CATH-2-derived antimicrobial peptide inhibits multidrug-resistant Escherichia coli infection in chickens.

Avian colibacillosis (AC), caused by infection with Escherichia coli (E. coli), is a major threat to poultry health, food safety and public health, and results in high mortality and significant economic losses. Currently, new drugs are urgently needed to replace antibiotics due to the continuous emergence and increasing resistance of multidrug-resistant (MDR) strains of E. coli caused by the irrational use of antibiotics in agriculture and animal husbandry. In recent years, antimicrobial peptides (AMPs), which uniquely evolved to protect the host, have emerged as a leading alternative to antibiotics in clinical settings. CATH-2, a member of the antimicrobial cathelicidin peptide family, has been reported to have antibacterial activity. To enhance the antimicrobial potency and reduce the adverse effects on animals, we designed five novel AMPs, named C2-1, C2-2, C2-3, C2-4 and C2-5, based on chicken CATH-2, the secondary structures of these AMPs were consistently α-helical and had an altered net charge and hydrophobicity compared to those of the CATH-2 (1-15) sequences. Subsequently, the antimicrobial activities of CATH-2 (1-15) and five designed peptides against MDR E. coli were evaluated in vitro. Specifically, C2-2 showed excellent antimicrobial activity against either the ATCC standard strain or veterinary clinical isolates of MDR E. coli, with concentrations ranging from 2-8 µg/mL. Furthermore, C2-2 maintained its strong antibacterial efficacy under high temperature and saline conditions, demonstrating significant stability. Similarly, C2-2 retained a high level of safety with no significant hemolytic activity on chicken mature red blood cells or cytotoxicity on chicken kidney cells over the concentration range of 0-64 µg/mL. Moreover, the administration of C2-2 improved the survival rate and reduced the bacterial load in the heart, liver and spleen during MDR E. coli infection in chickens. Additionally, pathological damage to the heart, liver and intestine was prevented when MDR E. coli infected chickens were treated with C2-2. Together, our study showed that C2-2 may be a promising novel therapeutic agent for the treatment of MDR E. coli infections and AC.

Novel 4-triazole phenyl amide (4-TPA) molecules: Potent promoters of α-synuclein fibril disassembly.

Parkinson's disease profoundly compromises patients' daily lives, and the disassembly of α-synuclein aggregates, a primary pathological factor, represents a promising therapeutic approach. In this study, we conducted a systematic screening and optimization process to identify the novel scaffold B37, a 4-triazolyl-phenylamine derivative, exhibiting a potent disassembly activity of 1.1 µM against α-synuclein preformed fibrils. Notably, B37 demonstrated significant neuroprotective effects, ameliorated autophagic dysfunction induced by preformed fibrils, mitigated oxidative stress, and restored the co-localization of preformed fibrils with lysosomes. Transmission electron microscopy corroborated its in vitro disassembly function. Pharmacokinetic profiling revealed favorable parameters with a receptible blood-brain barrier permeability. B37 emerges as a promising lead compound for further optimization, aiming to develop a highly effective agent targeting the disassembly of α-synuclein aggregates to treat neurodegenerative diseases like Parkinson's disease.

Michael Addition Reaction between Dehydroalanines and Phosphites Enabled the Introduction of Phosphonates into Oligopeptides.

A method for introducing a range of phosphonates into oligopeptides through a Michael addition reaction between dehydroalanine and phosphite is presented. The method offers a mild, cheap, and straightforward approach to peptide phosphorylation that has potential applications in chemical biology and medicinal chemistry. Moreover, the introduction of a phosphonate group into short antibacterial peptides is described to demonstrate its utility, leading to the discovery of phosphonated antibacterial peptides with potent broad-spectrum antibacterial activity.

Enhancing the stability and therapeutic potential of the antimicrobial peptide Feleucin-K3 against Multidrug-Resistant a. Baumannii through rational utilization of a D-amino acid substitution strategy.

Antimicrobial peptides (AMPs), which have a low probability of developing resistance, are considered the most promising antimicrobial agents for combating antibiotic resistance. Feleucin-K3 is an amphiphilic cationic AMP that exhibits broad-spectrum antimicrobial activity. In our previous research, the first phenylalanine residue was identified as the critical position affecting its biological activity. Here, a series of Feleucin-K3 analogs containing hydrophobic D-amino acids were developed, leveraging the low sensitivity of proteases to unnatural amino acids and the regulatory effect of hydrophobicity on antimicrobial activity. Among them, K-1dF, which replaced the phenylalanine of Feleucin-K3 with its enantiomer (D-phenylalanine), exhibited potent antimicrobial activity with a therapeutic index of 46.97 and MICs between 4 to 8 µg/ml against both sensitive and multidrug-resistant Acinetobacter baumannii. The introduction of D-phenylalanine increased the salt tolerance and serum stability of Feleucin-K3. Moreover, K-1dF displayed a rapid bactericidal effect, a low propensity to develop resistance, and a synergistic effect when combined with antibiotics. More importantly, it exhibited considerable or superior efficacy to imipenem against pneumonia and skin abscess infection. In brief, the K-1dF obtained by simple and effective modification strategy has emerged as a promising candidate antimicrobial agent for tackling multidrug-resistant Acinetobacter baumannii infections.

High-efficiency reinforcement learning with hybrid architecture photonic integrated circuit.

Reinforcement learning (RL) stands as one of the three fundamental paradigms within machine learning and has made a substantial leap to build general-purpose learning systems. However, using traditional electrical computers to simulate agent-environment interactions in RL models consumes tremendous computing resources, posing a significant challenge to the efficiency of RL. Here, we propose a universal framework that utilizes a photonic integrated circuit (PIC) to simulate the interactions in RL for improving the algorithm efficiency. High parallelism and precision on-chip optical interaction calculations are implemented with the assistance of link calibration in the hybrid architecture PIC. By introducing similarity information into the reward function of the RL model, PIC-RL successfully accomplishes perovskite materials synthesis task within a 3472-dimensional state space, resulting in a notable 56% improvement in efficiency. Our results validate the effectiveness of simulating RL algorithm interactions on the PIC platform, highlighting its potential to boost computing power in large-scale and sophisticated RL tasks.

Novel antimicrobial peptides modified with fluorinated sulfono-γ-AA having high stability and targeting multidrug-resistant bacteria infections.

The emergence and increasing prevalence of multidrug-resistant (MDR) bacteria have posed an urgent demand for novel antibacterial drugs. Currently, antimicrobial peptides (AMPs), potential novel antimicrobial agents with rare antimicrobial resistance, represent an available strategy to combat MDR bacterial infections but suffer the limitation of protease degradation. In this study, we developed a highly effective method for optimizing the stability of AMPs by introducing fluorinated sulfono-γ-AApeptides, and successfully synthesized novel Feleucin-K3-analogs. The results demonstrated that the incorporation of fluorinated sulfono-γ-AA into Feleucin-K3 effectively improved stability and afforded optimal peptides, such as CF3-K11, which exhibited 8-9 times longer half-lives than Feleucin-K3. Moreover, CF3-K11 displayed potent antimicrobial activity against clinically isolated Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA), excellent biosafety, low resistance propensity, and possessed powerful antimicrobial efficacy for both local skin infection and pneumonia infection. The optimal CF3-K11 exhibited strong therapeutic potential and offered a superior approach for treating MDR bacterial infections.

A novel off-line multi-dimensional high-speed countercurrent chromatography strategy for preparative separation of bioactive neolignan isomers from Piper betle. L.

Separation and purification of naturally occurring isomers from herbs are still challenging. High-speed counter-current chromatography (HSCCC) has been applied to isolate natural products. In this study, an off-line multi-dimensional high-speed counter-current chromatography (multi-D HSCCC) strategy was developed utilizing the in situ concentration technique with online storage recycling elution to rapidly separate bioactive isomeric neolignans from chloroform-partitioned samples of the plant Piper betle L. In the procedure, the crude sample (105 mg) was implemented using the online storage recycling technique in a two-phase solvent system composed of petroleum ether-ethyl acetate-methanol-water (7: 5: 12: 3), which first simply afforded a neolignane kadsurenone (1, 5.3 mg) and its epimer (-)-denudatin B (2, 6.4 mg). Then, the remains fr a was subjected to the second-dimensional HSCCC elution using the in situ concentration technique with online storage recycling technique in another solvent system of petroleum ether-ethyl acetate-methanol-water (5: 5: 11, 15). As a result, kadsurenin I (3, 0.6 mg) and its regioisomer pibeneolignan C (4, 5.0 mg), together with the fractional remaining fr b and fr c, were obtained. Thirdly, the fr c was reloaded to allow the HSCCC for recycling elution with the former solvent system employing the in situ concentration strategy and yielded a pair of epimers, (7R,8S,1'S)-1'-allyl-5-methoxy-8-methyl-7-piperonyl-7,8,3,6-tetrahydro-2-oxobenzofuran (5, 10.2 mg), and 3-epi-(-)-burchullin (6, 2.6 mg). Finally, the three pairs of less amount and the structurally similar isomers 1-6 were isolated from the crude fraction of P. betle with a high HPLC purity of over 95.0 % for compound 2, 4-6 and 92.5 % for compound 1, 91.0 % for 3, while the purity of 1 and 3 in 1H NMR were 89.9 % and 91.1 %, respectively. The whole isolation process was quick and efficient. Compounds 1, 2, 4 and 5 showed significantly synergistic activities combining several antibiotics against five drug-resistant Staphylococcus aureus with FICIs from 0.156 to 0.375. This novel off-line multi-dimensional HSCCC strategy could be broadened to application for the rapid separation of complex natural products.

Visible-Light Mediated Deoxygenation of Carboxylic Acid for Late-Stage Peptide Modification Targeting Dehydroalanine.

A visible-light mediated deoxygenative radical addition of carboxylic acids to dehydroalanines has been disclosed. The method can be used in ß-acyl alanine derivative synthesis, including those chiral and deuterated variants, and late-stage peptide modification with various functional groups, both in the homogeneous phase and on the resin in SPPS. It provides a new tool kit for rapid construction of bioactive peptide analogues, which has been demonstrated by modification of the antimicrobial peptide Feleucin-K3.

The novel peptide DR4penA attenuates the bleomycin- and paraquat-induced pulmonary fibrosis by suppressing the TGF-ß/Smad signaling pathway.

Pulmonary fibrosis (PF), which is caused by continuous alveolar epithelial cell injury and abnormal repair, is referred to as a difficult disease of the lung system by the World Health Organization due to its rapid progression, poor prognosis, and high mortality rate. However, there is still a lack of ideal therapeutic strategies. The peptide DR8 (DHNNPQIR-NH2 ), which is derived from rapeseed, exerted antifibrotic activity in the lung, liver, and kidney in our previous studies. By studying the structure-activity relationship and rational design, we introduced an unnatural hydrophobic amino acid (α-(4-pentenyl)-Ala) into DR8 and screened the novel peptide DR4penA (DHNα-(4-pentenyl)-APQIR-NH2 ), which had higher anti-PF activity, higher antioxidant activity and a longer half-life than DR8. Notably, DR4penA attenuated bleomycin- and paraquat-induced PF, and the anti-PF activity of DR4penA was equivalent to that of pirfenidone. Additionally, DR4penA suppressed the TGF-ß/Smad pathway in TGF-ß1-induced A549 cells and paraquat-induced rats. This study demonstrates that the novel peptide DR4penA is a potential candidate compound for PF therapy, and its antifibrotic activity in different preclinical models of PF provides a theoretical basis for further study.

Chaos with Gaussian invariant distribution by quantum-noise random phase feedback.

We experimentally present a random phase feedback based on quantum noise to generate a chaotic laser with Gaussian invariant distribution. The quantum noise from vacuum fluctuations is acquired by balanced homodyne detection and injected into a phase modulator to form a random phase feedback. An optical switch using high-speed intensity modulator is employed to reset the chaotic states repeatedly and the time evolutions of intensity statistical distributions of the chaotic states stemming from the initial noise are measured. By the quantum-noise random phase feedback, the transient intensity distributions of the chaotic outputs are improved from asymmetric invariant distributions to Gaussian invariant distributions, and the Gaussian invariant distribution indicates a randomly perturbed dynamical transition from microscopic initial noise to macroscopic stochastic fluctuation. The effects of phase feedback bandwidth and modulation depth on the invariant distributions are investigated experimentally. The chaotic time-delay signature and mean permutation entropy are suppressed to 0.036 and enhanced to 0.999 using the random phase feedback, respectively. The high-quality chaotic laser with Gaussian invariant distribution can be a desired random source for ultrafast random number generation and secure communication.

Corrigendum: Cathelicidin-derived antiviral peptide inhibits herpes simplex virus 1 infection.

[This corrects the article DOI: 10.3389/fmicb.2023.1201505.].

Cathelicidin-derived antiviral peptide inhibits herpes simplex virus 1 infection.

Herpes simplex virus 1 (HSV-1) is a widely distributed virus. HSV-1 is a growing public health concern due to the emergence of drug-resistant strains and the current lack of a clinically specific drug for treatment. In recent years, increasing attention has been paid to the development of peptide antivirals. Natural host-defense peptides which have uniquely evolved to protect the host have been reported to have antiviral properties. Cathelicidins are a family of multi-functional antimicrobial peptides found in almost all vertebrate species and play a vital role in the immune system. In this study, we demonstrated the anti-HSV-1 effect of an antiviral peptide named WL-1 derived from human cathelicidin. We found that WL-1 inhibited HSV-1 infection in epithelial and neuronal cells. Furthermore, the administration of WL-1 improved the survival rate and reduced viral load and inflammation during HSV-1 infection via ocular scarification. Moreover, facial nerve dysfunction, involving the abnormal blink reflex, nose position, and vibrissae movement, and pathological injury were prevented when HSV-1 ear inoculation-infected mice were treated with WL-1. Together, our findings demonstrate that WL-1 may be a potential novel antiviral agent against HSV-1 infection-induced facial palsy.

Tracking the spatial-temporal distribution and regional differences of carbon footprint in grid scale of China's construction industry.

As the largest contributor to global carbon emissions (CEs), construction industry (CI) is regarded as one of the most significant sources in China. Previous studies on carbon emission (CE) of CI, however, are often limited to the quantitative level and provincial or local administrative unit scales, lacking relevant studies at the spatial raster resolution scale, due to data limits. Here, using the energy consumption, social economic data, and a series of remote sensing data from EU EDGAR, this study explored the spatial-temporal distribution and changing characteristics of CEs from CI in typical years of 2007, 2010, and 2012. This study found, from 2007 to 2010, then 2012, in addition to subtle differences, that the direct, indirect, and total CEs of CI all showed an increasing trend overall. In all provincial units except Tianjin and Guangdong, indirect CEs took up more than 50% of the total CEs, which can clearly indicate the "dominant low carbon, recessive high carbon" characteristics of CI. The direct, indirect, and total CEs of the CI in 2007, 2010, and 2012 all showed a positive spatial clustering. Specifically, hot spots were mainly distributed in Beijing-Tianjin-Hebei and Yangtze River Delta, and cold spots were mainly focused in the west and northeast of China, presenting a similar distribution pattern with population-economy characteristics. These findings can provide references for the policy formulation of regional differentiated emission reduction.

A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis.

Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH2) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH2) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.

Z-Scheme CuOx/Ag/TiO2 Heterojunction as Promising Photoinduced Anticorrosion and Antifouling Integrated Coating in Seawater.

In the marine environment, steel materials usually encounter serious problems with chemical or electrochemical corrosion and fouling by proteins, bacteria, and other marine organisms. In this work, a green bifunctional Z-scheme CuOx/Ag/P25 heterostructure coating material was designed to achieve the coordination of corrosion prevention and antifouling by matching the redox potential of the reactive oxygen species and the corrosion potential of 304SS. When CuOx/Ag/P25 heterostructure was coupled with the protected metal, the open circuit potential under illumination negatively shifted about 240 mV (vs. Ag/AgCl) and the photoinduced current density reached 16.6 µA cm-2. At the same time, more reactive oxygen species were produced by the Z-shape structure, and then the photocatalytic sterilization effect was stronger. Combined with the chemical sterilization of Ag and the oxide of Cu, the bacterial survival rate of CuOx/Ag/P25 was low (0.006%) compared with the blank sample. This design provides a strategy for developing green dual-functional coating materials with photoelectrochemical anticorrosion and antifouling properties.

Spatio-temporal interaction heterogeneity and driving factors of carbon emissions from the construction industry in China.

Global warming caused by carbon emissions has become a major issue that countries need to address. As the largest carbon emitter globally, the construction industry is one of the major contributors to carbon emissions in China. It is of significance for carbon reduction to study carbon emission from construction industry. Based on various methods, this study explored the spatio-temporal characteristics of carbon emissions and the driving factors of construction industry. This study found, in 2007, 2010, and 2012, carbon emissions from the construction industry exhibited an increasing trend, and the indirect carbon emissions accounted for approximately 77% of the total carbon emissions overall; in addition, the regional gaps in carbon emissions are widening. The space centers of gravity of direct, indirect, and total carbon emissions showed similar rotations in the counterclockwise direction and gradually shifted to the northeast direction. Carbon emissions from the construction industry were predominantly influenced by the total population, number of employees in construction industry, labor productivity in construction industry, added value of the construction industry, energy consumption in construction industry in 2007, evolution to the mutual influence of the total population, labor productivity in construction industry, and energy consumption in construction industry in 2012. The finds can make references for the regional sustainable development.

Novel Feleucin-K3-Derived Peptides Modified with Sulfono-γ-AA Building Blocks Targeting Pseudomonas aeruginosa and Methicillin-Resistant Staphylococcus aureus Infections.

The prevalence of multidrug-resistant bacterial infections has led to dramatically increased morbidity and mortality. Antimicrobial peptides (AMPs) have great potential as new therapeutic agents to reverse this dangerous trend. Herein, a series of novel AMP Feleucin-K3 analogues modified with unnatural peptidomimetic sulfono-γ-AA building blocks were designed and synthesized. The structure-activity, structure-toxicity, and structure-stability relationships were investigated to discover the optimal antimicrobial candidates. Among them, K122 exhibited potent and broad-spectrum antimicrobial activity and high selectivity. K122 had a rapid bactericidal effect and a low tendency to induce resistance. Surprisingly, K122 showed excellent effectiveness against bacterial pneumonia. For biofilm and local skin infections, K122 significantly decreased the bacterial load and improved tissue injury at a dose of only 0.25 mg/kg, which was 160 times lower than the concentration deemed to be safe for local dermal applications. In summary, K122 is an outstanding candidate for the treatment of multidrug-resistant bacteria and biofilm infections.

Electroencephalographic power spectrum changes in cerebral small vessel disease combined with cognitive dysfunction and its relationship with neutrophil/lymphocyte ratio and its clinical value - a pilot study.

Objective: The study aimed to explore the changes in the electrical power spectrum of the brain and its correlation with neutrophil/lymphocyte ratio (NLR) in patients with cognitively impaired cerebral small vessel disease (CSVD) and to explore its clinical application. Methods: A total of 61 patients with CSVD who attended the People's Hospital of Shaanxi Province from September 2021 to September 2022 were divided into the group with cognitive impairment (cerebral small vascular with cognitive impairment, CSVCI group, n = 29) and the group without cognitive impairment (CSVD group, n = 32) based on the Montreal Cognitive Assessment Scale (MoCA) score, while 20 healthy subjects were recruited as the control group (healthy control, HC group). EEG was performed in the three groups, and the difference in whole brain quantitative EEG power spectral density (PSD) was calculated and compared between the three groups. Results: The PSD values in the δ and θ bands of the CSVCI group were higher than those of the CSVD group, while the PSD values in the α band were lower than those of the CSVD and HC groups. In addition, PSD values in the δ-band in the CSVD group were lower than those in the HC group (all p < 0.05). Multifactorial logistic regression showed that reduced α-band global average PSD and low years of education were independent risk factors for cognitive impairment in patients with CSVD (p < 0.05). In patients with cerebral small-vessel disease, α-band PSD was positively and δ-band PSD negatively correlated with MoCA score, and paraventricular, deep white matter, and total Fazekas scores were negatively correlated with MoCA score. Furthermore, θ-band PSD is positively correlated with NLR (all p < 0.05). Conclusion: EEG activity was slowed down in patients with CSVD with cognitive impairment. The α-band global mean PSD values independently affected the occurrence of cognitive impairment in CSVD patients beyond the Fazekas score. NLR may be one of the mechanisms leading to the slowing down of the EEG, which can be used as an objective indicator for the early prediction of cognitive impairment but still needs to be clarified by further studies.

Evaluation of soil and water conservation function in the Wugong mountain meadow based on the comprehensive index method.

Wugong Mountain meadow landscape is well-known both at home and abroad because of its ornamental value. Our study aimed to comprehensively evaluate the function of soil and water conservation at different altitudes of Wugong Mountain meadow soil. The hydro-physical characteristics, including the soil bulk density, porosity, water content, water holding capacity, and permeability of meadow soil at 1600 m-1900 m altitudes, were analyzed. The results showed that the mountain meadow soil's hydro-physiological characteristics and water conservation function significantly differed with altitude. However, the trend of each index did not follow the same law with altitude change. There was a decrease in bulk density of the soil from 1700 m to 1900 m, but a significant increase in porosity and water-holding capacity. Despite the higher porosity and water holding capacity found at 1600 m than at 1700 m and 1800 m, a similar bulk density was found at 1600 m as 1700 m. In addition, the bulk density in the 0-20 cm layer was lower than that in the 20-40 cm layer, while the porosity and water-holding capacity were higher. A higher sequence of soil water conservation capacity was found in soil layers 0-20 cm depth at 1900, 1600, 1800, and 1700 m; in soil layers 20-40 cm depth, it was at 1900, 1800, 1700, and 1600 m. The study found that the sequence of the comprehensive performance of soil water conservation function was at 1900, 1600, 1800, and 1700 m altitudes in the Wugong mountain meadow area. Our comprehensive study of soil water conservation capacity provides a theoretical basis for the rational use of mountain meadow resources in subtropical regions.

Spatio-temporal effect of provincial technological innovation on environmental pollution in China.

The relationship between technological innovation (TL) and environmental pollution (EP) and its action mechanisms are complex and controversial aspects of discussion. Using the spatial autocorrelation analysis, standard deviation ellipse analysis, kernel density function, spatial econometric model, this study analyzed the spatial distribution, evolution characteristics, and influencing factors of the EP and TL from 2000 to 2020 in China. Results found there was a significant spatial autocorrelation between the EP and TL in 2000-2020. The standard deviation ellipse of EP was broadly distributed in the "southwest-northeast" direction, indicating that EP presented a trend of concentration in the direction of "southwest-northeast." The moving trajectory of the center of gravity for the EP in 2000-2020 was essentially moved from the northeast to southwest. Overall, the national level of TL exhibited a "north-south change, high in the east, and low in the west" trend. Regional differences were gradually expanding, and the polarization was evident. Regardless of using least squares method (OLS) or quantile regression (QR) models, TL, human capital (HC), and industrial structure (IS) all had an inhibitory effect on the EP at the effective significance level. Total population (TP), foreign direct investment (FDI), and local fiscal expenditure (LFE) were positively related to the EP.