Residue-Free Orally Administered Drug Carrier Based on a Porous Aromatic Framework for Efficient Multisite Treatment.

Nowadays, oral medications are the primary method of treating disease due to their convenience, low cost, and safety, without the need for complex medical procedures. To maximize treatment effectiveness, almost all oral medications utilize drug carriers, such as capsules, liposomes, and sugar coatings. However, these carriers rely on dissolution or fragmentation to achieve drug release, which leads to drugs and carriers coabsorption in the body, causing unnecessary adverse drug reactions, such as nausea, vomiting, abdominal pain, and even death caused by allergy. Therefore, the ideal oral drug carrier should avoid degradation and absorption and be totally excreted after drug release at the desired location. Herein, a gastrointestinally stable oral drug carrier based on porous aromatic framework-1 (PAF-1) is constructed, and it is modified with famotidine (a well-known gastric drug) and mesalazine (a well-known ulcerative colitis drug) to verify the excellent potential of PAF-1. The results demonstrate that PAF-1 can accurately release famotidine in stomach, mesalazine in the intestine, and finally be completely excreted from the body without any residue after 12 h. The use of PAF materials for the construction of oral drug carriers with no residue in the gastrointestinal tract provides a new approach for efficient disease treatment.

Hunting for the Intermolecular Diels-Alderase.

ConspectusThe Diels-Alder reaction is well known as a concerted [4 + 2] cycloaddition governed by the Woodward-Hoffmann rules. Since Prof. Otto Diels and his student Kurt Alder initially reported the intermolecular [4 + 2] cycloaddition between cyclopentadiene and quinone in 1928, it has been recognized as one of the most powerful chemical transformations to build C-C bonds and construct cyclic structures. This named reaction has been widely used in synthesizing natural products and drug molecules. Driven by the synthetic importance of the Diels-Alder reaction, identifying the enzyme that stereoselectively catalyzes the Diels-Alder reaction has become an intriguing research area in natural product biosynthesis and biocatalysis. With significant progress in sequencing and bioinformatics, dozens of Diels-Alderases have been characterized in microbial natural product biosynthesis. However, few are evolutionally dedicated to catalyzing an intermolecular Diels-Alder reaction with a concerted mechanism.This Account summarizes our endeavors to hunt for the naturally occurring intermolecular Diels-Alderase from plants. Our research journey started from the biomimetic syntheses of D-A-type terpenoids and flavonoids, showing that plants use both nonenzymatic and enzymatic intermolecular [4 + 2] cycloadditions to create complex molecules. Inspired by the biomimetic syntheses, we identify an intermolecular Diels-Alderase hidden in the biosynthetic pathway of mulberry Diels-Alder-type cycloadducts using a biosynthetic intermediate probe-based target identification strategy. This enzyme, MaDA, is an endo-selective Diels-Alderase and is then functionally characterized as a standalone intermolecular Diels-Alderase with a concerted but asynchronous mechanism. We also discover the exo-selective intermolecular Diels-Alderases in Morus plants. Both the endo- and exo-selective Diels-Alderases feature a broad substrate scope, but their mechanisms for controlling the endo/exo pathway are different. These unique intermolecular Diels-Alderases phylogenetically form a subgroup of FAD-dependent enzymes that can be found only in moraceous plants, explaining why this type of [4 + 2] cycloadduct is unique to moraceous plants. Further studies of the evolutionary mechanism reveal that an FAD-dependent oxidocyclase could acquire the Diels-Alderase activity via four critical amino acid mutations and then gradually lose its original oxidative activity to become a standalone Diels-Alderase during the natural evolution. Based on these insights, we designed new Diels-Alderases and achieved the diversity-oriented chemoenzymatic synthesis of D-A products using either naturally occurring or engineered Diels-Alderases.Overall, this Account describes our decade-long efforts to discover the intermolecular Diels-Alderases in Morus plants, particularly highlighting the importance of biomimetic synthesis and chemical proteomics in discovering new intermolecular Diels-Alderases from plants. Meanwhile, this Account also covers the evolutionary and catalytic mechanism study of intermolecular Diels-Alderases that may provide new insights into how to discover and design new Diels-Alderases as powerful biocatalysts for organic synthesis.

Quercetin protects against hypertensive renal injury by attenuating apoptosis: an integrated approach using network pharmacology and RNA-Seq.

Quercetin is kown for its antihypertensive effects. However, its role on hypertensive renal injury has not been fully eucidated. In this study, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining, and Annexin V staining were used to assess the pathological changes and cells apoptosis in the renal tissues of Ang II-infused mice and Ang II- stimulated renal tubular epithelial cell line (NRK-52E). A variety of technologies, including network pharmacology, RNA-sequencing, immunohistochemistry, and Western blotting were performed to investigate its underlying mechanisms. Network pharmacology analysis identified multiple potential candidate targets (including TP53, Bcl-2 and Bax) and enriched signaling pathways (including apoptosis and p53 signaling pathway). Quercetin treatment significantly alleviated the pathological changes in renal tissues of Ang II-infused mice and reversed 464 differentially expressed transcripts (DETs), as well as enriched several signaling pathways, including those related apoptosis and p53 pathway. Furthermore, quercetin treatment significantly inhibited the cell apoptosis in renal tissues of Ang II-infused mice and Ang II-stimulated NRK-52E cells. Additionally, quercetin treatment inhibited the upregulation of p53, Bax, cleaved-caspase-9, and cleaved-caspase-3 protein expression and the downregulation of Bcl-2 protein expression in both renal tissue of Ang II-infused mice and Ang II-stimulated NRK-52E cells. Moreover, the molecular docking results indicated a potential binding interaction between quercetin and TP53. Quercetin treatment significantly attenuated hypertensive renal injury and cell apoptosis in renal tissues of Ang II-infused mice and Ang II-stimulated NRK-52E cells, and by targeting p53 may be one of the potential underlying mechanisms.

Strong Coupling of Resonant Metasurfaces with Epsilon-Near-Zero Guided Modes.

We study, both theoretically and experimentally, strong interaction between a quasi-bound state in the continuum (QBIC) supported by a resonant metasurface with an epsilon-near-zero (ENZ) guided mode excited in an ultrathin ITO layer. We observe and quantify the strong coupling regime of the QBIC-ENZ interaction in the hybrid metasurface manifested through the mode splitting over 200 meV. We also measure experimentally the resonant nonlinear response enhanced near the ENZ frequency and observe the effective nonlinear refractive index up to ∼4 × 10-13 m2/W in the ITO-integrated dielectric nanoresonators, which provides a promising platform for low-power nonlinear photonic devices.

[Estimation of soil moisture and organic matter content in saline alkali farmland by using CARS algorithm combined with covariates]. / 利用CARS算法联合协变量估算盐碱农田土壤水分和有机质含量.

Rapid acquisition of the data of soil moisture content (SMC) and soil organic matter (SOM) content is crucial for the improvement and utilization of saline alkali farmland soil. Based on field measurements of hyperspectral reflectance and soil properties of farmland soil in the Hetao Plain, we used a competitive adaptive reweighted sampling algorithm (CARS) to screen sensitive bands after transforming the original spectral reflectance (Ref) into a standard normal variable (SNV). Strategies Ⅰ, Ⅱ, and Ⅲ were used to model the input variables of Ref, Ref SNV, Ref-SNV+ soil covariate (SC), and digital elevation model (DEM). We constructed SMC and SOM estimation models based on random forest (RF) and light gradient boosting machine (LightGBM), and then verified and compared the accuracy of the models. The results showed that after CARS screening, the sensitive bands of SMC and SOM were compressed to below 3.3% of the entire band, which effectively optimized band selection and reduced redundant spectral information. Compared with the LightGBM model, the RF model had higher accuracy in SMC and SOM estimation, and the input variable strategy Ⅲ was better than Ⅱ and Ⅰ. The introduction of auxiliary variables effectively improved the estimation ability of the model. Based on comprehensive analysis, the coefficient of determination (Rp2), root mean square error (RMSE), and relative analysis error (RPD) of the SMC estimation model validation based on strategy Ⅲ-RF were 0.63, 3.16, and 2.01, respectively. The SOM estimation models based on strategy Ⅲ-RF had Rp2, RMSE, and RPD of 0.93, 1.15, and 3.52, respectively. The strategy Ⅲ-RF model was an effective method for estimating SMC and SOM. Our results could provide a new method for the rapid estimation of soil moisture and organic matter content in saline alkali farmland.

Global evolutionary dynamics of virulence genes in ST11-KL47 carbapenem-resistant Klebsiella pneumoniae.

ST11-KL47 is a hypervirulent carbapenem-resistant Klebsiella pneumoniae (CRKP) that is highly prevalent in China and poses a major public health risk. To investigate the evolutionary dynamics of virulence genes in this subclone, we analysed 78 sequenced isolates obtained from a long-term study across 29 centres from 17 cities in China. Virulence genes were located in large hybrid pNDM-Mar-like plasmids (length: ∼266 kilobases) rather than in classical pK2044-like plasmids. These hybrid plasmids, derived from the fusion of pK2044 and pNDM-Mar plasmids mediated by insertion sequence (IS) elements (such as ISKpn28 and IS26), integrated virulence gene fragments into the chromosome. Analysis of 217 sequences containing the special IncFIB (pNDM-Mar) replicon using public databases indicated that these plasmids typically contained T4SS-related and multiple antimicrobial resistance genes, were present in 24 countries, and were found in humans, animals, and the environment. Notably, the chromosomal integration of virulence genes was observed in strains across five countries across two continents. In vivo and in vitro models showed that the large hybrid plasmid increased the host fitness cost while increasing virulence. Conversely, virulence genes transferred to chromosomes resulted in increased fitness and lower virulence. In conclusion, virulence genes in the plasmids of ST11-KL47 CRKP are evolving, driven by adaptive negative selection, to enable vertical chromosomal inheritance along with conferring a survival advantage and low pathogenicity.

Comparative Analysis of Short-Term and Long-Term Clinical Efficacy of Mesenchymal Stem Cells from Different Sources in Knee Osteoarthritis: A Network Meta-Analysis.

Background: Joint articular injection of mesenchymal stem cells (MSCs) has emerged as a novel treatment approach for osteoarthritis (OA). However, the effectiveness of MSCs derived from different sources in treating OA patients remains unclear. Therefore, this study aimed to explore the differences between the effectiveness and safety of different sources of MSCs. Materials and Methods: For inclusion consideration, we searched trial registries and published databases, including PubMed, Cochrane Library, Embase, and Web of Science databases. Revman (V5.3), STATA (V16.0), and R (V4.0) were utilized for conducting data analysis, while the Cochrane Risk of Bias Tool was employed for assessing the quality of the studies. We derived outcome measures at 6 and 12 months based on the duration of study follow-up, including visual analog scale (VAS) score, WOMAC score, WOMAC pain, WOMAC Functional Limitation, and WOMAC stiffness. The evaluation time for short-term effectiveness is set at 6 months, while 12 months is utilized as the longest follow-up time for most studies to assess long-term effectiveness. Results: The evaluation of literature quality showed that the included studies had excellent methodological quality. A meta-analysis revealed that different sources of MSCs improved knee function and pain more effectively among patients suffering from knee OA (KOA) than controls. The results of the network meta-analysis showed the following: short-term functional improvement (the indexes were evaluated after 6 months of follow-up) (WOMAC total score: bone marrow-derived MSC (BMMSC) vs. adipose-derived MSC (ADMSC) (mean difference (MD) = -20.12, 95% confidence interval (CI) -125.24 to 42.88), umbilical cord-derived MSC (UCMSC) (MD = -7.81, 95% CI -158.13 to 74.99); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.51, 95% CI -7.27 to 4.29), UCMSC (MD = -0.75, 95% CI -9.74 to 6.63); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -12.22, 95% CI -35.05 to 18.86), UCMSC (MD = -9.31, 95% CI -44.26 to 35.27)). Long-term functional improvement (the indexes were evaluated after 12 months of follow-up) (WOMAC total: BMMSC vs. ADMSC (MD = -176.77, 95% CI -757.1 to 378.25), UCMSC (MD = -181.55, 95% CI -937.83 to 541.13); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.5, 95% CI -26.05 to 18.61), UCMSC (MD = -1.03, 95% CI -30.44 to 21.69); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -5.18, 95% CI -316.72 to 177.1), UCMSC (MD = -8.33, 95% CI -358.78 to 218.76)). Short-term pain relief (the indexes were evaluated after 6 months of follow-up) (VAS score: UCMSC vs. BMMSC (MD = -10.92, 95% CI -31.79 to 12.03), ADMSC (MD = -14.02, 95% CI -36.01 to 9.81), PLMSC (MD = -17.09, 95% CI -46.31 to 13.17); WOMAC pain relief: BMMSC vs. ADMSC (MD = -11.42, 95% CI -39.52 to 11.77), UCMSC (MD = -6.73, 95% CI -47.36 to 29.15)). Long-term pain relief (the indexes were evaluated after 12 months of follow-up) (VAS score: BMMSC vs. UCMSC (MD = -4.33, 95% CI -36.81 to 27.08), ADMSC (MD = -11.43, 95% CI -37.5 to 13.42); WOMAC pain relief: UCMSC vs. ADMSC (MD = 0.23, 95% CI -37.87 to 38.11), BMMSC (MD = 5.89, 95% CI -25.39 to 51.41)). According to the GRADE scoring system, WOMAC, VAS, and AE scores were of low quality. Conclusion: Meta-analysis suggests MSCs can effectively treat KOA by improving pain and knee function compared to control groups. In terms of functional improvement in KOA patients, both short-term (6-month follow-up) and long-term (12-month follow-up) results indicated that while the differences between most treatments were not statistically significant, bone marrow-derived MSCs may have some advantages over other sources of MSCs. Additionally, BM-MSCs and UC-MSCs may offer certain benefits over ADMSCs in terms of pain relief for KOA patients, although the variances between most studies were not statistically significant. Therefore, this study suggests that BM-MSCs may present clinical advantages over other sources of MSCs.

Strong and Robust Core-Shell Ceramic Fibers Composed of Highly Compacted Nanoparticles for Multifunctional Electronic Skin.

Functional fibers composed of textiles are considered a promising platform for constructing electronic skin (e-skin). However, developing robust electronic fibers with integrated multiple functions remains a formidable task especially when a complex service environment is concerned. In this work, a continuous and controllable strategy is demonstrated to prepare e-skin-oriented ceramic fibers via coaxial wet spinning followed by cold isostatic pressing. The resulting core-shell structured fiber with tightly compacted Al-doped ZnO nanoparticles in the core and highly ordered aramid nanofibers in the shell exhibit excellent tensile strength (316 MPa) with ultra-high elongation (33%). Benefiting from the susceptible contacts between conducting ceramic nanoparticles, the ceramic fiber shows both ultrahigh sensitivity (gauge factor = 2141) as a strain sensor and a broad working range up to 70 °C as a temperature sensor. Furthermore, the tunable core-shell structure of the fiber enables the optimization of impedance matching and attenuation of electromagnetic waves for the corresponding textile, resulting in a minimum reflection loss of -39.1 dB and an effective absorption bandwidth covering the whole X-band. Therefore, the versatile core-shell ceramic fiber-derived textile can serve as a stealth e-skin for monitoring the motion and temperature of robots under harsh conditions.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of a soluble guanylate cyclase stimulator, HEC95468, in healthy volunteers: a randomized, double-blinded, placebo-controlled phase 1 trial.

Heart failure is the most costly cardiovascular disorder. New treatments are urgently needed. This study aims to evaluate the safety, pharmacokinetics, and pharmacodynamic profile of HEC95468, a soluble guanylate cyclase (sGC) stimulator, in healthy volunteers. Sixty-two, eighteen, and forty-eight participants were enrolled in the single ascending dose (SAD) study, the food effect (FE) study, and the multiple ascending dose (MAD) study, respectively. The study conforms to good clinical practice and the Declaration of Helsinki. Overall, HEC95468 was safe and tolerable; a higher proportion of HEC95468-treated participants reported mild headaches, dizziness, decreased blood pressure, increased heart rate, and gastrointestinal-related treatment-emergent adverse events (TEAEs), similar to the sGC stimulators riociguat and vericiguat. In terms of pharmacokinetic parameters, the maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC0-t) were dose-proportional over the dose range. Moderate accumulation was observed after multiple administrations of HEC95468. Systolic blood pressure (SBP) and diastolic blood pressure decreased, while 3',5'-cyclic guanosine monophosphate (cGMP) concentration in plasma increased and heart rate was induced. Vasoactive hormones (renin, angiotensin II, and norepinephrine) in plasma were compensatorily elevated after oral administration. These data supported further clinical trials of HEC95468 in the treatment of heart failure and pulmonary arterial hypertension. Systematic Review Registration: http://www.chinadrugtrials.org.cn, identifier CTR20210064.

Tunable intrinsic strong light-matter coupling in transition metal dichalcogenide nanoresonators.

Self-hybridizing structures based on transition metal dichalcogenides (TMDCs) are becoming promising candidates for the study of an intrinsic strong light-matter coupling because of the efficient mode overlap with much simplified geometries. However, realizing flexible tuning of intrinsic strong coupling in such TMDC-based structures is still challenging. Here, we propose a strategy for flexible tuning of the intrinsic strong light-matter coupling based on a bulk TMDC material. We report the first demonstration of the strong coupling of intrinsic excitons to whispering gallery modes (WGMs) supported by an all-TMDC nanocavity. Importantly, by simply controlling angles of incidence, a selective excitation of WGMs and an anapole can be realized, which enables a direct modulation of self-hybridized interactions from a bright WGM-exciton coupling to a dark anapole-exciton coupling. Our work is expected to provide unique opportunities for engineering a strong light-matter coupling and to open exciting avenues for highly integrated novel nanophotonic devices.

Fluorescent Probes for Disease Diagnosis.

The identification and detection of disease-related biomarkers is essential for early clinical diagnosis, evaluating disease progression, and for the development of therapeutics. Possessing the advantages of high sensitivity and selectivity, fluorescent probes have become effective tools for monitoring disease-related active molecules at the cellular level and in vivo. In this review, we describe current fluorescent probes designed for the detection and quantification of key bioactive molecules associated with common diseases, such as organ damage, inflammation, cancers, cardiovascular diseases, and brain disorders. We emphasize the strategies behind the design of fluorescent probes capable of disease biomarker detection and diagnosis and cover some aspects of combined diagnostic/therapeutic strategies based on regulating disease-related molecules. This review concludes with a discussion of the challenges and outlook for fluorescent probes, highlighting future avenues of research that should enable these probes to achieve accurate detection and identification of disease-related biomarkers for biomedical research and clinical applications.

A Highly Deficient Medium-Entropy Perovskite Ceramic for Electromagnetic Interference Shielding under Harsh Environment.

Materials that can provide reliable electromagnetic interference (EMI) shielding in highly oxidative atmosphere at elevated temperature are indispensable in the fast-developing aerospace field. However, most of conductor-type EMI shielding materials such as metals can hardly withstand the high-temperature oxidation, while the conventional dielectric-type materials cannot offer sufficient shielding efficiency in gigahertz (GHz) frequencies. Here, a highly deficient medium-entropy (ME) perovskite ceramic as an efficient EMI shielding material in harsh environment, is demonstrated. The synergistic effect of entropy stabilization and aliovalent substitution on A-site generate abnormally high concentration of Ti and O vacancies that are stable under high-temperature oxidation. Due to the clustering of vacancies, the highly deficient perovskite ceramic exhibits giant complex permittivity and polarization loss in GHz, leading to the specific EMI shielding effectiveness above 30 dB/mm in X-band even after 100 h of annealing at 1000 °C in air. Along with the low thermal conductivity, the aliovalent ME perovskite can serve as a bifunctional shielding material for applications in aircraft engines and reusable rockets.

Hidden hotspots of amphibian biodiversity in China.

Identifying and protecting hotspots of endemism and species richness is crucial for mitigating the global biodiversity crisis. However, our understanding of spatial diversity patterns is far from complete, which severely limits our ability to conserve biodiversity hotspots. Here, we report a comprehensive analysis of amphibian species diversity in China, one of the most species-rich countries on Earth. Our study combines 20 y of field surveys with new molecular analyses of 521 described species and also identifies 100 potential cryptic species. We identify 10 hotspots of amphibian diversity in China, each with exceptional species richness and endemism and with exceptional phylogenetic diversity and phylogenetic endemism (based on a new time-calibrated, species-level phylogeny for Chinese amphibians). These 10 hotspots encompass 59.6% of China's described amphibian species, 49.0% of cryptic species, and 55.6% of species endemic to China. Only four of these 10 hotspots correspond to previously recognized biodiversity hotspots. The six new hotspots include the Nanling Mountains and other mountain ranges in South China. Among the 186 species in the six new hotspots, only 9.7% are well covered by protected areas and most (88.2%) are exposed to high human impacts. Five of the six new hotspots are under very high human pressure and are in urgent need of protection. We also find that patterns of richness in cryptic species are significantly related to those in described species but are not identical.

OPN silencing reduces hypoxic pulmonary hypertension via PI3K-AKT-induced protective autophagy.

Hypoxic pulmonary hypertension (HPH) is a pulmonary vascular disease primarily characterized by progressive pulmonary vascular remodeling in a hypoxic environment, posing a significant clinical challenge. Leveraging data from the Gene Expression Omnibus (GEO) and human autophagy-specific databases, osteopontin (OPN) emerged as a differentially expressed gene, upregulated in cardiovascular diseases such as pulmonary arterial hypertension (PAH). Despite this association, the precise mechanism by which OPN regulates autophagy in HPH remains unclear, prompting the focus of this study. Through biosignature analysis, we observed significant alterations in the PI3K-AKT signaling pathway in PAH-associated autophagy. Subsequently, we utilized an animal model of OPNfl/fl-TAGLN-Cre mice and PASMCs with OPN shRNA to validate these findings. Our results revealed right ventricular hypertrophy and elevated mean pulmonary arterial pressure (mPAP) in hypoxic pulmonary hypertension model mice. Notably, these effects were attenuated in conditionally deleted OPN-knockout mice or OPN-silenced hypoxic PASMCs. Furthermore, hypoxic PASMCs with OPN shRNA exhibited increased autophagy compared to those in hypoxia alone. Consistent findings from in vivo and in vitro experiments indicated that OPN inhibition during hypoxia reduced PI3K expression while increasing LC3B and Beclin1 expression. Similarly, PASMCs exposed to hypoxia and PI3K inhibitors had higher expression levels of LC3B and Beclin1 and suppressed AKT expression. Based on these findings, our study suggests that OPNfl/fl-TAGLN-Cre effectively alleviates HPH, potentially through OPN-mediated inhibition of autophagy, thereby promoting PASMCs proliferation via the PI3K-AKT signaling pathway. Consequently, OPN emerges as a novel therapeutic target for HPH.

Modulation by Co (II) Ion of Optical Activities of L/D-glutathione (GSH)-modified Chiral Copper Nanoclusters for Sensitive Adenosine Triphosphate Detection.

Chiral nanoscale enantiomers exhibit different biological effects in living systems. However, their chirality effect on the detection sensitivity for chiral biological targets still needs to be explored. Here, we discovered that Co2+ can modulate the luminescence performance of L/D-glutathione (GSH)-modified copper nanoclusters (L/D-Cu NCs) and induce strong chiroptical activities as the asymmetric factor was enhanced 223-fold with their distribution regulating from the ultraviolet to visible region. One Co2+ coordinated with two GSH molecules that modified on the surface of Cu NCs in the way of CoN2O2. On this basis, dual-modal chiral and luminescent signals of Co2+ coordinated L/D-Cu NCs (L/D-Co-Cu NCs) were used to detect the chiral adenosine triphosphate (ATP) based on the competitive interaction between surficial GSH and ATP molecules with Co2+. The limits of detection of ATP obtained with fluorescence and circular dichroism intensity were 9.15 µM and 15.75 nM for L-Co-Cu NCs, and 5.35 µM and 4.69 nM for D-Co-Cu NCs. This demonstrated that selecting suitable chiral configurations of nanoprobes effectively enhances detection sensitivity. This study presents not only a novel method to modulate and enhance the chiroptical activity of nanomaterials but also a unique perspective of chirality effects on the detection performances for bio-targets.

A novel mixed frequency sampling discrete grey model for forecasting hard disk drive failure.

The mixed data sampling (MIDAS) model has attracted increasing attention due to its outstanding performance in dealing with mixed frequency data. However, most MIDAS model extension studies are based on statistical methods or machine learning models, which suffer from insufficient prediction performance and stability in small sample environments. To solve this problem, this paper proposes a novel mixed frequency sampling discrete grey model (MDGM(1, N)), which is a coupled form of the MIDAS model and discrete grey multivariate model. By adjusting the structure parameters, the model can be adapted to different sampling frequencies data, and degenerate into several types of grey models. Then, the unbiasedness and stability of the model are proved using the mathematical analysis method and numerical random experiment. The meta-heuristic algorithm is introduced to obtain the optimal weight parameters and the maximum lag order, improving the model's fitting ability to mixed frequency data. To demonstrate the effectiveness of the new model, a model evaluation system consisting of traditional evaluation metrics and a monotonicity test is established. Taking four hard disk drive failure datasets as research cases, the performance of the proposed model is compared with seven mainstream benchmark models. The results show that the proposed model has excellent applicability and outperforms other competition models in terms of validity, stability, and robustness. Furthermore, it is observed that the reported uncorrectable errors and the command timeout have a greater impact on hard disk drive failure. Finally, the new model is employed to forecast the failure of four hard disk drives. The forecasting results indicate that in the next four time points with a cycle of 21 days beginning in April 2023, the failure of the smaller capacity hard disk drives (0055 and 0086, corresponding to 8TB and 10TB) show a decreasing trend, reaching 67.442% and 89.7683%, respectively. The failure of the other larger capacity hard disk drives (0007 and 0138, corresponding to 12TB and 14TB) has increased, with a growth rate of 17.1016% and 123.7899%.

The evolutionary origin of naturally occurring intermolecular Diels-Alderases from Morus alba.

Biosynthetic enzymes evolutionarily gain novel functions, thereby expanding the structural diversity of natural products to the benefit of host organisms. Diels-Alderases (DAs), functionally unique enzymes catalysing [4 + 2] cycloaddition reactions, have received considerable research interest. However, their evolutionary mechanisms remain obscure. Here, we investigate the evolutionary origins of the intermolecular DAs in the biosynthesis of Moraceae plant-derived Diels-Alder-type secondary metabolites. Our findings suggest that these DAs have evolved from an ancestor functioning as a flavin adenine dinucleotide (FAD)-dependent oxidocyclase (OC), which catalyses the oxidative cyclisation reactions of isoprenoid-substituted phenolic compounds. Through crystal structure determination, computational calculations, and site-directed mutagenesis experiments, we identified several critical substitutions, including S348L, A357L, D389E and H418R that alter the substrate-binding mode and enable the OCs to gain intermolecular DA activity during evolution. This work provides mechanistic insights into the evolutionary rationale of DAs and paves the way for mining and engineering new DAs from other protein families.

Effects of Erythromycin on Nereis succinea and the Intestinal Microbiome across Different Salinity Levels.

The exposure of aquatic organisms to pollutants often occurs concomitantly with salinity fluctuations. Here, we reported the effects of erythromycin (0.250, 7.21, and 1030 µg/L) on marine invertebrate N. succinea and its intestinal microbiome under varying salinity levels (5‰, 15‰, and 30‰). The salinity elicited significant effects on the growth and intestinal microbiome of N. succinea. The susceptibility of the intestinal microbiome to erythromycin increased by 8.7- and 6.2-fold at salinities of 15‰ and 30‰, respectively, compared with that at 5‰ salinity. Erythromycin caused oxidative stress and histological changes in N. succinea intestines, and inhibited N. succinea growth in a concentration-dependent manner under 30‰ salinity with a maximum inhibition of 25%. At the intestinal microbial level, erythromycin enhanced the total cell counts at 5‰ salinity but reduced them at 15‰ salinity. Under all tested salinities, erythromycin diminished the antibiotic susceptibility of the intestinal microbiome. Two-way ANOVA revealed significant interactive effects (p < 0.05) between salinity and erythromycin on various parameters, including antibiotic susceptibility and intestinal microbial diversity. The present findings demonstrated the significant role of salinity in modulating the impacts of erythromycin, emphasizing the necessity to incorporate salinity fluctuations into environmental risk assessments.

Investigation of New Accelerometer Based on Capacitive Micromachined Ultrasonic Transducer (CMUT) with Ring-Perforation Membrane.

Capacitive micromachined ultrasonic transducer (CMUT) has been widely studied due to its excellent resonance characteristics and array integration. This paper presents the first study of the CMUT electrostatic stiffness resonant accelerometer. To improve the sensitivity of the CMUT accelerometer, this paper innovatively proposes the CMUT ring-perforation membrane structure, which effectively improves the acceleration sensitivity by reducing the mechanical stiffness of the elastic membrane. The acceleration sensitivity is 10.9 (Hz/g) in the acceleration range of 0-20 g, which is 100% higher than that of the conventional CMUT structure. This research contributes to the acceleration measurement field of CMUT and can effectively contribute to the breakthrough of vibration acceleration monitoring technology in aerospace, medical equipment, and automotive electronics.