Rational Design of Triazinone Derivatives with Low Bee Toxicity Based on the Binding Mechanism of Neonicotinoids to Apis mellifera.

Bees, one of the most vital pollinators in the ecosystem and agriculture, are currently threatened by neonicotinoids. To explore the molecular mechanisms of neonicotinoid toxicity to bees, the different binding modes of imidacloprid, thiacloprid, and flupyradifurone with nicotinic acetylcholine receptor (nAChR) α1ß1 and cytochrome P450 9Q3 (CYP9Q3) were studied using homology modeling and molecular dynamics simulations. These mechanisms provided a basis for the design of compounds with a potential low bee toxicity. Consequently, we designed and synthesized a series of triazinone derivatives and assessed their bioassays. Among them, compound 5a not only displayed substantially insecticidal activities against Aphis glycines (LC50 = 4.40 mg/L) and Myzus persicae (LC50 = 6.44 mg/L) but also had low toxicity to Apis mellifera. Two-electrode voltage clamp recordings further confirmed that compound 5a interacted with the M. persicae nAChR α1 subunit but not with the A. mellifera nAChR α1 subunit. This work provides a paradigm for applying molecular toxic mechanisms to the design of compounds with low bee toxicity, thereby aiding the future rational design of eco-friendly nicotinic insecticides.

Monitoring of Chlorophyll Content of Potato in Northern Shaanxi Based on Different Spectral Parameters.

Leaf chlorophyll content (LCC) is an important physiological index to evaluate the photosynthetic capacity and growth health of crops. In this investigation, the focus was placed on the chlorophyll content per unit of leaf area (LCCA) and the chlorophyll content per unit of fresh weight (LCCW) during the tuber formation phase of potatoes in Northern Shaanxi. Ground-based hyperspectral data were acquired for this purpose to formulate the vegetation index. The correlation coefficient method was used to obtain the "trilateral" parameters with the best correlation between potato LCCA and LCCW, empirical vegetation index, any two-band vegetation index constructed after 0-2 fractional differential transformation (step size 0.5), and the parameters with the highest correlation among the three spectral parameters, which were divided into four combinations as model inputs. The prediction models of potato LCCA and LCCW were constructed using the support vector machine (SVM), random forest (RF) and back propagation neural network (BPNN) algorithms. The results showed that, compared with the "trilateral" parameter and the empirical vegetation index, the spectral index constructed by the hyperspectral reflectance after differential transformation had a stronger correlation with potato LCCA and LCCW. Compared with no treatment, the correlation between spectral index and potato LCC and the prediction accuracy of the model showed a trend of decreasing after initial growth with the increase in differential order. The highest correlation index after 0-2 order differential treatment is DI, and the maximum correlation coefficients are 0.787, 0.798, 0.792, 0.788 and 0.756, respectively. The maximum value of the spectral index correlation coefficient after each order differential treatment corresponds to the red edge or near-infrared band. A comprehensive comparison shows that in the LCCA and LCCW estimation models, the RF model has the highest accuracy when combination 3 is used as the input variable. Therefore, it is more recommended to use the LCCA to estimate the chlorophyll content of crop leaves in the agricultural practices of the potato industry. The results of this study can enhance the scientific understanding and accurate simulation of potato canopy spectral information, provide a theoretical basis for the remote sensing inversion of crop growth, and promote the development of modern precision agriculture.

A Novel Peptidomimetic Insecticide: Dippu-AstR-Based Rational Design and Biological Activity of Allatostatin Analogs.

Insect neuropeptides play an essential role in regulating growth, development, reproduction, nerve conduction, metabolism, and behavior in insects; therefore, G protein-coupled receptors of neuropeptides are considered important targets for designing green insecticides. Cockroach-type allatostatins (ASTs) (FGLamides allatostatins) are important insect neuropeptides in Diploptera punctata that inhibit juvenile hormone (JH) synthesis in the corpora allata and affect growth, development, and reproduction of insects. Therefore, the pursuit of novel insecticides targeting the allatostatin receptor (AstR) holds significant importance. Previously, we identified an AST analogue, H17, as a promising candidate for pest control. Herein, we first modeled the 3D structure of AstR in D. punctata (Dippu-AstR) and predicted the binding mode of H17 with Dippu-AstR to study the critical interactions and residues favorable to its bioactivity. Based on this binding mode, we designed and synthesized a series of H17 derivatives and assessed their insecticidal activity against D. punctata. Among them, compound Q6 showed higher insecticidal activity than H17 against D. punctata by inhibiting JH biosynthesis, indicating that Q6 is a potential candidate for a novel insect growth regulator (IGR)-based insecticide. Moreover, Q6 exhibited insecticidal activity against Plutella xylostella, indicating that these AST analogs may have a wider insecticidal spectrum. The underlying mechanisms and molecular conformations mediating the interactions of Q6 with Dippu-AstR were explored to understand its effects on the bioactivity. The present work clarifies how a target-based strategy facilitates the discovery of new peptide mimics with better bioactivity, enabling improved IGR-based insecticide potency in sustainable agriculture.

Target-Based Design, Synthesis, and Biological Evaluation of Novel 1,2,4-Triazolone Derivatives as Potential nAChR Modulators.

Novel agrochemicals have been successfully developed using target-based drug design (TBDD). To discover a novel, efficient, and highly selective nicotinic insecticide candidate, we developed a unified pharmacological model using TBDD by studying the binding modes of 11 nicotinic acetylcholine receptor (nAChR) modulators with acetylcholine binding protein (AChBP) targets for the first time. This model was used to design and develop a series of 1,2,4-triazolone derivatives. Bioassays demonstrated excellent insecticidal activities against Aphis glycines of compounds 4k (LC50 = 4.95 mg/L) and 4q (LC50 = 3.17 mg/L), and low toxicities to Apis mellifera. Additionally, compound 4q was stably bound to Aplysia californica AChBP, which was consistent with the pharmacological model obtained via molecular docking and molecular dynamics simulations. Therefore, compound 4q could be a potential lead candidate targeting nAChR. The explicit pharmacological model of nAChR modulators with Ac-AChBP in this study may facilitate the future rational design of eco-friendly nicotinic insecticides.

Silencing AHNAK promotes nasopharyngeal carcinoma progression by upregulating the ANXA2 protein.

PURPOSE: Nasopharyngeal carcinoma (NPC) is an aggressive head and neck disease with a high incidence of distant metastases. Enlargeosomes are cytoplasmic organelles marked by, desmoyokin/AHNAK. This study aimed to evaluate the expression of AHNAK in NPC and its effect on enlargeosomes and to investigate the correlation between AHNAK expression levels and clinical NPC patient characteristics. METHODS: Primary nasopharyngeal carcinoma (NPC) and NPC specimens were evaluated by analyzing public data, and immunohistochemistry. Systematic in vitro and in vivo experiments were performed using different NPC-derived cell lines and mouse models. RESULTS: In this study, we detected AHNAK and Annexin A2(ANXA2), a protein coating the surface of enlargeosomes, in NPC samples. We found that AHNAK was down-regulated. Down-regulation of AHNAK was associated with poor overall survival in NPC patients. Moreover, transcription factor FOSL1-mediated transcriptional repression was responsible for the low expression of AHNAK by recruiting EZH2. Whereas Annexin A2 was upregulated in human NPC tissues. Upregulation of Annexin A2 was associated with lymph node metastasis and distant metastasis in NPC patients. Functional studies confirmed that silencing of AHNAK enhanced the growth, invasion, and metastatic properties of NPC cells both in vitro and in vivo. In terms of mechanism, loss of AHNAK led to an increase of annexin A2 protein level in NPC cells. Silencing ANXA2 restored NPC cells' migrative and invasive ability upon loss of AHNAK. CONCLUSION: Here, we report AHNAK as a tumor suppressor in NPC, which may act through annexin A2 oncogenic signaling in enlargeosome, with potential implications for novel approaches to NPC treatment.

Super Enhancer Driven Hyaluronan Synthase 3 Promotes Malignant Progression of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with high metastatic and invasive nature. Super enhancers (SEs) control the expression of cell identity genes and oncogenes during tumorigenesis. As a glycosaminoglycan in the tumor microenvironment, hyaluronan (HA) is associated with cancer development. High expression of hyaluronan synthase 3 (HAS3) resulted in HA deposition, which promoted the growth of cancer cell. However, its role in NPC development remains elusive. We demonstrated that the levels of HAS3 mRNA or protein were increased in NPC cell lines. Transcription of HAS3 is associated with SE. Disruption of SE by bromodomain containing 4 (BRD4) inhibitor JQ1 resulted in downregulation of HAS3 and inhibition of cell proliferation and invasiveness in NPC cells. Inhibition of HA synthesis by HAS inhibitor 4-MU suppressed cell growth and invasion of NPC cells, whereas HA treatment exerted opposite effects. Genetically silencing HAS3 in HK1 and FaDu NPC cells attenuated cell proliferation and mobility, while re-expression of HAS3 enhanced malignant potential of CNE1 and CNE2 NPC cells. Furthermore, loss of HAS3 impaired metastatic potential of HK1 cells in nude mice. Mechanistically, inhibition of HA synthesis by chemical inhibitor or silencing HAS3 led to reduction of the levels of phosphorylation of EGFR, AKT, and ERK proteins. In contrast, exogenous HA treatment or forced expression of HAS3 activated EGFR/AKT/ERK signaling cascade. This study suggested that HAS3 is driven by SE and overexpressed in NPC. High expression of HAS3 promotes the malignant features of NPC via activation of EGFR/AKT/ERK signaling pathway.

Design, Synthesis, and Fungicidal Activity against Rice Sheath Blight of Novel N-Acyl-1,2,3,4-tetrahydroquinoline Derivatives.

To discover fungicides with novel targets, a series of N-acyl-1,2,3,4-tetrahydroquinoline (NATHQ) derivatives were designed and synthesized by linking the active substructure NATHQ moiety in aspernigerin with the O-benzyl oxime-ether scaffold in commercial agrochemicals. Target compound structures were identified using proton and carbon-13 nuclear magnetic resonance spectroscopies and high-resolution mass spectrometry. Preliminary bioassays indicated that at 40 mg/L, some target compounds exhibited moderate to considerable in vitro fungicidal activities against Rhizoctonia solani and Botrytis cinerea. In particular, compound 3j exhibited higher fungicidal activities both in vitro (EC50 = 0.733 mg/L) and in vivo (EC50 = 15.2 mg/L) against R. solani than the commercial fungicide prochloraz; therefore, it should be a promising fungicide candidate against rice sheath blight. Additionally, compound 3j exhibited good laccase inhibitory activity (73.2% at 200 mg/L). Molecular docking revealed that the bis-cyano-oxime-ether moiety of compound 3j exhibited an excellent binding mode with the laccase target protein and could be used as a lead compound for developing laccase inhibitors. The structural features of these NATHQ derivatives will provide inspiration for developing laccase inhibitors and discovering more effective fungicides to control agricultural diseases.

Rational design and identification of novel thiosemicarbazide derivatives as laccase inhibitors.

BACKGROUND: Laccase is a key enzyme in the fungal 1,8-dihydroxynaphthalene (DHN) melanin biosynthesis pathway, which is a potential target for the control of pathogenic fungi. In our previous work, compound a2 was found with higher inhibition activity against laccase and antifungal activity than laccase inhibitor PMDD-5Y. The introduction of hydrogen-bonded receptors in the amino part was found to be beneficial in improving laccase inhibitory activity by target-based-biological rational design. In this work, the hydrogen-bonded receptors morpholine and piperazine were introduced for structure optimization to enhancing biological activity. RESULTS: Enzyme activity tests indicated that all target compounds had inhibitory activity against laccase, and some compounds exhibited better activity against laccase than a2, it was further verified that the introduction of hydrogen-bonded receptors in the amino portion could enhance the laccase inhibitory activity of target compounds. Most compounds showed excellent antifungal activities in vitro. Compound m14 displayed good activity against Magnaporthe oryzae both in vitro and in vivo. The scanning electron microscopy (SEM) analysis showed that the mycelium of M. oryzae treated with m14 were destroyed. Molecular docking revealed the binding mode between laccase and target compounds. CONCLUSION: Thirty-eight compounds were synthesized and showed good inhibitory activity against laccase, the introduction of morpholine and piperazine in the amino part was beneficial to improve antifungal activity and laccase activity. Further validation of laccase as a potential target for rice blast control, while m14 can be used as a candidate compound for the control of rice blast. © 2023 Society of Chemical Industry.

Analysis of cognitive function and its related factors after treatment in Meniere's disease.

A growing body of research recently suggested the association between vestibular dysfunction and cognitive impairment. Meniere's disease (MD), a common clinical vestibular disorder, is usually accompanied by hearing loss and emotional stress, both of which may mediate the relationship between vestibule dysfunction and cognition. It is currently unknown whether the cognitive decline in MD patients could improve through treatment and how it relates to multiple clinical characteristics, particularly the severity of vertigo. Therefore, in the present study, the MD patients were followed up for 3, 6, and 12 months after treatment, and the cognitive functions, vertigo symptoms, and related physical, functional, and emotional effects of the patients were assessed using the Montreal Cognitive Assessment (MoCA) and Dizziness Handicap Inventory (DHI), aiming to explore the change in cognition before and after therapy and the correlation with various clinical features. It was found that cognitive decline in MD patients compared to healthy controls before therapy. Importantly, this cognitive impairment could improve after effective therapy, which was related to the severity of vertigo, especially in functional and physical impacts. Our results support the view that vestibular dysfunction is a potentially modifiable risk factor for cognitive decline.

Spatial-temporal analysis of pulmonary tuberculosis in Hubei Province, China, 2011-2021.

BACKGROUND: Pulmonary tuberculosis (PTB) is an infectious disease of major public health problem, China is one of the PTB high burden counties in the word. Hubei is one of the provinces having the highest notification rate of tuberculosis in China. This study analyzed the temporal and spatial distribution characteristics of PTB in Hubei province for targeted intervention on TB epidemics. METHODS: The data on PTB cases were extracted from the National Tuberculosis Information Management System correspond to population in 103 counties of Hubei Province from 2011 to 2021. The effect of PTB control was measured by variation trend of bacteriologically confirmed PTB notification rate and total PTB notification rate. Time series, spatial autonomic correlation and spatial-temporal scanning methods were used to identify the temporal trends and spatial patterns at county level of Hubei. RESULTS: A total of 436,955 cases were included in this study. The total PTB notification rate decreased significantly from 81.66 per 100,000 population in 2011 to 52.25 per 100,000 population in 2021. The peak of PTB notification occurred in late spring and early summer annually. This disease was spatially clustering with Global Moran's I values ranged from 0.34 to 0.63 (P< 0.01). Local spatial autocorrelation analysis indicated that the hot spots are mainly distributed in the southwest and southeast of Hubei Province. Using the SaTScan 10.0.2 software, results from the staged spatial-temporal analysis identified sixteen clusters. CONCLUSIONS: This study identified seasonal patterns and spatial-temporal clusters of PTB cases in Hubei province. High-risk areas in southwestern Hubei still exist, and need to focus on and take targeted control and prevention measures.

Effect of sodium trimetaphosphate on the physicochemical properties of modified soy protein isolates and its lutein-loaded emulsion.

Due to people's pursuit of healthy and green life, soy protein isolate (SPI) is occupying a larger and larger market share. However, the low solubility of SPI affects its development in the field of food and medicine. This paper aimed to investigate the effects of sodium trimetaphosphate (STMP) on the functional properties and structures of phosphorylated SPI and its lutein-loaded emulsion. After modification by STMP, the phosphorus content of phosphorylated SPI reached 1.2-3.61 mg/g. Infrared spectrum and X-ray photoelectron spectrum analysis confirmed that PO4 3- had phosphorylation with -OH in serine of SPI molecule. X-ray diffraction analysis showed that phosphorylation destroyed the crystal structure of protein molecules. Zeta potential value of phosphorylated SPI decreased significantly. When STMP addition was 100 g/kg, particle size of protein solution decreased to 203 nm, and solubility increased to 73.5%. Furthermore, emulsifying activity and emulsifying stability increased by 0.51 times and 8 times, respectively. At the same protein concentration (1%-3% [w/w]), lutein-loaded emulsion prepared by phosphorylated SPI had higher absolute potential and smaller particle size. The phosphorylated protein emulsion at 2% concentration had the best emulsion stability after storage for 17 days. PRACTICAL APPLICATION: Phosphorylation significantly improved the emulsifying properties and solubility of SPI. Phosphorylated SPI significantly improved the stability of lutein-loaded emulsion. It provides theoretical basis for the application of phosphorylated SPI as emulsifier in delivery system and broadens the development of lutein in food and medicine field.

Terahertz spectroscopic monitoring and analysis of citrus leaf water status under low temperature stress.

Low temperature stress, in the form of chilling and freezing, is one of the major environmental factors impacting on citrus yield, which changes plant's water state and results in the crops' sub-health or injury. The innovative terahertz (THz) spectroscopy and imaging based sensing technology has been shown to be a suitable tool for plant leaf water status determination, due to THz radiation's innate sensitivity to hydrogen bond vibration in aqueous solutions, which is usually related to plant phenotype change. We demonstrate experimentally that the THz absorption coefficient of leaf could be used for distinguishing plant's physiological stress status, exhibiting clear decreasing or increasing trend under chilling or freezing stress respectively. The underlying rationale might be that membrane damage shows a diverse pattern, changing the intra- or extra-cellular liquid environments, likely being linked to the various THz spectral characteristics. There were different adaptations in leaf morphology, leading to different leaf density, which in turn affects the water volume fraction. Moreover, different patterns of the dynamic equilibrium state of free water and bound water under chilling and freezing treatment were revealed by THz spectroscopy. Here, THz spectroscopic monitoring has shown unique potential for judging citrus's low temperature stress state through bio-water detection and discrimination.

Design, Synthesis and Fungicidal Activity of N-(thiophen-2-yl) Nicotinamide Derivatives.

Based on the modification of natural products and the active substructure splicing method, a series of new N-(thiophen-2-yl) nicotinamide derivatives were designed and synthesized by splicing the nitrogen-containing heterocycle natural molecule nicotinic acid and the sulfur-containing heterocycle thiophene. The structures of the target compounds were identified through 1H NMR, 13C NMR and HRMS spectra. The in vivo bioassay results of all the compounds against cucumber downy mildew (CDM, Pseudoperonospora cubensis (Berk.et Curt.) Rostov.) in a greenhouse indicated that compounds 4a (EC50 = 4.69 mg/L) and 4f (EC50 = 1.96 mg/L) exhibited excellent fungicidal activities which were higher than both diflumetorim (EC50 = 21.44 mg/L) and flumorph (EC50 = 7.55 mg/L). The bioassay results of the field trial against CDM demonstrated that the 10% EC formulation of compound 4f displayed excellent efficacies (70% and 79% control efficacies, respectively, each at 100 mg/L and 200 mg/L) which were superior to those of the two commercial fungicides flumorph (56% control efficacy at 200 mg/L) and mancozeb (76% control efficacy at 1000 mg/L). N-(thiophen-2-yl) nicotinamide derivatives are significant lead compounds that can be used for further structural optimization, and compound 4f is also a promising fungicide candidate against CDM that can be used for further development.

Design, Synthesis, and Biological Activity of Novel Laccase Inhibitors as Fungicides against Rice Blast.

Laccase is a potential target for novel agricultural fungicide discovery. PMDD-5Y was the first agent reported with high activity against laccase to control phytopathogenic fungi. Thirty-two novel agents containing cinnamaldehyde thiosemicarbazide were synthesized with PMDD-5Y as the lead compound, with most of the target compounds exhibiting excellent activity in vitro. Compound a2 (EC50 = 9.71 µg/mL) exhibited greater potency against Magnaporthe oryzae than the commercial fungicide isoprothiolane (EC50 = 18.62 µg/mL). The curative and protective effects of a2 against M. oryzae on rice were more than those of PMDD-5Y. Scanning electron microscopy indicated that a2 could cause mycelial growth atrophy and malformation. Furthermore, a2 (IC50 = 0.18 mmol/L) showed higher activity against laccase than PMDD-5Y (IC50 = 0.33 mmol/L) and cysteine (IC50 = 0.30 mmol/L). Molecular docking analysis revealed the nature of interaction between these compounds and laccase. This research identified a novel laccase inhibitor a2 as a fungicide candidate to control rice blast in agriculture.

Design, Synthesis and Bioactivity of Novel Low Bee-Toxicity Compounds Based on Flupyrimin.

Neonicotinoids are important insecticides for controlling aphids in agriculture. Growing research suggested that neonicotinoid insecticides are a key factor causing the decline of global pollinator insects, such as bees. Flupyrimin (FLP) is a novel nicotinic insecticide with unique biological properties and no cross-resistance, and is safe for pollinators. Using FLP as the lead compound, a series of novel compounds were designed and synthesized by replacing the amide fragment with a sulfonamideone. Their structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Bioassay results showed that compound 2j had good insecticidal activity against Aphis glycines with an LC50 value of 20.93 mg/L. Meanwhile, compound 2j showed significantly lower acute oral and contact toxicity to Apis mellifera. In addition, compound 2j interacted well with the protein in insect acetylcholine binding protein (AChBP). The molecular docking on honeybee nicotinic acetylcholine receptor (nAChR) indicated that the sulfonamide group of compound 2j did not form a hydrogen bond with Arg173 of the ß subunit, which conforms to the reported low bee-toxicity conformation. In general, target compound 2j can be regarded as a bee-friendly insecticide candidate.

Synthesis, Antifungal Activity, and 3D-QASR of Novel 1,2,3,4-Tetrahydroquinoline Derivatives Containing a Pyrimidine Ether Scaffold as Chitin Synthase Inhibitors.

The introduction of active groups of natural products into the framework of pesticide molecules is an effective approach for discovering active lead compounds, and thus has been widely used in the development of new agrochemicals. In this work, a novel series of 1,2,3,4-tetrahydroquinoline derivatives containing a pyrimidine ether scaffold were designed and synthesized by the active substructure splicing method. The new compounds showed good antifungal activities against several fungi. Especially, compound 4fh displayed excellent in vitro activity against Valsa mali and Sclerotinia sclerotiorum with EC50 values of 0.71 and 2.47 µg/mL, respectively. 4fh had slightly stronger inhibitory activity (68.08% at 50 µM) against chitin synthase (CHS) than that of polyoxin D (63.84% at 50 µM) and exhibited obvious curative and protective effects on S. sclerotiorum in vivo. Thus, 4fh can be considered as a new candidate fungicide as a chitin synthase inhibitor. An accurate and reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) model presented a useful direction for the further excogitation of more highly active fungicides. Molecular docking revealed that the conventional hydrogen bond mainly affected the binding affinity of 4fh with chitin synthase. The present results will provide a guidance to discover potential CHS-based fungicides for plant disease control in agriculture.

AUP1 regulates lipid metabolism and induces lipid accumulation to accelerate the progression of renal clear cell carcinoma.

Lipid metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Lipid accumulation affects cellular energy homeostasis, biofilm synthesis, lipid signal transduction, and phenotypic transformation in ccRCC. Herein, a prognostic-related model was constructed, and the prognostic utility of AUP1, a lipid droplet-regulating very low-density lipoprotein assembly factor, in ccRCC was determined through multiparameter analysis. AUP1 expression was significantly higher in clinical samples than in normal tissues and was closely associated with the clinical stage. The inhibition of AUP1 expression impaired the proliferation, migration, and invasion of ACHN and A498 ccRCC cells in vitro and in vivo. RNA-seq analysis revealed that AUP1 inhibition can significantly reduce the contents of intracellular triglyceride and cholesterol and regulate cell growth by cell cycle arrest, promoting apoptosis and reversing epithelial-mesenchymal transition. AUP1 regulated the synthesis of cholesterol esters and fatty acids (FAs) in ccRCC cells by targeting sterol O-acyltransferase 1 and partially promoted the progression of ccRCC. AUP1 also induced lipid accumulation in ccRCC by promoting the de novo synthesis of FAs (inhibiting protein kinase AMP-activated catalytic subunit alpha 2), inhibiting the rate-limiting enzyme of FA ß oxidation (carnitine palmitoyltransferase 1A), regulating the key enzyme of lipolysis (monoglyceride lipase, MGLL), and inhibiting the lipid transporter StAR-related lipid transfer domain containing 5 (STARD5). However, it did not affect the intracellular cholesterol synthesis pathway. The differential expression and prognostic significance of MGLL and STARD5 in ccRCC should be further studied. AUP1 may serve as a new and effective potential target and prognostic marker for ccRCC.

Transition From Parenteral to Enteral Nutrition and Postnatal Growth in Very Preterm Infants During Their First 28 Days of Life.

Background: Nutrition practices for preterm infants during the first few weeks of life can be divided into three phases: the parenteral nutrition (PN), enteral nutrition (EN), and transition (TN) phases; the TN phase includes both PN and EN. Our purpose was to analyze nutrition practices for very preterm infants during the TN phase and their association with the infants' growth during the first 28 days of life. Methods: Data from 268 very preterm infants <32 weeks old from six neonatal intensive care units were analyzed retrospectively. The TN phase was defined as enteral feedings of 30-120 ml/kg/d. Postnatal growth failure (PGF) was defined as a 28-day growth velocity <15 g/kg/d. Differences in protein and energy intake between the PGF and non-PGF groups during the TN phase were calculated, and risk factors for PGF were identified using multivariate regression analysis. Results: The total protein (parenteral + enteral) intake during the TN was 3.16 (2.89, 3.47) g/kg/d, which gradually decreased as the enteral feeding volume increased in the TN phase. The total energy (parenteral + enteral) intake during the TN phase was 115.72 (106.98, 122.60) kcal/kg/d. The PGF group had a lower total protein intake (parenteral + enteral) than the non-PGF group had [3.09 (2.85, 3.38) g/kg/d vs. 3.27 (3.06, 3.57) g/kg/d, P = 0.007, respectively]. No significant difference was found in energy intake during the TN phase. The variables associated with PGF included a lower total protein (parenteral + enteral) intake, a smaller day of age at the end of the TN phase, and a higher birth weight z-score. Conclusion: Increasing the total protein intake (parenteral + enteral) during the TN could reduce the incidence of PGF.

Design, Synthesis, and Biological Activity of Novel Fungicides Containing a 1,2,3,4-Tetrahydroquinoline Scaffold and Acting as Laccase Inhibitors.

Laccase is a novel target for fungicides. We previously developed a new fungicide, 4-chlorocinnamaldehyde thiosemicarbazide (PMDD-5Y), as a laccase inhibitor. The introduction of active groups of natural products into the framework of a pesticide molecular structure is an effective method for discovering active lead compounds, and it has applications in the discovery of new pesticides. In this work, PMDD-5Y was selected as a lead compound, and we designed and synthesized a series of novel sulfonyl hydrazide derivatives containing the natural product scaffold 1,2,3,4-tetrahydroquinoline. The new compounds had antifungal activities against several fungi, especially Valsa mali and Sclerotinia sclerotiorum. One compound (4bl) displayed very good in vitro activity against S. sclerotiorum and V. mali, with EC50 values of 3.32 and 2.78 µg/mL, respectively. The results of an enzyme activity assay showed that 4bh had the best inhibitory activity against laccase, with an EC50 value of 14.85 µg/mL. This was more active than the lead compound PMDD-5Y and the positive control cysteine. Using a molecular docking method, we studied the binding mode of the title compounds with laccase. The structural features of these new laccase inhibitors as fungicides will advance research and impact the field of discovering more potent fungicides to control diseases in agriculture.