Exploring the immune evasion of SARS-CoV-2 variant harboring E484K by molecular dynamics simulations.

Although the current coronavirus disease 2019 (COVID-19) vaccines have been used worldwide to halt spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the emergence of new SARS-CoV-2 variants with E484K mutation shows significant resistance to the neutralization of vaccine sera. To better understand the resistant mechanism, we calculated the binding affinities of 26 antibodies to wild-type (WT) spike protein and to the protein harboring E484K mutation, respectively. The results showed that most antibodies (~85%) have weaker binding affinities to the E484K mutated spike protein than to the WT, indicating the high risk of immune evasion of the mutated virus from most of current antibodies. Binding free energy decomposition revealed that the residue E484 forms attraction with most antibodies, while the K484 has repulsion from most antibodies, which should be the main reason of the weaker binding affinities of E484K mutant to most antibodies. Impressively, a monoclonal antibody (mAb) combination was found to have much stronger binding affinity with E484K mutant than WT, which may work well against the mutated virus. Based on binding free energy decomposition, we predicted that the mutation of four more residues on receptor-binding domain (RBD) of spike protein, viz., F490, V483, G485 and S494, may have high risk of immune evasion, which we should pay close attention on during the development of new mAb therapeutics.

D3AI-CoV: a deep learning platform for predicting drug targets and for virtual screening against COVID-19.

Target prediction and virtual screening are two powerful tools of computer-aided drug design. Target identification is of great significance for hit discovery, lead optimization, drug repurposing and elucidation of the mechanism. Virtual screening can improve the hit rate of drug screening to shorten the cycle of drug discovery and development. Therefore, target prediction and virtual screening are of great importance for developing highly effective drugs against COVID-19. Here we present D3AI-CoV, a platform for target prediction and virtual screening for the discovery of anti-COVID-19 drugs. The platform is composed of three newly developed deep learning-based models i.e., MultiDTI, MPNNs-CNN and MPNNs-CNN-R models. To compare the predictive performance of D3AI-CoV with other methods, an external test set, named Test-78, was prepared, which consists of 39 newly published independent active compounds and 39 inactive compounds from DrugBank. For target prediction, the areas under the receiver operating characteristic curves (AUCs) of MultiDTI and MPNNs-CNN models are 0.93 and 0.91, respectively, whereas the AUCs of the other reported approaches range from 0.51 to 0.74. For virtual screening, the hit rate of D3AI-CoV is also better than other methods. D3AI-CoV is available for free as a web application at http://www.d3pharma.com/D3Targets-2019-nCoV/D3AI-CoV/index.php, which can serve as a rapid online tool for predicting potential targets for active compounds and for identifying active molecules against a specific target protein for COVID-19 treatment.

3D-printed PCL framework assembling ECM-inspired multi-layer mineralized GO-Col-HAp microscaffold for in situ mandibular bone regeneration.

BACKGROUND: In recent years, natural bone extracellular matrix (ECM)-inspired materials have found widespread application as scaffolds for bone tissue engineering. However, the challenge of creating scaffolds that mimic natural bone ECM's mechanical strength and hierarchical nano-micro-macro structures remains. The purposes of this study were to introduce an innovative bone ECM-inspired scaffold that integrates a 3D-printed framework with hydroxyapatite (HAp) mineralized graphene oxide-collagen (GO-Col) microscaffolds and find its application in the repair of mandibular bone defects. METHODS: Initially, a 3D-printed polycaprolactone (PCL) scaffold was designed with cubic disks and square pores to mimic the macrostructure of bone ECM. Subsequently, we developed multi-layer mineralized GO-Col-HAp microscaffolds (MLM GCH) to simulate natural bone ECM's nano- and microstructural features. Systematic in vitro and in vivo experiments were introduced to evaluate the ECM-inspired structure of the scaffold and to explore its effect on cell proliferation and its ability to repair rat bone defects. RESULTS: The resultant MLM GCH/PCL composite scaffolds exhibited robust mechanical strength and ample assembly space. Moreover, the ECM-inspired MLM GCH microscaffolds displayed favorable attributes such as water absorption and retention and demonstrated promising cell adsorption, proliferation, and osteogenic differentiation in vitro. The MLM GCH/PCL composite scaffolds exhibited successful bone regeneration within mandibular bone defects in vivo. CONCLUSIONS: This study presents a well-conceived strategy for fabricating ECM-inspired scaffolds by integrating 3D-printed PCL frameworks with multilayer mineralized porous microscaffolds, enhancing cell proliferation, osteogenic differentiation, and bone regeneration. This construction approach holds the potential for extension to various other biomaterial types.

Ligand-based approach for predicting drug targets and for virtual screening against COVID-19.

Discovering efficient drugs and identifying target proteins are still an unmet but urgent need for curing coronavirus disease 2019 (COVID-19). Protein structure-based docking is a widely applied approach for discovering active compounds against drug targets and for predicting potential targets of active compounds. However, this approach has its inherent deficiency caused by e.g. various different conformations with largely varied binding pockets adopted by proteins, or the lack of true target proteins in the database. This deficiency may result in false negative results. As a complementary approach to the protein structure-based platform for COVID-19, termed as D3Docking in our previous work, we developed in this study a ligand-based method, named D3Similarity, which is based on the molecular similarity evaluation between the submitted molecule(s) and those in an active compound database. The database is constituted by all the reported bioactive molecules against the coronaviruses, viz., severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus (MERS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human betacoronavirus 2c EMC/2012 (HCoV-EMC), human CoV 229E (HCoV-229E) and feline infectious peritonitis virus (FIPV), some of which have target or mechanism information but some do not. Based on the two-dimensional (2D) and three-dimensional (3D) similarity evaluation of molecular structures, virtual screening and target prediction could be performed according to similarity ranking results. With two examples, we demonstrated the reliability and efficiency of D3Similarity by using 2D × 3D value as score for drug discovery and target prediction against COVID-19. The database, which will be updated regularly, is available free of charge at https://www.d3pharma.com/D3Targets-2019-nCoV/D3Similarity/index.php.

Chirality Discrimination at Binary Organic|Water Interfaces Monitored by Interfacial Tension Measurements with Preliminary Comparison with Molecular Dynamics Simulations.

Chirality discrimination at a binary toluene (organic)/water(aqueous) interface between R- or S-Tol-BINAP (2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl) molecules and the water-soluble serine chiral specie is examined for the first time, using a combination of interfacial tension measurements and molecular dynamic simulations. Experimental interfacial measurements exhibit a clear chirality-controlled difference when a homochiral versus a heterochiral enantiomeric pairs are introduced at the interfaces. The related molecular dynamics simulations support the experimental results and provide further molecular insight of intermolecular interactions at the interfaces. The results indicate that interfacial tension measurements can capture the preferential interactions which exist between different pairs of enantiomers at the binary interfaces, opening up a new way for probing chirality discrimination at liquid-liquid interfaces.

Fabrication of Flower-like Rhodium-Doped ß-Ni(OH)2 as an Efficient Electrocatalyst for Methanol Oxidation Reaction in Alkaline Media.

In this study, ß-Ni(OH)2 with a unique flower-like morphology was synthesized through a hydrothermal method. The doping of Rh in ß-Ni(OH)2 was achieved by a reduction method. The as-synthesized catalysts were characterized by X-ray diffraction, transmission electron microscopy, and X-ray photoelectron spectroscopy for the crystal structure, morphology, composition, and chemical state analysis. The electrochemical tests revealed that the doping of Rh can significantly increase the electrocatalytic performance of ß-Ni(OH)2 in 1.0 M KOH solution. The methanol oxidation peak current density of Rh-doped ß-Ni(OH)2 reached 95 mA cm-2 with a Tafel slope of 40 mV dec-1. The reason for these improvements is that Rh can suppress the phase transformation of NiOOH from ß to α. Meanwhile, the electronic structure change of nickel in ß-Ni(OH)2 and the defect ratio increase caused by Rh doping are beneficial to methanol oxidation reaction (MOR) catalytic activity. Furthermore, the synergistic effect between Rh and Ni(OH)2 improved the surface activity of ß-NiOOH. The doping of Rh in ß-Ni(OH)2 is initiative in this work, which provides a new strategy to design highly efficient and cost-effective MOR electrocatalysts for alkaline DMFCs.

Serum biomarker panel for disease severity and prognosis in patients with COVID-19.

BACKGROUND: Coronavirus disease-2019 (COVID-19) has become a worldwide emergency and has had a severe impact on human health. Inflammatory factors have the potential to either enhance the efficiency of host immune responses or damage the host organs with immune overreaction in COVID-19. Therefore, there is an urgent need to investigate the functions of inflammatory factors and serum markers that participate in disease progression. METHODS: In total, 54 COVID-19 patients were enrolled in this study. Disease severity was evaluated by clinical evaluation, laboratory tests, and computed tomography (CT) scans. Data were collected at: admission, 3-5 days after admission, when severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA detection became negative, and composite endpoint. RESULTS: We found that the positive rate in sputum was three times higher than that in throat swabs. Higher levels of C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer (D-D), interleukin-6 (IL-6) and neutrophil-to-lymphocyte ratio (NLR) or lower lymphocyte counts suggested more severe disease, and the levels of cytokines and serum markers were intrinsically correlated with disease progression. When SARS-CoV-2 RNA detection became negative, the receiver operating characteristic (ROC) curve demonstrated that LDH had the highest sensitivity independently, and four indicators (NLR, CRP, LDH, and D-D) when combined had the highest sensitivity in distinguishing critically ill patients from mild ones. CONCLUSIONS: Monitoring dynamic changes in NLR, CRP, LDH, IL-6, and D-D levels, combined with CT imaging and viral RNA detection in sputum, could aid in severity evaluation and prognosis prediction and facilitate COVID-19 treatment.

Observing Dislocations Transported by Twin Boundaries in Al Thin Film: Unusual Pathways for Dislocation-Twin Boundary Interactions.

Twins are generally regarded as obstacles to dislocations in face-centered cubic metals and can modify individual dislocations by locking them in twin boundaries or obliging them to dissociate. Through in situ tensile experiments on Al thin film in a transmission electron microscope, we report a dynamic process of dislocations being transported by twin lamella via periodic twinning and detwinning at the atomic scale. Following this process, a 60° dislocation first transforms into a sessile step of the twin boundary, then migrates under stress as a step and finally reverts back into a 60° dislocation. Our results reveal a novel evolution route of dislocations by a dislocation-twin interaction where the twins act as transport vehicles rather than as obstacles. The potential implications of this mechanism on toughening are also discussed.

Conformations of Steroid Hormones: Infrared and Vibrational Circular Dichroism Spectroscopy.

Steroid hormone molecules may exhibit very different functionalities based on the associated functional groups and their 3D arrangements in space, i.e., absolute configurations and conformations. Infrared (IR) and vibrational circular dichroism (VCD) spectra of four different steroid hormones, namely dehydroepiandrosterone (DHEA), 17α-methyltestosterone (MTTT), (16α,17)-epoxyprogesterone (Epoxy-P4), and dehydroepiandrosterone acetate (AcO-DHEA), were measured in deuterated dimethyl sulfoxide and some also in carbon tetrachloride. Extensive conformational searches were carried out using the recent developed conformer-rotamer ensemble sampling tool (CREST) which also accounts for solvent effects using an implicit solvation model. All the CREST conformational candidates were then reoptimized at the B3LYP-D3BJ/def2-TZVPD with the PCM of solvent. The good agreements between the experimental IR and VCD spectra and the theoretical simulations provide a conclusive information about their conformational distribution and absolute configurations. The experimental and theoretical IR and VCD spectra of AcO-DHEA in the carbonyl and alkene stretching region showed some discrepancies, and the possible causes related to solvent effects, large amplitude motions and levels of theory used in the modelling were explored in detail. As part of the investigation, additional calculations at the B3LYP-D3BJ/6-31++G (2d,p) and B3LYP-D3BJ/cc-pVTZ levels, as well as some 'mixed' calculations with the double-hybrid functional B2PLYP-D3 were also carried out. The results indicate that the double-hybrid functional is important for predicting the correct IR band pattern in the carbonyl and alkene stretching region.

[Effect of platelet-derived growth factor-BB on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension and its mechanism]. / è¡€å°æ¿æºæ€§ç”Ÿé•¿å› å­-BBå¯¹ç¼ºæ°§æ€§è‚ºåŠ¨è„‰é«˜åŽ‹æ–°ç”Ÿå¤§é¼ è‚ºè¡€ç®¡é‡å¡‘çš„å½±å“åŠæœºåˆ¶ç ”ç©¶.

OBJECTIVES: To study the effect of platelet-derived growth factor-BB (PDGF-BB) on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH). METHODS: A total of 128 neonatal rats were randomly divided into four groups: PDGF-BB+HPH, HPH, PDGF-BB+normal oxygen, and normal oxygen (n=32 each). The rats in the PDGF-BB+HPH and PDGF-BB+normal oxygen groups were given an injection of 13 µL 6×1010 PFU/mL adenovirus with PDGF-BB genevia the caudal vein. After 24 hours of adenovirus transfection, the rats in the HPH and PDGF-BB+HPH groups were used to establish a neonatal rat model of HPH. Right ventricular systolic pressure (RVSP) was measured on days 3, 7, 14, and 21 of hypoxia. Hematoxylin-eosin staining was used to observe pulmonary vascular morphological changes under an optical microscope, and vascular remodeling parameters (MA% and MT%) were also measured. Immunohistochemistry was used to measure the expression levels of PDGF-BB and proliferating cell nuclear antigen (PCNA) in lung tissue. RESULTS: The rats in the PDGF-BB+HPH and HPH groups had a significantly higher RVSP than those of the same age in the normal oxygen group at each time point (P<0.05). The rats in the PDGF-BB+HPH group showed vascular remodeling on day 3 of hypoxia, while those in the HPH showed vascular remodeling on day 7 of hypoxia. On day 3 of hypoxia, the PDGF-BB+HPH group had significantly higher MA% and MT% than the HPH, PDGF-BB+normal oxygen, and normal oxygen groups (P<0.05). On days 7, 14, and 21 of hypoxia, the PDGF-BB+HPH and HPH groups had significantly higher MA% and MT% than the PDGF-BB+normal oxygen and normal oxygen groups (P<0.05). The PDGF-BB+HPH and HPH groups had significantly higher expression levels of PDGF-BB and PCNA than the normal oxygen group at all time points (P<0.05). On days 3, 7, and 14 of hypoxia, the PDGF-BB+HPH group had significantly higher expression levels of PDGF-BB and PCNA than the HPH group (P<0.05), while the PDGF-BB+normal oxygen group had significantly higher expression levels of PDGF-BB and PCNA than the normal oxygen group (P<0.05). CONCLUSIONS: Exogenous administration of PDGF-BB in neonatal rats with HPH may upregulate the expression of PCNA, promote pulmonary vascular remodeling, and increase pulmonary artery pressure.

D3PM: a comprehensive database for protein motions ranging from residue to domain.

BACKGROUND: Knowledge of protein motions is significant to understand its functions. While currently available databases for protein motions are mostly focused on overall domain motions, little attention is paid on local residue motions. Albeit with relatively small scale, the local residue motions, especially those residues in binding pockets, may play crucial roles in protein functioning and ligands binding. RESULTS: A comprehensive protein motion database, namely D3PM, was constructed in this study to facilitate the analysis of protein motions. The protein motions in the D3PM range from overall structural changes of macromolecule to local flip motions of binding pocket residues. Currently, the D3PM has collected 7679 proteins with overall motions and 3513 proteins with pocket residue motions. The motion patterns are classified into 4 types of overall structural changes and 5 types of pocket residue motions. Impressively, we found that less than 15% of protein pairs have obvious overall conformational adaptations induced by ligand binding, while more than 50% of protein pairs have significant structural changes in ligand binding sites, indicating that ligand-induced conformational changes are drastic and mainly confined around ligand binding sites. Based on the residue preference in binding pocket, we classified amino acids into "pocketphilic" and "pocketphobic" residues, which should be helpful for pocket prediction and drug design. CONCLUSION: D3PM is a comprehensive database about protein motions ranging from residue to domain, which should be useful for exploring diverse protein motions and for understanding protein function and drug design. The D3PM is available on www.d3pharma.com/D3PM/index.php .

A genome-wide association study provides insights into fatty acid synthesis and metabolism in Malus fruits.

As a precursor of aromatic compounds, fatty acids play important roles in apple fruit quality; however, the genetic and molecular basis underlying fatty acid synthesis and metabolism is largely unknown. In this study, we conducted a genome-wide association study (GWAS) of seven fatty acids using genomic data of 149 Malus accessions and identified 232 significant signals (-log10P>5) associated with 99 genes from GWAS of four fatty acids across 2 years. Among these, a significant GWAS signal associated with linoleic acid was identified in the transcriptional regulator SUPERMAN-like (SUP) MD13G1209600 at chromosome 13 of M. × domestica. Transient overexpression of MdSUP increased the contents of linoleic and linolenic acids and of three aromatic components in the fruit. Our study provides genetic and molecular information for improving the flavor and nutritional value of apple.

Raman Optical Activity of N-Acetyl-L-Cysteine in Water and in Methanol: The "Clusters-in-a-Liquid" Model and ab Initio Molecular Dynamics Simulations.

Raman and Raman Optical Activity (ROA) spectra of N-acetyl-L-cysteine (NALC), a flexible chiral molecule, were measured in water and in methanol to evaluate the solvent effects. Two different solvation approaches, that is, the DFT based "clusters-in-a-liquid" solvent model and the ab initio molecular dynamics (AIMD) simulations, were applied to simulate the Raman and ROA spectra. Systematic conformational searches were carried out using a recently developed conformational searching tool, CREST, with the inclusion of polarizable continuum model of water and of methanol. The CREST candidates of NALC and the NALC-solvent complexes were re-optimized and their Raman and ROA simulations were done at the B3LYP-D3BJ/def2-TZVP and the B3LYP-aug-cc-pVDZ//cc-pVTZ levels. Also, AIMD simulations, which includes some anharmonic effects and all intermolecular interactions in solution, were performed. By empirically weighting the computed Raman and ROA spectra of each conformer, good agreements with the experimental data were achieved with both approaches, while AIMD offered some improvements in the carbonyl and in the low wavenumber regions over the static DFT approach. The pros and cons of these two different approaches for accounting the solvent effects on Raman and ROA of this flexible chiral system will also be discussed.

Hepatocyte steatosis inhibits hepatitis B virus secretion via induction of endoplasmic reticulum stress.

The effects of hepatocyte steatosis on hepatitis B virus (HBV) DNA replication and HBV-related antigen secretion are incompletely understood. The aims of this study are to explore the effects and mechanism of hepatocyte steatosis on HBV replication and secretion. Stearic acid (SA) and oleic acid (OA) were used to induce HepG2.2.15 cell steatosis in this study. The expressions of glucose-regulated protein 78 (GRP78), phosphorylation of protein kinase R-like endoplasmic reticulum (ER) kinase (p-PERK), and eukaryotic translation initiation factor 2α (p-eIF2α) were detected by Western blotting (WB). HBV DNA, HBsAg, and HBeAg in the supernatant were determined by real-time fluorescent polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. Intracellular HBV DNA, HBsAg level, and HBV RNA were measured by real-time fluorescent PCR, WB, and real-time quantitative reverse transcriptase-PCR, respectively. The results showed that SA and OA significantly increased intracellular lipid droplets and triglyceride levels. SA and OA significantly induced GRP78, p-PERK, and p-eIF2α expressions from 24 to 72 h. 4-phenylbutyric acid (PBA) alleviated ER stress induced by SA. SA promoted intracellular HBsAg and HBV DNA accumulation; however, it inhibited the transcript of HBV 3.5 kb mRNA and S mRNA. The secretion of HBsAg and HBV DNA inhibited by SA or OA could be partially restored by pretreatment with PBA but not by inhibiting GRP78 expression with siRNA. Hepatocyte steatosis inhibits HBsAg and HBV DNA secretion via induction of ER stress in hepatocytes, but not via induction of GRP78.

Predicting spike protein NTD mutations of SARS-CoV-2 causing immune evasion by molecular dynamics simulations.

The coronavirus disease 2019 (COVID-19) pandemic was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Among all the potential targets studied for developing drugs and antibodies, the spike (S) protein is the most striking one, which is on the surface of the virus. In contrast with the intensively investigated immunodominant receptor-binding domain (RBD) of the protein, little is known about the neutralizing antibody binding mechanisms of the N-terminal domain (NTD), let alone the effects of NTD mutations on antibody binding and thereby the risk of immune evasion. Based on 400 ns molecular dynamics simulation for 11 NTD-antibody complexes together with other computational approaches in this study, we investigated critical residues for NTD-antibody binding and their detailed mechanisms. The results show that 36 residues on the NTD including R246, Y144, K147, Y248, L249 and P251 are critically involved in the direct interaction of the NTD with many monoclonal antibodies (mAbs), indicating that the viruses harboring these residue mutations may have a high risk of immune evasion. Binding free energy calculations and an interaction mechanism study reveal that R246I, which is present in the Beta (B.1.351/501Y.V2) variant, may have various impacts on current NTD antibodies through abolishing the hydrogen bonds and electrostatic interaction with the antibodies or affecting other interface residues. Therefore, special attention should be paid to the mutations of these key residues in future antibody and vaccine design and development.

Effects of group psychological intervention combined with pulmonary rehabilitation exercises on anxiety and sleep disorders in patients with mild coronavirus disease 2019 (COVID-19) infections in a Fangcang hospital.

Fangcang hospitals, as tentative hospitals built to treat a huge turnover of patients with mild coronavirus disease 2019 (COVID-19) infections, have played a pivotal role to slow down the pandemic spread in China in 2020. However, anxiety and sleep disorders remain tough to address during the treatments. In this study, group psychological intervention in combination with pulmonary rehabilitation exercises were conducted in the trial group for the patients with mild COVID-19 infections in a Fangcang Hospital to mitigate the patients' anxiety and sleep disorders, while conventional nursing methods were done in the control group, with 70 randomly picked patients in each group. Effects were assessed through questionnaire method using state anxiety questionnaire (SAI) and Pittsburgh sleep quality index scale (PQSI) rating investigation. Results showed that both SAI and PSQI scores of the trial group were significantly lower than those of the control group (P < 0.05). The SAI scores of the trial group and the control group were 38.5 ± 13.2 and 45.8 ± 10.4 points (t = 3.600, P < 0.001), respectively, and the PSQI scores were 5.6 ± 3.0 and 7.1 ± 3.0 points (t = 2.982, P < 0.01), respectively. Our methods have significant advantages over conventional nursing methods to mitigate anxiety and sleep disorders for the patients with mild COVID-19 infections in the Fangcang Hospital.

Role of decontamination treatment for implant surface in the treatment of peri-implantitis. / 种植体表面去污处理在种植体周围炎治疗中的作用.

Peri-implantitis, characterized by inflammation of tissues around implants and gradual loss of supporting bone tissue, has become one of the main causes for implant failure. Thoroughly removing the plaque biofilm on the implant surface is the first principle in the treatment of peri-implantitis. For this reason, various decontamination methods have been proposed, which can be divided into 2 categories: Removing biofilm and killing microorganisms according to the effect of plaque biofilm on the implant surface. However, at present, there is no decontamination method that can completely remove the plaque biofilm on the implant surface, and it lacks of clinical recommended guidelines. To understand the advantages and disadvantages, effectiveness and safety for different implant surface decontamination methods is of great significance to guide the clinical selection for peri-implantitis treatment.

NIR-II Absorbing Semiconducting Polymer-Triggered Gene-Directed Enzyme Prodrug Therapy for Cancer Treatment.

Exploration of facile strategies for precise regulation of target gene expression remains highly challenging in the development of gene therapies. Especially, a stimuli-responsive nanocarrier integrated with ability of noninvasive remote control for treating wide types of cancers is rarely developed. Herein, a NIR-II absorbing semiconducting polymer (PBDTQ) is employed to remotely activate the heat-inducible heat-shock protein 70 (HSP70) promoter under laser irradiation, further realizing regulation of gene-directed enzyme prodrug therapy (GDEPT) for cancer treatment in mild hyperthermia. In this multifunctional nanocomposite, the PBDTQ and double suicide gene plasmid (pSG) based on HSP70 promoter are incorporated into a lipid complex. Upon NIR-II laser excitation, the mild photothermal effect (≈43 °C) generated from PBDTQ can cause the release of pSG and activation of HSP70 promoter, and then upregulate suicide gene expression triggered by the HSP70 promoter which can further convert the nontoxic prodrug into its cytotoxic metabolites. Therefore, this work demonstrates a universal NIR-II laser-triggered GDEPT using semiconducting polymers as the photothermal generator for cancer treatment with minimized collateral damage and nontargeted side effects.

Orchestration of NLRP3 Inflammasome Activation by Ion Fluxes.

The assembly of the NLRP3 inflammasome can promote the release of IL-1ß/IL-18 and initiate pyroptosis. Accordingly, the dysregulation of NLRP3 inflammasome activation is involved in a variety of human diseases, including gout, diabetes, and Alzheimer's disease. NLRP3 can sense a variety of structurally unrelated pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) to trigger inflammation, but the unifying mechanism of NLRP3 activation is still poorly understood. Increasing evidence suggests that intracellular ions, such as K+, Ca2+, and Cl-, have a significant role in NLRP3 inflammasome activation. Here, we review the current knowledge about the role of ionic fluxes in NLRP3 inflammasome activation and discuss how disturbances in intracellular ionic levels orchestrate different signaling events upstream of NLRP3.

Matrix Isolation-Vibrational Circular Dichroism Spectroscopic Study of Conformations and Non-Covalent Interactions of Tetrahydro-2-Furoic Acid.

The conformational landscape and aggregation behaviour of tetrahydro-2-furoic acid (THFA) were investigated by using matrix isolation-vibrational circular dichroism (MI-VCD). The well-resolved experimental MI-IR and MI-VCD features in an argon matrix at 10 K allow one to identify two dominant monomeric conformations as trans-THFA where the hydroxyl and carbonyl groups of COOH are at opposite sides, as well as one cis-conformer. At 24 K and 30 K deposition temperatures, the experimental IR and VCD spectral features reveal further growth of the binary THFA aggregates. Systematic conformational searches identified three vastly different binary binding topologies, resulting in a few hundred stable (THFA)2 conformers. Interestingly, the main binary structures observed correspond to an unusual type of structure which is made of two trans-THFA subunits, in contrast to the usual double H-bonded ring binary structures, identified in a previous solution study. The present work showcases the power of MI-VCD spectroscopy in revealing unusual structures formed in a cold rare gas matrix.