Structural and functional insights into the self-sufficient flavin-dependent halogenase.

Flavin-dependent halogenases (FDHs) have tremendous applications in synthetic chemistry. A single-component FDH, AetF, exhibits both halogenase and reductase activities in a continuous polypeptide chain. AetF exhibits broad substrate promiscuity and catalyzes the two-step bromination of l-tryptophan (l-Trp) to produce 5-bromotryptophan (5-Br-Trp) and 5,7-dibromo-l-tryptophan (5,7-di-Br-Trp). To elucidate the mechanism of action of AetF, we solved its crystal structure in complex with FAD, FAD/NADP+, FAD/l-Trp, and FAD/5-Br-Trp at resolutions of 1.92-2.23 Å. The obtained crystal structures depict the unprecedented topology of single-component FDH. Structural analysis revealed that the substrate flexibility and dibromination capability of AetF could be attributed to its spacious substrate-binding pocket. In addition, highly-regulated interaction networks between the substrate-recognizing residues and 5-Br-Trp are crucial for the dibromination activity of AetF. Several Ala variants underwent monobromination with >98 % C5-regioselectivity toward l-Trp. These results reveal the catalytic mechanism of single-component FDH for the first time and contribute to efficient FDH protein engineering for biocatalytic halogenation.

The structural and functional investigation into an unusual nitrile synthase.

The biosynthesis of neurotoxin aetokthonotoxin (AETX) that features a unique structure of pentabrominated biindole nitrile involves a first-of-its-kind nitrile synthase termed AetD, an enzyme that shares very low sequence identity to known structures and catalyzes an unprecedented mechanism. In this study, we resolve the crystal structure of AetD in complex with the substrate 5,7-di-Br-L-Trp. AetD adopts the heme oxygenase like fold and forms a hydrophobic cavity within a helical bundle to accommodate the indole moiety. A diiron cluster comprising two irons that serves as a catalytic center binds to the carboxyl O and the amino N of the substrate. Notably, we demonstrate that the AetD-catalyzed reaction is independent of the bromination of the substrate and also solved crystal structures of AetD in complex with 5-Br-L-Trp and L-Trp. Altogether, the present study reveals the substrate-binding pattern and validates the diiron cluster-comprising active center of AetD, which should provide important basis to support the mechanistic investigations into this class of nitrile synthase.

Magnesium intake and all-cause mortality after stroke: a cohort study.

BACKGROUND: Population-based studies have shown that adequate magnesium intake is associated with a lower risk of stroke and all-cause mortality. Whether adequate magnesium intake is important for reducing all-cause mortality risk after stroke remains unclear. METHODS: We analyzed data from 917 patients with a self-reported history of stroke from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. The total magnesium intake was calculated by summing the magnesium intake from dietary and dietary supplements, and then adjusting for total energy intake according to the nutrient density method. Mortality status was determined using public-use linked mortality files from 2019. Cox regression model and restricted cubic splines were used to explore the relationship between magnesium intake and all-cause mortality. RESULTS: The average total magnesium intake across all patients was 251.0 (184.5-336.5) mg/d, and 321 (70.2%) males and 339 (73.7%) females had insufficient magnesium intake. During a median follow-up period of 5.3 years, 277 deaths occurred. After fully adjusting for confounding factors, total magnesium intake levels were inversely associated with all-cause mortality risk (HR per 1-mg/(100 kcal*d) increase, 0.97; 95% CI, 0.94-1.00; p = 0.017). Participants with the highest quartile of total magnesium intake (≥ 18.5 mg/(100 kcal*d)) had a 40% reduction in all-cause mortality risk compared to those with the lowest quartile (≤ 12.0 mg/(100 kcal*d)) (HR, 0.60; 95% CI, 0.38-0.94; p = 0.024). Stratified analyses showed that this inverse association was statistically significant in those who were older, female, without hypertension, and had smoking, normal renal function, and adequate energy intake. Dietary magnesium intake alone might be not related to all-cause mortality. CONCLUSIONS: Stroke survivors who consumed adequate amounts of magnesium from diet and supplements had a lower risk of all-cause mortality.

Transdermal drug delivery via microneedles for musculoskeletal systems.

As the population is ageing and lifestyle is changing, the prevalence of musculoskeletal (MSK) disorders is gradually increasing with each passing year, posing a serious threat to the health and quality of the public, especially the elderly. However, currently prevalent treatments for MSK disorders, mainly administered orally and by injection, are not targeted to the specific lesion, resulting in low efficacy along with a series of local and systemic adverse effects. Microneedle (MN) patches loaded with micron-sized needle array, combining the advantages of oral administration and local injection, have become a potentially novel strategy for the administration and treatment of MSK diseases. In this review, we briefly introduce the basics of MNs and focus on the main characteristics of the MSK systems and various types of MN-based transdermal drug delivery (TDD) systems. We emphasize the progress and broad applications of MN-based transdermal drug delivery (TDD) for MSK systems, including osteoporosis, nutritional rickets and some other typical types of arthritis and muscular damage, and in closing summarize the future prospects and challenges of MNs application.

Implementation and Optimization of Zero-Knowledge Proof Circuit Based on Hash Function SM3.

With the increasing demand for privacy protection in the blockchain, the universal zero-knowledge proof protocol has been developed and widely used. Because hash function is an important cryptographic primitive in a blockchain, the zero-knowledge proof of hash preimage has a wide range of application scenarios. However, it is hard to implement it due to the transformation of efficiency and execution complexity. Currently, there are only zero-knowledge proof circuits of some widely used hash functions that have been implemented, such as SHA256. SM3 is a Chinese hash function standard published by the Chinese Commercial Cryptography Administration Office for the use of electronic authentication service systems, and hence might be used in several cryptographic applications in China. As the national cryptographic hash function standard, the zero-knowledge proof circuit of SM3 (Chinese Commercial Cryptography) has not been implemented. Therefore, this paper analyzed the SM3 algorithm process, designed a new layered circuit structure, and implemented the SM3 hash preimage zero-knowledge proof circuit with a circuit size reduced by half compared to the automatic generator. Moreover, we proposed several extended practical protocols based on the SM3 zero-knowledge proof circuit, which is widely used in blockchain.

MMP-10 rs17435959 Polymorphism is Associated with the Formation and Stability of Carotid Atherosclerosis Plaque: A Case-Control Study.

BACKGROUND: Matrix metalloproteinase 10 (MMP-10) has a close relationship with carotid atherosclerosis (CAS) and cerebral infarction. The MMP-10 rs17435959 polymorphism causes a leucine to valine transition at codon 4 in exon 1 of the MMP-10 gene and may have functional effects. OBJECTIVES: To investigate the relationship between the MMP-10 rs17435959 polymorphism and the formation and stability of CAS plaques. MATERIALS AND METHODS: The present case-control study contains 738 visitors who came to our health examination center for the first time. According to the carotid ultrasound examinations, visitors were classified into the vulnerable plaque group (41-86 years old, 141 male, 105 female), the stable plaque group (41-86 years old, 141 male, 105 female) and the no plaque group (41-85 years old, 141 male, 105 female). All visitors in the three groups were sex- and- age-matched, and cardiovascular and cerebrovascular diseases were absent. The polymorphism was genotyped by real-time polymerase chain reaction- restriction. RESULTS: Compared to the GG genotype, the frequency of the CC and CG genotypes was significantly more common in the vulnerable plaque group than in the no plaque group (18.7% vs. 7.7%, unadjusted P = 0.002). Moreover, compared to the G allele, the frequency of the C allele was significantly more common in the vulnerable plaque group than in the no plaque group (10.4% vs. 3.9%, unadjusted P = 0.000) and in the vulnerable plaque group than in the stable plaque group (10.4% vs. 5.1%, unadjusted P = 0.008). Binary logistic regression showed that the CC and CG genotype was independent risk factor for the formation (P = 0.019, OR = 1.961, 95% CI [1.117, 3.444]) and vulnerability (P = 0.035, OR = 1.842, 95% CI [1.045, 3.247]) of CAS plaques. Moreover, individuals who have the C allele showed a higher level of fibrinogen, which was an independent risk factor for the formation of CAS plaques (P = 0.000, OR = 2.425, 95% CI [1.475, 3.985]). CONCLUSIONS: The rs17435959 polymorphism was associated with the formation and vulnerability of CAS plaques. Individuals who had variant-type MMP-10 showed higher levels of fibrinogen, which promoted the formation of CAS plaques.

Time-Domain Line-Shape Analysis from 2D Spectroscopy to Precisely Determine Hamiltonian Parameters for a Photosynthetic Complex.

Optical signals come from coherences between quantum states, with spectral line widths determined by the coherences' dephasing dynamics. Using a 2D electronic spectrometer, we observe weak coherence- and rephasing-time-domain signals persisting to 1 ps in the Fenna-Matthews-Olson complex at 77 K. These are coherences between the ground and excited states prepared after the complex interacts once or three times with light, rather than zero-quantum coherences that are more frequently investigated following two interactions. Here, we use these small but persistent signal components to isolate spectral contributions with narrowed peaks and reveal the system's eigenenergies.

Proinflammatory properties and lipid disturbance of polystyrene microplastics in the livers of mice with acute colitis.

Microplastics (MPs) are ubiquitous contaminants in the environment and can be transferred along the food chain, thus causing adverse effects in organisms, even human beings. Therefore, it is of practical importance to identify the environmental risks of MPs, which could lead to a significant impact on public health. In addition to the healthy population, there are large numbers of patients with chronic diseases around the world whose responses to MPs are understudied, representing a significant knowledge gap within the health risk assessment of MPs. In this study, the response sensitivity to MPs of mice with acute colitis was compared with that of healthy mice. The mice were fed water containing polystyrene microplastics (PS MP) at a concentration of 500 µg/L for 28 days. The results showed that PS MP exposure induced inflammatory effects and exerted great disturbance on liver metabolites. Moreover, exposure to PS MP exaggerated dextran sodium sulfate (DSS)-induced acute colitis, as well as lipid disorders, as verified by typical inflammatory factor expression and triglyceride accumulation. The increased intestinal permeability of mice with acute colitis caused by exposure to PS MP may be responsible for the upregulated adverse effects. The results of this study suggest that populations with chronic diseases might be more sensitive to environmental contamination, which should be considered during health risk assessments.

Optical properties of a hexagonal C/BN framework with sp2 and sp3 hybridized bonds.

We investigated the optical properties and roles of sp2- and sp3-hybridized bonds of a hexagonal C/BN family using first-principles calculations. The calculated phonon dispersions confirm the dynamic stability of Hex-(BN)6C12 and Hex-C12(BN)6. The complex dielectric function evolves from the infrared to the ultraviolet region and has a significant anisotropy for different polarizations. The reflectivity and refractive index spectra show that the sp2-hybridized C atoms are more sensitive to the light from infrared to visible region than B-N pairs while the C atoms and B-N pairs have a similar sensitivity to high frequencies. The sharp peaks of the energy-loss spectrum are all concentrated in the 23-30 eV energy region, which can be used to identify these hexagonal structures. The calculated band structures show Hex-C24 and Hex-(BN)6C12 are metals, but Hex-C12(BN)6 and Hex-(BN)12 are semiconductors with indirect band gaps of 3.47 and 3.25 eV, respectively. The electronic states near the Fermi level primarily originate from sp2-hybridized atoms. In addition, sp2-hybridized bonds are the main elements affecting the optical and electronic structure of C/BN materials with sp2- and sp3-hybridizations. We expect that the results presented will help understand the optical properties of C/BN materials containing sp2- and sp3-hybridized C atoms and B-N pairs.

Generative dynamic link prediction.

In networks, a link prediction task aims at learning potential relations between nodes to predict unknown potential linkage states. At present, most link prediction methods are used to process static networks. These methods cannot produce good prediction results for dynamic networks. However, for most dynamic networks in the real world, the vertices and links of these networks change over time. Dynamic link prediction (DLP) has attracted more attention as it can better mimic the evolution nature of the networks. Inspired by successful applications of the generative adversarial network in generating fake images, which are comparable with the real ones, we propose a novel generative dynamic link prediction (GDLP) method. Different from other DLP methods, we model the link prediction task as a network generation process. More specifically, GDLP utilizes the historical networks structure information to generate the network snapshot of next time stamp by an end-to-end deep generative model. This model contains a generator and a discriminator. The generator of GDLP is a spatiotemporal prediction model, which is responsible for generating the future networks based on the historical network snapshots, while the discriminator is a classification model to classify the generated networks and the ground-truth ones. With the two-player game training and learning strategy, GDLP is capable of accurate prediction for dynamic networks using the structural and temporal information. Experimental results validate that GDLP significantly outperforms several existing baseline methods on many types of dynamic networks, which improves the effectiveness of dynamic link prediction.

Iliac Aneurysms Treated with Endovascular Iliac Branch Device: A Systematic Review and Meta-analysis.

BACKGROUND: Iliac branch devices (IBDs) have been increasingly reported for treating aortoiliac aneurysms. However, there are still concerns regarding this device. The aim of this study was to evaluate the safety and outcomes of IBDs in treating aortoiliac aneurysms by performing a systematic review and meta-analysis. METHODS: The Medline, EMBASE, and Cochrane databases were systematically searched to identify studies on the management of aortoiliac aneurysms using IBDs. Studies were reviewed and selected using defined criteria by 2 independent investigators who abstracted data on the study characteristics, study quality, and outcomes. The extracted data were presented as a rate and converted through arcsine transformations. Individual studies were evaluated and analyzed for 7 outcomes, including technical success rate, 30-day mortality, 30-day patency, follow-up patency, endoleak rate, buttock claudication, and IBD-associated reintervention. The heterogeneity of the studies was determined using the chi-squared distribution-based Q test and quantified by I2 statistics. Meta-analyses were performed using both a random effects model and fixed effects model. RESULTS: Twenty-two studies with a total of 1064 patients met the inclusion criteria and were selected for analysis. The pooled technical success rate of IBD was 93% (95% confidence interval [CI]: 91-95%). After patients were treated with the IBD, the 30-day mortality rate was 2% (95% CI, 1-4%), 30-day patency rate was 93% (95% CI, 91-94%), follow-up patency was 86% (95% CI, 84-88%), endoleak rate was 12% (95% CI, 8-17%), buttock claudication rate was 6% (95% CI, 5-8%), and IBD-associated reintervention rate was 11% (95% CI, 8-14%). CONCLUSIONS: Our study demonstrates that treating aortoiliac aneurysm with IBD produces satisfactory outcomes in midterm follow-up.

The role of sp2 and sp3 hybridized bonds on the structural, mechanical, and electronic properties in a hard BN framework.

A first-principles approach is used to systematically investigate the role of sp2 and sp3 hybridized bonds on the structural, mechanical, and electronic properties in a new BN phase (denoted Hex-(BN)12). Hex-(BN)12 has the same number of sp2 and sp3 hybridized atoms. The calculated cohesion energy, phonon frequencies, and elastic constants unambiguously confirm the structural stability of this compound. Due to the different types of hybridization and B-N covalent bonds with ionic characteristics, Hex-(BN)12 has unequal bond lengths and bond angles in these hybrid orbitals. These cause the relative energetic stability to be slightly lower than c-BN and w-BN. The hardness of Hex-(BN)12 is estimated to range from 33 to 40 GPa. The bond-breaking order under stress is sp3-sp3, sp2-sp3, and sp2-sp2. DFT calculations with the gradient approximation (GGA) and HSE06 functional indicate the electronic structure contains an indirect band gap at 3.21 and 4.42 eV, respectively. The electronic states in the region near the Fermi level primarily arise from the 2p orbitals in sp2-hybridized atoms. In general, sp3 bonded B and N atoms guarantee higher mechanical properties, and sp2 bonded atoms ensure ductility and even conductivity, although all changes vary with spatial structure. Hex-(BN)12 can be obtained from multilayer yne-BN, and BN nanosheets, nanotubes and nanoribbons under pressure.

Bacteriophytochrome Photoisomerization Proceeds Homogeneously Despite Heterogeneity in Ground State.

Phytochromes are red/far-red photoreceptors that are widely distributed in plants and prokaryotes. Ultrafast photoisomerization of a double bond in a biliverdin cofactor or other linear tetrapyrrole drives their photoactivity, but their photodynamics are only partially understood. Multiexponential dynamics were observed in previous ultrafast spectroscopic studies and were attributed to heterogeneous populations of the pigment-protein complex. In this work, two-dimensional photon echo spectroscopy was applied to study dynamics of the bacteriophytochromes RpBphP2 and PaBphP. Two-dimensional photon echo spectroscopy can simultaneously resolve inhomogeneity in ensembles and fast dynamics by correlating pump wavelength with the emitted signal wavelength. The distribution of absorption and emission energies within the same state indicates an ensemble of heterogeneous protein environments that are spectroscopically distinct. However, the lifetimes of the dynamics are uniform across the ensemble, suggesting a homogeneous model involving sequential intermediates for the initial photodynamics of isomerization.

[Silymarin Protects Umbilical Cord-Derived Mesenchymal Stem Cells against Apoptosis Induced by Serum-Deprivation].

OBJECTIVE: To investigate the protection of silymarin against the human mesenchymal stem cell (MSC) apoptosis induced by serum deprivation and its underlying mechanism. METHODS: Human umbilical cord MSCs were cultured in the absence of serum, and the silymain of different concentration (1-10 µg/ml) was added into the medium. MTT test was performed to observe the cell proliferation status. After being cultured for 72 hours, the cells were collected, and flow cytometry with Annexin-V-PI double-staining was used to detect the apoptotic cells from the control and silymarin-treated groups. Furthermore, the intracellular contents of BAX and BCL-2 were detected by Western blot for exploring the potential mechanism. RESULTS: The silymarin promoted the proliferation of human UC-MSCs in a dose-dependent manner, reaching its maximal at a dose of 5 µg/ml. Moreover, silymarin could inhibit the serum deprivation-induced apoptosis of MSCs and, the inhibitory rate reached up to 30% when it was added at a concentration of 5 µg/ml. The content of intracellular BAX was obviously elevated after serum-deprivation treatment, and this increase could be blunted by the addition of silymarin. Meanwhile, the content of BCL-2 was not obviously changed. CONCLUSION: The silymarin can stimulate MSC growth and inhibit the apoptosis of MSCs probably by the mitochondria pathway.

Shaped Ceria Nanocrystals Catalyze Efficient and Selective Para-Hydrogen-Enhanced Polarization.

Intense para-hydrogen-enhanced NMR signals are observed in the hydrogenation of propene and propyne over ceria nanocubes, nano-octahedra, and nanorods. The well-defined ceria shapes, synthesized by a hydrothermal method, expose different crystalline facets with various oxygen vacancy densities, which are known to play a role in hydrogenation and oxidation catalysis. While the catalytic activity of the hydrogenation of propene over ceria is strongly facet-dependent, the pairwise selectivity is low (2.4% at 375 °C), which is consistent with stepwise H atom transfer, and it is the same for all three nanocrystal shapes. Selective semi-hydrogenation of propyne over ceria nanocubes yields hyperpolarized propene with a similar pairwise selectivity of (2.7% at 300 °C), indicating product formation predominantly by a non-pairwise addition. Ceria is also shown to be an efficient pairwise replacement catalyst for propene.

Parahydrogen-induced polarization by pairwise replacement catalysis on Pt and Ir nanoparticles.

Pairwise and random addition processes are ordinarily indistinguishable in hydrogenation reactions. The distinction becomes important only when the fate of spin correlation matters, such as in parahydrogen-induced polarization (PHIP). Supported metal catalysts were not expected to yield PHIP signals given the rapid diffusion of H atoms on the catalyst surface and in view of the sequential stepwise nature of the H atom addition in the Horiuti-Polanyi mechanism. Thus, it seems surprising that supported metal hydrogenation catalysts can yield detectable PHIP NMR signals. Even more remarkably, supported Pt and Ir nanoparticles are shown herein to catalyze pairwise replacement on propene and 3,3,3-trifluoropropene. By simply flowing a mixture of parahydrogen and alkene over the catalyst, the scalar symmetrization order of the former is incorporated into the latter without a change in molecular structure, producing intense PHIP NMR signals on the alkene. An important indicator of the mechanism of the pairwise replacement is its stereoselectivity, which is revealed with the aid of density matrix spectral simulations. PHIP by pairwise replacement has the potential to significantly diversify the substrates that can be hyperpolarized by PHIP for biomedical utilization.

Persistent Inter-Excitonic Quantum Coherence in CdSe Quantum Dots.

The creation and manipulation of quantum superpositions is a fundamental goal for the development of materials with novel optoelectronic properties. In this letter, we report persistent (~80 fs lifetime) quantum coherence between the 1S and 1P excitonic states in zinc-blende colloidal CdSe quantum dots at room temperature, measured using Two-Dimensional Electronic Spectroscopy. We demonstrate that this quantum coherence manifests as an intradot phenomenon, the frequency of which depends on the size of the dot excited within the ensemble of QDs. We model the lifetime of the coherence and demonstrate that correlated interexcitonic fluctuations preserve relative phase between excitonic states. These observations suggest an avenue for engineering long-lived interexcitonic quantum coherence in colloidal quantum dots.

Dispersion-free continuum two-dimensional electronic spectrometer.

Electronic dynamics span broad energy scales with ultrafast time constants in the condensed phase. Two-dimensional (2D) electronic spectroscopy permits the study of these dynamics with simultaneous resolution in both frequency and time. In practice, this technique is sensitive to changes in nonlinear dispersion in the laser pulses as time delays are varied during the experiment. We have developed a 2D spectrometer that uses broadband continuum generated in argon as the light source. Using this visible light in phase-sensitive optical experiments presents new challenges in implementation. We demonstrate all-reflective interferometric delays using angled stages. Upon selecting an ~180 nm window of the available bandwidth at ~10 fs compression, we probe the nonlinear response of broadly absorbing CdSe quantum dots and electronic transitions of Chlorophyll a.