Design, synthesis, antifungal evaluation and mechanism study of novel norbornene derivatives as potential laccase inhibitors.

BACKGROUND: To discover novel fungicide candidates, five series of novel norbornene hydrazide, bishydrazide, oxadiazole, carboxamide and acylthiourea derivatives (2a-2t, 3a-3f, 4a-4f, 5a-5f and 7a-7f) were designed, synthesized and assayed for their antifungal activity toward seven representative plant fungal pathogens. RESULTS: In the in vitro antifungal assay, some title norbornene derivatives presented good antifungal activity against Botryosphaeria dothidea, Sclerotinia sclerotiorum and Fusarium graminearum. Especially, compound 2b exhibited the best inhibitory activity toward B. dothidea with the median effective concentration (EC50) of 0.17 mg L-1, substantially stronger than those of the reference fungicides boscalid and carbendazim. The in vivo antifungal assay on apples revealed that 2b had significant curative and protective effects, both of which were superior to boscalid. In the preliminary antifungal mechanism study, 2b was able to injure the surface morphology of hyphae, destroy the cell membrane integrity and increase the intracellular reactive oxygen species (ROS) level of B. dothidea. In addition, 2b could considerably inhibit the laccase activity with the median inhibitory concentration (IC50) of 1.02 µM, much stronger than that of positive control cysteine (IC50 = 35.50 µM). The binding affinity and interaction mode of 2b with laccase were also confirmed by molecular docking. CONCLUSION: This study presented a promising lead compound for the study of novel laccase inhibitors as fungicidal agrochemicals, which demonstrate significant anti-B. dothidea activity and laccase inhibitory activity. © 2024 Society of Chemical Industry.

Synthesis and Antifungal Activity of Norbornene Carboxamide/sulfonamide Derivatives as Potential Fungicides Targeting Laccase.

To explore more potential fungicides with new scaffolds, thirty-seven norbornene carboxamide/sulfonamide derivatives were designed, synthesized, and assayed for inhibitory activity against six plant pathogenic fungi and oomycetes. The preliminary antifungal assay suggested that the title derivatives showed moderate to good antifungal activity against six plant pathogens. Especially, compound 6 e presented excellent in vitro antifungal activity against Sclerotinia sclerotiorum (EC50=0.71 mg/L), which was substantially stronger than pydiflumetofen. In vivo antifungal assay indicated 6 e displayed prominent protective and curative effects on rape leaves infected by S. sclerotiorum. The preliminary mechanism research displayed that 6 e could damage the surface morphology and inhibit the sclerotia formation of S. sclerotiorum. In addition, the in vitro enzyme inhibition bioassay indicated that 6 e displayed pronounced laccase inhibition activity (IC50=0.63 µM), much stronger than positive control cysteine. Molecular docking elucidated the binding modes between 6 e and laccase. The bioassay results and mechanism investigation demonstrated that this class of norbornene carboxamide/sulfonamide derivatives could be promising laccase inhibitors for novel fungicide development.

Ubiquitin ligase MDM2 mediates endothelial inflammation in Kawasaki disease vasculitis development.

Background: Kawasaki disease (KD) often complicates coronary artery lesions (CALs). Despite the established significance of STAT3 signaling during the acute phase of KD and signal transducer and activator of transcription 3 (STAT3) signaling being closely related to CALs, it remains unknown whether and how STAT3 was regulated by ubiquitination during KD pathogenesis. Methods: Bioinformatics and immunoprecipitation assays were conducted, and an E3 ligase, murine double minute 2 (MDM2) was identified as the ubiquitin ligase of STAT3. The blood samples from KD patients before and after intravenous immunoglobulin (IVIG) treatment were utilized to analyze the expression level of MDM2. Human coronary artery endothelial cells (HCAECs) and a mouse model were used to study the mechanisms of MDM2-STAT3 signaling during KD pathogenesis. Results: The MDM2 expression level decreased while the STAT3 level and vascular endothelial growth factor A (VEGFA) level increased in KD patients with CALs and the KD mouse model. Mechanistically, MDM2 colocalized with STAT3 in HCAECs and the coronary vessels of the KD mouse model. Knocking down MDM2 caused an increased level of STAT3 protein in HCAECs, whereas MDM2 overexpression upregulated the ubiquitination level of STAT3 protein, hence leading to significantly decreased turnover of STAT3 and VEGFA. Conclusions: MDM2 functions as a negative regulator of STAT3 signaling by promoting its ubiquitination during KD pathogenesis, thus providing a potential intervention target for KD therapy.

Larger aggregate formed by self-assembly process of the mixture surfactants enhance the dissolution and oxidative removal of non-aqueous phase liquid contaminants in aquifer.

Surfactants can transfer non-aqueous phase liquid (NAPL) contaminants to the aqueous phase, and enhance the removal of the latter in groundwater. However, the extensive use of surfactants causes secondary contamination and increases the non-target consumption of oxidants. It is pressing to develop a surfactant with high phase transfer efficiency and sound compatibility with oxidants to minimize the use of surfactants for groundwater remediation. The phase transfer capability of different surfactants and their binary mixtures, their enhanced KMnO4 oxidation performance for NAPL contaminants as well as influencing factors were investigated to solve the above-mentioned question. The results showed that Tween20, SDBS and BS-12 perform best in terms of phase transfer capability among nonionic, anionic and amphoteric surfactants respectively, and only SDBS and BS-12 produce a synergistic effect among the binary mixtures. The CMC of SDBS/BS-12 was lower than its ideal CMC value, and the self-assembly process of SDBS/BS-12 also formed larger aggregates, which improved the phase transfer performance. Compared to other single surfactants, the removal efficiency of petroleum hydrocarbons in the aquifer sediments was raised by 7.4-33.8 % using the mixed surfactant. The SDBS/BS-12 mixture was compatible with KMnO4 and boosted the reaction of NAPL contaminants with KMnO4 by transferring from the NAPL phase to the aqueous phase. As a result, the NAPL toluene and phenanthrene removal efficiency increased from 37 % and 29 % to 80 % and 86 % respectively. Natural organic matters inhibited the phase transfer efficiency of the SDBS/BS-12 mixture, whereas anions and monovalent cations enhanced the phase transfer capability of the mixture. High-valent cations led to precipitation in the SDBS/BS-12, which could be eliminated by adding Na2Si2O5. The SDBS/BS-12 mixture delivered the same phase transfer efficiency with the dosage of 1.73-23.07 % of other single surfactants, and its cost was equivalent to 0.25-41.7 % of the latter, thus embracing bright application prospects.

Varicella-zoster virus meningitis with hypoglycorrhachia: A case report.

BACKGROUND: Varicella-zoster virus (VZV) is a common viral infection, but meningitis is a rare complication of VZV infection. The cerebrospinal fluid glucose of viral meningitis is usually within the normal range, which is different from bacteria, fungi, and cancerous meningitis. This paper reports a case of VZV meningitis with hypoglycorrhachia and the relevant literature was reviewed. CASE SUMMARY: We report a case of an immunocompetent 39-year-old male, presenting with severe headache and fevers, without meningeal signs or exanthem, found to have VZV meningitis by the metagenomic next-generation sequencing of cerebrospinal fluid. The cerebrospinal fluid analysis revealed hypoglycorrhachia (cerebrospinal fluid glucose of 2.16) and he was treated successfully with intravenous acyclovir. Our literature review identified only ten cases diagnosed with VZV meningitis with hypoglycorrhachia previously reported to date in the English literature whose cerebrospinal fluid glucose was from 1.6 to 2.7mmol/L, with a ratio of cerebrospinal fluid to serum glucose from 0.30 to 0.49. CONCLUSION: Although rare, the cerebrospinal fluid of patients with VZV meningitis may have hypoglycorrhachia, which broadens the understanding of the disease.

Synthesis and Antifungal Activity of Novel L-Menthol Hydrazide Derivatives as Potential Laccase Inhibitors.

To discover novel laccase inhibitors as potential fungicides, twenty-six novel L-menthol hydrazide derivatives were designed and synthesized. In the in vitro antifungal assay, most of the target compounds displayed pronounced antifungal activity against Sclerotinia sclerotiorum, Fusarium graminearum, and Botryosphaeria dothidea. Especially, the EC50 of compounds 3 b and 3 q against B. dothidea was 0.465 and 0.622 mg/L, which was close to the positive compound fluxapyroxad (EC50 =0.322 mg/L). Scanning electron microscopy (SEM) analysis showed that compound 3 b could significantly damage the mycelial morphology of B. dothidea. In vivo antifungal experiments on apple fruits showed that 3 b exhibited excellent protective and curative effects. Furthermore, in the in vitro laccase inhibition assay, 3 b showed outstanding inhibitory activity with the IC50 value of 2.08 µM, which is much stronger than positive control cysteine and PMDD-5Y. These results indicated that this class of L-menthol derivatives could be promising leads for the discovery of laccase-targeting fungicides.

Insufficiency of Mrpl40 disrupts testicular structure and semen parameters in a murine model.

Approximately 31% of patients with 22q11.2 deletion syndrome (22q11.2DS) have genitourinary system disorders and 6% of them have undescended testes. Haploinsufficiency of genes on chromosome 22q11.2 might contribute to the risk of 22q11.2DS. In this study, we used mice with single-allele deletion in mitochondrial ribosomal protein L40 (Mrpl40 +/- ) as models to investigate the function of Mrpl40 in testes and spermatozoa development. The penetrance of cryptorchidism in Mrpl40 +/- mice was found to be higher than that in wild-type (WT) counterparts. Although the weight of testes was not significantly different between the WT and Mrpl40 +/- mice, the structure of seminiferous tubules and mitochondrial morphology was altered in the Mrpl40 +/- mice. Moreover, the concentration and motility of spermatozoa were significantly decreased in the Mrpl40 +/- mice. In addition, data-independent acquisition mass spectrometry indicated that the expression of genes associated with male infertility was altered in Mrpl40 +/- testes. Our study demonstrated the important role of Mrpl40 in testicular structure and spermatozoa motility and count. These findings suggest that Mrpl40 is potentially a novel therapeutic target for cryptorchidism and decreased motility and count of spermatozoa.

Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Normal Older Adults: The CABLE Study.

BACKGROUND: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer's disease (AD) pathology is still less known. OBJECTIVE: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. METHODS: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF < 60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-ß 42 (Aß42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. RESULTS: Participants with low LVEF had higher levels of CSF t-tau (ß= -0.009, p = 0.006) and t-tau/Aß42 ratios (ß= -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (< 65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (ß= -0.002, p = 0.043) in middle-aged group. CONCLUSION: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function.

A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy.

Mutations in the DNAJB6 gene have been identified as rare causes of myofibrillar myopathies. However, the underlying pathophysiologica mechanisms remain elusive. DNAJB6 has two known isoforms, including the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, which was thought to be the pathogenic isoform. Here, we report a novel recessive mutation c.695_699del (p. Val 232 Gly fs*7) in the DNAJB6 gene, associated with an apparently recessively inherited late onset distal myofibrillar myopathy in a Chinese family. Notably, the novel mutation localizes to exon 9 and uniquely encodes DNAJB6a. We further identified that this mutation decreases the mRNA and protein levels of DNAJB6a and results in an age-dependent recessive toxic effect on skeletal muscle in knock-in mice. Moreover, the mutant DNAJB6a showed a dose-dependent anti-aggregation effect on polyglutamine-containing proteins in vitro. Taking together, these findings reveal the pathogenic role of DNAJB6a insufficiency in myofibrillar myopathies and expand upon the molecular spectrum of DNAJB6 mutations.

Early Childhood Reading in Rural China and Obstacles to Caregiver Investment in Young Children: A Mixed-Methods Analysis.

Studies have shown that nearly half of rural toddlers in China have cognitive delays due to an absence of stimulating parenting practices, such as early childhood reading, during the critical first three years of life. However, few studies have examined the reasons behind these low levels of stimulating parenting, and no studies have sought to identify the factors that limit caregivers from providing effective early childhood reading practices (EECRP). This mixed-methods study investigates the perceptions, prevalence, and correlates of EECRP in rural China, as well as associations with child cognitive development. We use quantitative survey results from 1748 caregiver-child dyads across 100 rural villages/townships in northwestern China and field observation and interview data with 60 caregivers from these same sites. The quantitative results show significantly low rates of EECRP despite positive perceptions of early reading and positive associations between EECRP and cognitive development. The qualitative results suggest that low rates of EECRP in rural China are not due to the inability to access books, financial or time constraints, or the absence of aspirations. Rather, the low rate of book ownership and absence of reading to young children is driven by the insufficient and inaccurate knowledge of EECRP among caregivers, which leads to their delayed, misinformed reading decisions with their young children, ultimately contributing to developmental delays.

Correlates of participation in community-based interventions: Evidence from a parenting program in rural China.

A growing body of literature has documented that community-based early childhood development (ECD) interventions can improve child developmental outcomes in vulnerable communities. One critical element of effective community-based programs is consistent program participation. However, little is known about participation in community-based ECD interventions or factors that may affect participation. This paper examines factors linked to program participation within a community-based ECD program serving 819 infants and their caregivers in 50 rural villages in northwestern China. The results find that more than half of families did not regularly attend the ECD program. Both village-level social ties within the program and proximity to the program significantly predict program participation. Increased distance from the program site is linked with decreased individual program participation, while the number of social ties is positively correlated with participation. The average program participation rates among a family's social ties is also positively correlated with individual participation, indicating strong peer effects. Taken together, our findings suggest that attention should be given to promoting social interactions and reducing geographic barriers among households in order to raise participation in community-based ECD programs.

"Target" and "Sandwich" Signs in Thigh Muscles have High Diagnostic Values for Collagen VI-related Myopathies.

BACKGROUND: Collagen VI-related myopathies are autosomal dominant and recessive hereditary myopathies, mainly including Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). Muscle magnetic resonance imaging (MRI) has been widely used to diagnosis muscular disorders. The purpose of this study was to evaluate the diagnostic value of thigh muscles MRI for collagen VI-related myopathies. METHODS: Eleven patients with collagen VI gene mutation-related myopathies were enrolled in this study. MRI of the thigh muscles was performed in all patients with collagen VI gene mutation-related myopathies and in 361 patients with other neuromuscular disorders (disease controls). T1-weighted images were used to assess fatty infiltration of the muscles using a modified Mercuri's scale. We assessed the sensitivity and specificity of the MRI features of collagen VI-related myopathies. The relationship between fatty infiltration of muscles and specific collagen VI gene mutations was also investigated. RESULTS: Eleven patients with collagen VI gene mutation-related myopathies included six UCMD patients and five BM patients. There was no significant difference between UCMD and BM patients in the fatty infiltration of each thigh muscle except sartorius (P = 0.033); therefore, we combined the UCMD and BM data. Mean fatty infiltration scores were 3.1 and 3.0 in adductor magnus and gluteus maximus, while the scores were 1.3, 1.3, and 1.5 in gracilis, adductor longus, and sartorius, respectively. A "target" sign in rectus femoris (RF) was present in seven cases, and a "sandwich" sign in vastus lateralis (VL) was present in ten cases. The "target" and "sandwich" signs had sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96.9% for the diagnosis of collagen VI-related myopathies, respectively. Fatty infiltration scores were 2.0-3.0 in seven patients with mutations in the triple-helical domain, and 1.0-1.5 in three of four patients with mutations in the N- or C-domain of the collagen VI genes. CONCLUSIONS: The "target" sign in RF and "sandwich" sign in VL are common MRI features and are useful for the diagnosis of collagen VI-related myopathies. The severity of fatty infiltration of muscles may have a relationship with the mutation location of collagen VI gene.

[Leucine-rich glioma inactivated-1 protein antibody associated limbic encephalitis: one case report].

OBJECTIVE: To report a case of leucine-rich glioma inactivated-1 protein antibody (LGI1-Ab) associated limbic encephalitis. METHODS: A 76-year-old woman was admitted to the hospital because of cognitive impairment and faciobrachial dystonic seizures for six months. Hyponatremia was also noted in this patient. Antibodies to the LGI1 were positive.(18)F-FDG uptake was measured on the PET-CT scans of this patient. RESULTS: PET-CT showed bilateral putamen hypermetabolism with hypometabolism in other regions. Her symptoms were improved after intravenous immunoglobulin therapy. CONCLUSION: LGI1-Ab associated encephalitis can manifest as basal ganglia hypermetabolism and faciobrachial dystonic seizures.