in highly charged biosystems.

The aim of the present study was to identify the differentially expressed microRNAs (miRs) in cervical carcinoma (CC) tissues and cells and to explore the function of miR‑302c‑3p and miR‑520a‑3p in the proliferation of CC cells. Potential dysregulated miRNAs in CC tissues and tumour‑adjacent tissues were detected. Reverse transcription‑quantitative PCR (RT‑qPCR) was performed to determine the expression of miR‑302c‑3p, miR‑520a‑3p and CXCL8 in CC tissues and cell lines. The target genes of the miRNAs were predicted using miRTarBase and verified by luciferase reporter assays. RT‑qPCR and western blotting were performed to measure the expression of C‑X‑C motif ligand (CXCL)8 after transfection. The effect on proliferation was verified by Cell Counting Kit assay and ethynyl‑2‑deoxyuridine staining. Flow cytometry was utilised to assess the effect on apoptosis. In the present study, miR‑302c‑3p and miR‑520a‑3p were markedly downregulated in CC cell lines compared to the normal cervical cell line H8. Functionally, overexpression of miR‑302c‑3p and/or miR‑520a‑3p inhibited proliferation and promoted the apoptosis of CC cell lines in vitro , while the knockdown of miR‑302c‑3p and/or miR‑520a‑3p had the opposite effect. Furthermore, miR‑302c‑3p and miR‑520a‑3p could both bind to CXCL8. Inhibition of CXCL8 in combination with miR‑302c‑3p and/or miR‑520a‑3p overexpression exerted proliferation‑suppressive and apoptosis‑stimulating effects on CC cells, whereas restoring CXCL8 attenuated the miR‑302c‑3p‑ and miR‑520a‑3p‑induced anti‑proliferative and pro‑apoptotic effects. miR‑302c‑3p and miR‑520a‑3p suppress the proliferation of CC cells by downregulating the expression of CXCL8, which may provide a novel target for the treatment of CC.

Background: Myocardial injury is a life-threatening complication of coronavirus disease 2019 (COVID-19). Pre-existing health conditions and early morphological alterations may precipitate cardiac injury and dysfunction after contracting the virus. The current study aimed at assessing potential risk factors for COVID-19 cardiac complications in patients with pre-existing conditions and imaging predictors. Methods and Results: The multi-center, retrospective cohort study consecutively enrolled 400 patients with lab-confirmed COVID-19 in six Chinese hospitals remote to the Wuhan epicenter. Patients were diagnosed with or without the complication of myocardial injury by history and cardiac biomarker Troponin I/T (TnI/T) elevation above the 99th percentile upper reference limit. The majority of COVID-19 patients with myocardial injury exhibited pre-existing health conditions, such as hypertension, diabetes, hypercholesterolemia, and coronary disease. They had increased levels of the inflammatory cytokine interleukin-6 and more in-hospital adverse events (admission to an intensive care unit, invasive mechanical ventilation, or death). Chest CT scan on admission demonstrated that COVID-19 patients with myocardial injury had higher epicardial adipose tissue volume ([EATV] 139.1 (83.8-195.9) vs. 92.6 (76.2-134.4) cm 2 ; P = 0.036). The optimal EATV cut-off value (137.1 cm 2 ) served as a useful factor for assessing myocardial injury, which yielded sensitivity and specificity of 55.0% (95%CI, 32.0-76.2%) and 77.4% (95%CI, 71.6-82.3%) in adverse cardiac events, respectively. Multivariate logistic regression analysis showed that EATV over 137.1 cm 2 was a strong independent predictor for myocardial injury in patients with COVID-19 [OR 3.058, (95%CI, 1.032-9.063); P = 0.044]. Conclusions: Augmented EATV on admission chest CT scan, together with the pre-existing health conditions (hypertension, diabetes, and hyperlipidemia) and inflammatory cytokine production, is associated with increased myocardial injury and mortality in COVID-19 patients. Assessment of pre-existing conditions and chest CT scan EATV on admission may provide a threshold point potentially useful for predicting cardiovascular complications of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wei, Qiao, Chen, Huang, Wang, Yu, Xu, Wu, Wang, Gu, Li, Li, Liu, Yang, Ding, Lu, Yin, Wang, Li, Shi, Qian, Yang and Geng.)

Natural organic matter (NOM) that forms coronas on the surface of engineered nanoparticles (NPs) affects their stability, bio-uptake, and toxicity. After corona formation, a large amount of unbound NOM remains in the environment and their effects on organismal uptake of NPs remain unknown. Here, the effects of unbound NOM on the uptake of polyacrylate-coated hematite NPs (HemNPs) by the protozoan Tetrahymena thermophila were examined. HemNPs were well-dispersed without any detectable NOM adsorption. Kinetics experiments showed that unbound NOM decreased the uptake of HemNPs with greater inhibition at lower concentrations of the particles in the presence of NOM of higher molecular weight. The unbound NOM suppressed clathrin-mediated endocytosis but not the phagocytosis of HemNPs. Confirmation of these events was obtained using label-free hyperspectral stimulated Raman spectroscopy imaging and dissipative particle dynamics simulation. Overall, the present study demonstrates that unbound NOM can compete with HemNPs for internalization receptors on the surface of T. thermophila and inhibit particle uptake, highlighting the need to consider the direct effects of unbound NOM in bioapplication studies and in safety evaluations of NPs.

This study aimed to investigate the effects of Sargassum fusiforme polysaccharide (SFPS I, II, and III) on the apoptosis and regulation of human erythroleukemia (HEL) cells. The effect of different doses of SFPS on HEL cell growth was detected using the Cell Counting Kit-8 method, and apoptosis was detected by Hoechst staining. Cell cycle distribution and apoptosis were detected using flow cytometry. Expression of the cell cycle gene, p53, antiapoptotic genes, Bcl-xL and Bcl-2, and pro-apoptotic genes, Bax, Bad, and Caspase-3, as well as the expression of the corresponding proteins, were detected using real-time quantitative polymerase chain reaction (qPCR) and Western blot. The results showed that SFPS II and III decreased HEL cell viability and induced HEL cell apoptosis. Different concentrations of SFPS (I, II, and III) were detected that induced much less toxic effect in normal human embryonic lung (MRC-5) cells, and SFPS I increased cell proliferation, indicating its favorable selectivity towards cancer cells. The mechanism by which SFPS induced apoptosis was also found to be related to the induction of cell cycle arrest in the G 0 /G 1 phase and the increased expression of apoptosis-related genes and proteins. We concluded that SFPS induces HEL cell apoptosis, possibly via activation of the Caspase pathway, providing the theoretical basis for the development of SFPS-based anti-tumor drug products., (Copyright © 2020 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Selective ion transport through a nanochannel formed by stacked two-dimensional materials plays a key role in water desalination, nanofiltration, and ion separation. Although there have been many functional nanomaterials used in these applications, how to well control ion transport in a laminar structure so as to obtain the desired selectivity still remains a challenging problem. In the present work, the transport of ions through a C 2 N-based nanochannel is investigated by using all-atom molecular dynamics simulation. It is found that C 2 N-based nanochannels with different interlayer spacing posses diverse ion selectivity, which is mainly attributed to the distinct loading capability among ions and the different velocity of ions inside the nanochannel. Moreover, we also find that the ion selectivity is dependent on the electric field, but nearly independent of the salt concentration. The present study may provide some physical insights into the experimental design of C 2 N-based nanodevices in nanofiltration.

A protein Pascal triangle has been constructed as new type of supramolecular architecture by using the inducing ligand strategy that we previously developed for protein assemblies. Although mathematical studies on this famous geometry have a long history, no work on such Pascal triangles fabricated from native proteins has been reported so far due to their structural complexity. In this work, by carefully tuning the specific interactions between the native protein building block WGA and the inducing ligand R-SL, a 2D Pascal-triangle lattice with three types of triangular voids has been assembled. Moreover, a 3D crystal structure was obtained based on the 2D Pascal triangles. The distinctive carbohydrate binding sites of WGA and the intralayer as well as interlayer dimerization of RhB was the key to facilitate nanofabrication in solution. This strategy may be applied to prepare and explore various sophisticated assemblies based on native proteins., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)