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1.
Nanoscale ; 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39235476

ABSTRACT

The G-quadruplex (GQ) formed by guanine-rich DNA strands exhibits superior thermal stability and electric properties, which have generated substantial interest in applying GQ DNA to bioelectric interfaces. However, single G-wires formed by GQs have not yet surpassed the µm length due to the lack of an optimal assembly protocol and understanding of assembly mechanisms that limit application. Herein, we optimized a self-assembly protocol for a short 4-nt oligonucleotide (dG4) to achieve micrometer lengths of G-wires, including the buffer composition, incubation process and surface assembly. Furthermore, both theoretical modeling and chemical modifications were applied to unveil the atomic-level detail of GQ monomer interfaces and indicated that the assembly process follows a stepwise mechanism from nucleation to grow into oligomers and nanowires.

2.
J Agric Food Chem ; 2024 Sep 19.
Article in English | MEDLINE | ID: mdl-39300777

ABSTRACT

Indole, a compound in Chinese stinky tofu (ST), acts as a ligand for the aryl hydrocarbon receptor (AHR). Despite extensive research on prebiotic compounds, indole's specific role in ST remains unexplored. This study used an ethanol gavage method to create an ALD (alcoholic liver disease) mouse model and investigate dietary indole's effects on the intestinal barrier. Our findings indicate that after 6 weeks of being fed ST, the indole present (2 mg/day) robustly activated the intestinal AHR, upregulating its target gene, CYP1A1 (cytochrome P450 1A1 enzyme). This activation significantly reduced intestinal permeability, mitigated alcohol-induced oxidative stress and inflammation, and restored intestinal barrier function. Consequently, the study demonstrates that foodborne indole substantially reduces alcohol absorption and lowers the expression levels of liver inflammation-related factors, thereby slowing the progression of ALD. These results highlight indole's therapeutic potential for treating ALD and its role in developing functional foods.

3.
Sci Total Environ ; : 176234, 2024 Sep 15.
Article in English | MEDLINE | ID: mdl-39288873

ABSTRACT

Reducing VOCs can effectively reduce the concentration of PM2.5 and O3. Different gasoline compositions can impact the VOC species emitted by GDI and PFI vehicles. In this study, VOC species emitted from GDI and PFI vehicles combusting gasoline with different compositions (i.e., G1-market #92 gasoline, G2-high alkane gasoline, and G3-high heavy aromatic gasoline) were tested, and the influence of VOC species on O3 formation were investigated. The results indicated that the GDI vehicle consistently exhibited higher VOC emissions than the PFI vehicle in combusting three types of gasolines. The presence of short-chain alkanes and alkenes in the exhaust of combusting G2 and ethyne among the aromatics of combusting G3 resulted in higher VOC emissions from combusting G2 and G3 than from combusting G1 in the GDI vehicle. High alkane gasoline exhibited larger reductions of VOC emissions in the PFI vehicle but increased the proportions of propene, 1-butene, and ethyne emissions. High heavy aromatic gasoline increased the proportion of ethyne emissions in the GDI vehicle and increased the proportion of toluene, formaldehyde, and propane emissions in the PFI vehicle. The overall emission variation of ozone formation potential (OFP) was similar to those of VOC emissions. Alkene (C2-C6), monocyclic aromatic hydrocarbons (MAHs) and aldehydes had high contribution to O3 formation. Further research is needed to optimize fuel upgrading for GDI vehicles to ensure effective emission reduction. The results would help reduce vehicle emissions and provide support for achieving synergistic prevention and control of PM2.5 and O3 pollution.

4.
J Chem Theory Comput ; 2024 Sep 16.
Article in English | MEDLINE | ID: mdl-39279636

ABSTRACT

The particle-particle random phase approximation (ppRPA) within the hole-hole channel was recently proposed as an efficient tool for computing excitation energies of point defects in solids [J. Phys. Chem. Lett. 2024, 15, 2757-2764]. In this work, we investigate the application of ppRPA within the particle-particle channel for predicting correlated excited states of point defects, including the carbon-vacancy (VC) in diamond, the oxygen-vacancy (VO) in magnesium oxide (MgO), and the carbon dimer defect (CBCN) in two-dimensional hexagonal boron nitride (h-BN). Starting from a density functional theory calculation of the (N - 2)-electron ground state, vertical excitation energies of the N-electron system are obtained as the differences between the two-electron addition energies. We show that active-space ppRPA with the B3LYP functional yields accurate excitation energies, with errors mostly smaller than 0.1 eV for tested systems compared to available experimental values. We further develop a natural transition orbital scheme within ppRPA, which provides insights into the multireference character of defect states. This study, together with our previous work, establishes ppRPA as a low-cost and accurate method for investigating excited-state properties of point defect systems.

5.
CNS Neurosci Ther ; 30(9): e70030, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39233353

ABSTRACT

BACKGROUND: Ischemic stroke leads a primary cause of mortality in human diseases, with a high disability rate worldwide. This study aims to investigate the function of ß-1,4-galactosyltransferase 1 (B4galt1) in mouse brain ischemia/reperfusion (I/R) injury. METHODS: Recombinant human B4galt1 (rh-B4galt1) was intranasally administered to the mice model of middle cerebral artery occlusion (MCAO)/reperfusion. In this study, the impact of rh-B4galt1 on cerebral injury assessed using multiple methods, including the neurological disability status scale, 2,3,5-triphenyltetrazolium chloride (TTC), Nissl and TUNEL staining. This study utilized laser speckle Doppler flowmeter to monitor the cerebral blood flow. Western blotting was performed to assess the protein expression levels, and fluorescence-labeled dihydroethidium method was performed to determine the superoxide anion generation. Assay kits were used for the measurement of iron, malondialdehyde (MDA) and glutathione (GSH) levels. RESULTS: We demonstrated that rh-B4galt1 markedly improved neurological function, reduced cerebral infarct volume and preserved the completeness of blood-brain barrier (BBB) for preventing damage. These findings further illustrated that rh-B4galt1 alleviated oxidative stress, lipid peroxidation, as well as iron deposition induced by I/R. The vital role of ferroptosis was proved in brain injury. Furthermore, the rh-B4galt1 could increase the levels of TAZ, Nrf2 and HO-1 after I/R. And TAZ-siRNA and ML385 reversed the neuroprotective effects of rh-B4galt1. CONCLUSIONS: The results indicated that rh-B4galt1 implements neuroprotective effects by modulating ferroptosis, primarily via upregulating TAZ/Nrf2/HO-1 pathway. Thus, B4galt1 could be seen as a promising novel objective for ischemic stroke therapy.


Subject(s)
Brain Ischemia , Ferroptosis , Galactosyltransferases , Heme Oxygenase-1 , NF-E2-Related Factor 2 , Signal Transduction , Animals , Humans , Male , Mice , Brain Ischemia/metabolism , Brain Ischemia/prevention & control , Ferroptosis/drug effects , Ferroptosis/physiology , Galactosyltransferases/metabolism , Heme Oxygenase-1/metabolism , Infarction, Middle Cerebral Artery , Membrane Proteins , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , Reperfusion Injury/prevention & control , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction/physiology , Signal Transduction/drug effects , Transcription Factors/metabolism
6.
Int J Biol Macromol ; 280(Pt 1): 135696, 2024 Sep 14.
Article in English | MEDLINE | ID: mdl-39284464

ABSTRACT

The pseudorabies virus (PRV) causes severe and fatal acute respiratory disease in pigs. During PRV proliferation, the enzyme deoxyuridine 5'-triphosphate nucleotide hydrolase (dUTPase) plays a pivotal role in maintaining a low dUTP/dTTP ratio, thereby ensuring the accuracy of viral DNA replication. However, its structure and catalytic mechanisms have not been fully elucidated. Here, we report the crystal structure of PRV dUTPase at a 2.24 Å resolution and demonstrate an unprecedented dimeric architecture, with a conserved enzyme activity center of the herpesvirus family. The enzyme activity center is located in a cavity between the two domains, forming a pocket for binding substrate dUMP and magnesium ions. Remarkably, the exquisite interface of the dimer is primarily composed of four antiparallel ß-sheets, which form 11 hydrogen bonds between the residues P33-V36 and R242-A248 to maintain protein stability. To the best of our knowledge, this is the first report demonstrating that dUTPase exists as a dimer in the herpesvirus family. These findings not only present a novel fold dimeric structure but also deepen the scope of our comprehension of structural diversity in dUTPase family.

7.
Food Chem ; 460(Pt 3): 140658, 2024 Dec 01.
Article in English | MEDLINE | ID: mdl-39126949

ABSTRACT

This investigation explores the impact of various fermentation techniques and the inoculation of Bacillus subtilis spores on the physicochemical properties and principal flavor profiles of Huangjiu. Employing sensory analysis, headspace solid-phase microextraction, gas chromatography-tandem mass spectrometry (HS-SPME-GC-MS), and orthogonal partial least squares discriminant analysis (OPLS-DA), we observed that these variables significantly alter the physicochemical attributes of Huangjiu. Our analysis, integrating volatile organic compounds (VOCs) with odor activity values (OAV), revealed that while B. subtilis inoculation modifies the concentrations of key flavor compounds, it does not affect their types. Notably, the inoculation enhances the concentrations of 13 primary flavor compounds, thereby enriching floral and fruity notes while reducing higher alcohol levels. These findings contribute valuable insights into the flavor formation mechanisms of Huangjiu and guide the optimization of fermentation processes.


Subject(s)
Bacillus subtilis , Fermentation , Oryza , Taste , Volatile Organic Compounds , Wine , Adult , Female , Humans , Male , Gas Chromatography-Mass Spectrometry , Odorants/analysis , Oryza/chemistry , Oryza/microbiology , Solid Phase Microextraction , Volatile Organic Compounds/analysis , Volatile Organic Compounds/chemistry , Wine/analysis , Wine/microbiology
8.
Cell Metab ; 36(8): 1839-1857.e12, 2024 Aug 06.
Article in English | MEDLINE | ID: mdl-39111287

ABSTRACT

Lungs can undergo facultative regeneration, but handicapped regeneration often leads to fibrosis. How microenvironmental cues coordinate lung regeneration via modulating cell death remains unknown. Here, we reveal that the neurotransmitter dopamine modifies the endothelial niche to suppress ferroptosis, promoting lung regeneration over fibrosis. A chemoproteomic approach shows that dopamine blocks ferroptosis in endothelial cells (ECs) via dopaminylating triosephosphate isomerase 1 (TPI1). Suppressing TPI1 dopaminylation in ECs triggers ferroptotic angiocrine signaling to aberrantly activate fibroblasts, leading to a transition from lung regeneration to fibrosis. Mechanistically, dopaminylation of glutamine (Q) 65 residue in TPI1 directionally enhances TPI1's activity to convert dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP), directing ether phospholipid synthesis to glucose metabolism in regenerating lung ECs. This metabolic shift attenuates lipid peroxidation and blocks ferroptosis. Restoring TPI1 Q65 dopaminylation in an injured endothelial niche overturns ferroptosis to normalize pro-regenerative angiocrine function and alleviate lung fibrosis. Overall, dopaminylation of TPI1 balances lipid/glucose metabolism and suppresses pro-fibrotic ferroptosis in regenerating lungs.


Subject(s)
Endothelial Cells , Ferroptosis , Lung , Animals , Mice , Lung/metabolism , Lung/pathology , Humans , Endothelial Cells/metabolism , Regeneration , Triose-Phosphate Isomerase/metabolism , Mice, Inbred C57BL , Signal Transduction , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Male
9.
Biochem Biophys Res Commun ; 736: 150492, 2024 Aug 03.
Article in English | MEDLINE | ID: mdl-39116679

ABSTRACT

BACKGROUND: The risk of developing dementia is higher in individuals who suffer from perioperative neurocognitive disorder (PND), including postoperative cognitive dysfunction (POCD) and delirium. Recent studies have indicated correlations between anesthesia, surgery and PND. Acute metabolic changes induced by anesthesia and surgery may be related to cognitive impairments. Despite a paucity of research on acute metabolic changes in the hippocampus during surgery, there are conflicting about specific metabolites. METHODS: We developed a mouse model of cognitive impairment induced by isoflurane anesthesia and unilateral nephrectomy. Cognition was evaluated by Y maze and fear conditioning test (FCT). The hippocampus was harvested after the surgery. LC-MS (liquid chromatography-mass spectrometry) was performed. The differential metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were analyzed. RESULTS: Anesthesia and surgery exposure induced cognition decline. A total of 49 metabolites were significantly up-regulated and 122 down-regulated. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the metabolites identified purine, glutathione, nicotinate and nicotinamide metabolism. Metabolites involved in lipid, amino acid, nucleotide, carbohydrate metabolism were identified including nicotinamide adenine dinucleotide (NAD), 1-Methylnicotinamide, propionic acid, histidine, adenosine, and guanosine cyclic monophosphate. Some metabolites exhibited a consistent change trend in the hippocampus of aging mice. CONCLUSIONS: The study indicates that anesthesia and surgery can induce acute alterations in hippocampal metabolomics, including metabolites involved in lipid, amino acid, nucleotide, and carbohydrate metabolism. These metabolites may play a role in modulating PND through the regulation of neuroinflammation, oxidative stress, blood-brain barrier (BBB) permeability.

10.
Clin Exp Med ; 24(1): 201, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39196452

ABSTRACT

Behcet's syndrome (BS) is a vasculitis characterized by immune dysregulation. Biomarkers are valuable for assessing clinically atypical pathogenesis. We aimed to investigate the distribution of different biomarkers and their effects on the clinical features of patients with BS in a large-scale, real-world study. This is a retrospective, single-center study. In total, 502 patients diagnosed with BS were enrolled in this study. We analyzed the clinical features of this cohort and divided patients' symptoms into six categories, including mucocutaneous, articular, neurological, gastrointestinal, vascular, and ocular involvements. HLA-B51 cells, autoantibodies, and subsets of immune cells from the patients were tested. Pearson's correlation, Wilcoxon rank sum test and multivariate logistic regression were used for data analysis. Various autoantibodies were detected in the serum of 40.8% of patients with BS. The positivity rate of anti-endothelial cell antibodies (AECA) was the highest among autoantibodies and was found in 23.5% (118/502) of patients with BS. The positivity rate of HLA-B51 in patients with BS was 27.1%. Tumor necrosis factor (TNF)-α, IL-2, and IL-4 producing CD4+ T cells were positively correlated with the gastrointestinal BS. Increased IL-4+CD4+ T cell was a risk factor for gastrointestinal BS (P = 0.006, Overall rate [OR] = 2.491, 95% Confidence interval [CI]: [1.317, 5.100]). Various autoantibodies can be detected in patients with BS. HLA-B51 and AECA are the most common biomarkers. Increased IL-4+ CD4+ T cell was a risk factor for gastrointestinal involvement in BS.


Subject(s)
Autoantibodies , Behcet Syndrome , Biomarkers , Humans , Behcet Syndrome/blood , Behcet Syndrome/immunology , Behcet Syndrome/diagnosis , Male , Female , Adult , Biomarkers/blood , Retrospective Studies , Autoantibodies/blood , Middle Aged , HLA-B51 Antigen/blood , Tumor Necrosis Factor-alpha/blood , Young Adult , CD4-Positive T-Lymphocytes/immunology , Interleukin-4/blood
11.
Dalton Trans ; 53(35): 14648-14655, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39189431

ABSTRACT

The efficiency of silicon solar cells is still lower than theoretical values, partly due to their inability to utilize the ultraviolet and infrared portions of the solar spectrum. Herein, a novel method using a KCa2Mg2(VO4)3 phosphor with a down-shift effect to improve the photovoltaic performance of silicon solar cells and enhance the utilization of UV light in standard p-type silicon solar cells is proposed. The synthesized phosphors were mixed with an ethylene vinyl acetate (EVA) copolymer and pressed into a film, which was subsequently encapsulated in monocrystalline silicon solar cells. The results show that the addition of this film notably enhanced the photovoltaic performance of the silicon solar cells; the current density was increased by 2.89% (from 33.20 to 34.16 mA cm-2), and the photovoltaic conversion efficiency was improved by 5.69% (from 15.11% to 15.97%) at the optimal concentration compared to bare cells.

12.
Nat Commun ; 15(1): 5814, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38987527

ABSTRACT

For first-order phase transitions, the second derivatives of Gibbs free energy (specific heat and compressibility) diverge at the transition point, resulting in an effect known as super-elasticity along the pressure axis, or super-thermicity along the temperature axis. Here we report a chemical analogy of these singularity effects along the atomic doping axis, where the second derivative of Gibbs free energy (chemical susceptibility) diverges at the transition point, leading to an anomalously high energy barrier for dopant diffusion in co-existing phases, an effect we coin as super-susceptibility. The effect is realized in hydrogen diffusion in vanadium dioxide (VO2) with a metal-insulator transition (MIT). We show that hydrogen faces three times higher energy barrier and over one order of magnitude lower diffusivity when it diffuses across a metal-insulator domain wall in VO2. The additional energy barrier is attributed to a volumetric energy penalty that the diffusers need to pay for the reduction of latent heat. The super-susceptibility and resultant retarded atomic diffusion are expected to exist universally in all phase transformations where the transformation temperature is coupled to chemical composition, and inspires new ways to engineer dopant diffusion in phase-coexisting material systems.

13.
J Mater Chem B ; 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39072701

ABSTRACT

Periodontitis, a prevalent chronic oral disease, poses a significant threat to periodontal tissues, often resulting in substantial attachment loss and tooth shedding. Leveraging the principles of bone affinity and the mechanism underlying tetracycline pigmentation of teeth, this study strategically employed tetracycline (TC) as a bone-affinity group. We modified TC on the surface of polylactic-co-glycolic acid copolymer (PLGA) microspheres (MSs) through covalent binding, and then loaded berberine (BBR) MSs into a thermosensitive self-healing hydrogel delivery system (BBR/TC-MS). It was verified that the BBR/TC-MS gel rapidly formed an in situ reservoir in the periodontal pocket upon injection, and the chelation between TC and cementum in the periodontal pocket enhanced the anchoring effect of the TC-modified microspheres on cementum, preventing their loss through gingival crevicular fluid. Subsequently, we proved in vitro and in vivo that the BBR/TC-MS gel has excellent bacteriostatic effects against the periodontal pathogenic bacteria Fusobacterium necrophorum (Fn), anti-inflammation property in periodontal and gingival tissues, and osteogenic effect by regulating the RANKL-RANK-OPG pathway to diminish osteoclast activity, thus continuously exerting antibacterial, anti-inflammatory, osteogenic, and anti-osteoclastic effects. This innovative approach holds promise as a targeted and effective strategy for combating multifaceted challenges posed by periodontitis.

14.
ACS Nano ; 18(28): 18118-18128, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-38951984

ABSTRACT

The cost of annual energy consumption in buildings in the United States exceeds 430 billion dollars ( Science 2019, 364 (6442), 760-763), of which about 48% is used for space thermal management (https://www.iea.org/reports/global-status-report-for-buildings-and-construction-2019), revealing the urgent need for efficient thermal management of buildings and dwellings. Radiative cooling technologies, combined with the booming photonic and microfabrication technologies ( Nature 2014, 515 (7528), 540-544), enable energy-free cooling by radiative heat transfer to outer space through the atmospheric transparent window ( Nat. Commun. 2024, 15 (1), 815). To pursue all-season energy savings in climates with large temperature variations, switchable and tunable radiative coolers (STRC) have emerged in recent years and quickly gained broad attention. This Perspective introduces the existing STRC technologies and analyzes their benefits and challenges in future large-scale applications, suggesting ways for the development of future STRCs.

15.
Nicotine Tob Res ; 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39021120

ABSTRACT

INTRODUCTION: We evaluated the impact of heating conventional cigarettes with a novel heated tobacco product (HTP) device on biomarkers and cigarette use patterns in Chinese adult smokers unwilling to quit smoking. METHODS: In this pilot randomized controlled trial, 50 eligible participants were allocated to either Control group (smoking conventional cigarettes) or HTP device group (switching to using heated conventional cigarettes by the HTP device). Participants in the HTP device group went through a 2-day run-in period then used heated conventional cigarettes exclusively for 5 days, followed by flexible use for 14 days. Five biomarkers of exposure (BoEs) were measured at baseline and on Day 7. Thirteen biomarkers of biological effect (BoBEs) were measured at baseline and on Day 21. Safety, daily cigarette consumption, craving, withdrawal symptoms, and device acceptability, were assessed. RESULTS: BoE levels decreased by 26.4 % to 71.4% from baseline in the HTP device group, while BoBE levels did not significantly change in either group. In the HTP group, 56% exclusively used heated conventional cigarettes during the flexible use period, experiencing reduced cravings and withdrawal symptoms, while dual users consumed more cigarettes. Mild to moderate device-related reactions were reported in 36% of users. Satisfaction, taste, and harm reduction belief scores averaged 7.4, 6.6, and 8.7 (out of 10), respectively. CONCLUSIONS: Switching to heated cigarettes with the HTP device may reduce short-term exposure to smoke toxicants. However, it can lead to increased tobacco use among dual users. Further investigation is needed to confirm these preliminary findings. IMPLICATIONS: This study is the first to evaluate the impact of heating conventional cigarettes with a novel heated tobacco product (HTP) device on health-related biomarkers and cigarette use patterns among Chinese adult smokers. This novel HTP device can directly heat conventional cigarettes without the necessity for specifically designed tobacco products, avoiding potential additive risks of traditional HTPs. If the results of this study could be further verified by randomized controlled clinical trials with larger sample sizes, this novel HTP device could serve as a short-term harm reduction alternative for smokers unwilling to quit.

16.
J Phys Chem A ; 128(29): 6072-6083, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39011742

ABSTRACT

The Bethe-Salpeter equation using the GW approximation to the self-energy (BSE@GW) is a computationally attractive method for studying electronic excitation from first principles within the many-body Green's function theory framework. We examine its dependence on the underlying exchange-correlation (XC) approximation as well as on the GW approximation for predicting the charge transfer exciton formation at representative type-II interfaces between molecular systems of tetrachloro-1,2-benzoquinone (TCBQ) and acene derivatives. For the XC approximation, we consider several widely used generalized gradient approximation (GGA) and hybrid GGA functionals. For the GW self-energy approximation, we examine the recently proposed renormalized singles approach by Yang and coauthors [J. Phys. Chem. Lett. 2019, 10 (3), 447-452; J. Chem. Theory Comput. 2022, 18, 7570-7585] in addition to other commonly employed approximated GW schemes. We demonstrate a reliable prediction of the charge transfer exciton within the BSE@GW level of theory.

17.
Faraday Discuss ; 2024 Jul 30.
Article in English | MEDLINE | ID: mdl-39076013

ABSTRACT

Dynamical mean-field theory (DMFT) and its cluster extensions provide an efficient Green's function formalism to simulate spectral properties of periodic systems at the quantum many-body level. However, traditional cluster DMFT breaks translational invariance in solid-state materials, and the best strategy to capture non-local correlation effects within cluster DMFT remains elusive. In this work, we investigate the use of overlapping atom-centered impurity fragments in recently-developed ab initio all-orbital DMFT, where all local orbitals within the impurity are treated with high-level quantum chemistry impurity solvers. We demonstrate how the translational symmetry of the lattice self-energy can be restored by designing symmetry-adapted embedding problems, which results in an improved description of spectral functions in two-dimensional boron nitride monolayers and graphene at the levels of many-body perturbation theory (GW) and coupled-cluster theory. Furthermore, we study the convergence of self-energy and density of states as the embedding size is systematically expanded in one-shot and self-consistent DMFT calculations.

18.
J Mol Recognit ; 37(5): e3100, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39014869

ABSTRACT

Metallo-ß-lactamases (MßLs) hydrolyze and inactivate ß-lactam antibiotics, are a pivotal mechanism conferring resistance against bacterial infections. SMB-1, a novel B3 subclass of MßLs from Serratia marcescens could deactivate almost all ß-lactam antibiotics including ampicillin (AMP), which has posed a serious threat to public health. To illuminate the mechanism of recognition and interaction between SMB-1 and AMP, various fluorescence spectroscopy techniques and molecular dynamics simulation were employed. The results of quenching spectroscopy unraveled that AMP could make SMB-1 fluorescence quenching that mechanism was the static quenching; the synchronous and three-dimensional fluorescence spectra validated that the microenvironment and conformation of SMB-1 were altered after interaction with AMP. The molecular dynamics results demonstrated that the whole AMP enters the binding pocket of SMB-1, even though with a relatively bulky R1 side chain. Loop1 and loop2 in SMB-1 undergo significant fluctuations, and α2 (71-73) and local α5 (186-188) were turned into random coils, promoting zinc ion exposure consistent with circular dichroism spectroscopy results. The binding between them was driven by a combination of enthalpy and entropy changes, which was dominated by electrostatic force in agreement with the fluorescence observations. The present study brings structural insights and solid foundations for the design of new substrates for ß-lactamases and the development of effective antibiotics that are resistant to superbugs.


Subject(s)
Ampicillin , Molecular Dynamics Simulation , Serratia marcescens , Spectrometry, Fluorescence , beta-Lactamases , beta-Lactamases/chemistry , beta-Lactamases/metabolism , Ampicillin/chemistry , Ampicillin/metabolism , Ampicillin/pharmacology , Serratia marcescens/enzymology , Protein Binding , Binding Sites , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism
19.
Nat Commun ; 15(1): 4811, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844452

ABSTRACT

Human multidrug resistance protein 5 (hMRP5) effluxes anticancer and antivirus drugs, driving multidrug resistance. To uncover the mechanism of hMRP5, we determine six distinct cryo-EM structures, revealing an autoinhibitory N-terminal peptide that must dissociate to permit subsequent substrate recruitment. Guided by these molecular insights, we design an inhibitory peptide that could block substrate entry into the transport pathway. We also identify a regulatory motif, comprising a positively charged cluster and hydrophobic patches, within the first nucleotide-binding domain that modulates hMRP5 localization by engaging with membranes. By integrating our structural, biochemical, computational, and cell biological findings, we propose a model for hMRP5 conformational cycling and localization. Overall, this work provides mechanistic understanding of hMRP5 function, while informing future selective hMRP5 inhibitor development. More broadly, this study advances our understanding of the structural dynamics and inhibition of ABC transporters.


Subject(s)
Cryoelectron Microscopy , Humans , ATP-Binding Cassette Transporters/metabolism , ATP-Binding Cassette Transporters/chemistry , Biological Transport , HEK293 Cells , Models, Molecular , Multidrug Resistance-Associated Proteins/metabolism , Multidrug Resistance-Associated Proteins/chemistry , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Multidrug Resistance-Associated Proteins/genetics , Peptides/metabolism , Peptides/chemistry , Protein Conformation
20.
Opt Express ; 32(10): 16913-16924, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38858887

ABSTRACT

What we believe to be a novel reconfigurable multi-channel microwave photonic (MWP) receiver for multi-band RF signal is demonstrated for the first time, to the best of our knowledge. A reconfigurable MWP signal processing chip based on two cascaded microring filter banks is employed in the proposed receiver, which slices the multi-band RF input into several narrow band signals and selects optical frequency comb lines for frequency converting of each channel. Due to the significant reconfigurability of the signal processing chip, the proposed receiver can flexibly choose the output frequency band of each channel, and thus different frequency components of the multi-band RF input can be down converted to the intermediate frequency (IF) band for receiving or converted to other frequency band for forwarding. A multi-band RF signal composed of a linear frequency modulation (LFM) signal with 2 GHz bandwidth and a quad-phase shift keyed (QPSK) signal with 100 Mbit/s rate is experimentally received and reconstructed by the proposed receiver, where the reconstructed LFM component exhibits a signal to noise ratio (SNR) of 10.2 dB, and the reconstructed QPSK component reaches a high SNR of 26.1 dB and a great error vector magnitude (EVM) of 11.73%. On the other hand, the QPSK component of the multi-band RF signal centered at 13.5 GHz is successfully converted to 3.1 GHz.

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