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Background: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified., Methods: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test., Results: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits., Conclusions: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders., (© 2024. The Author(s).)

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders., (© 2024. The Author(s).)

Background: Polypodiales suborder Dennstaedtiineae contain a single family Dennstaedtiaceae, eleven genera, and about 270 species, and include some groups that were previously placed in Dennstaedtiaceae, Hypolepidaceae, Monachosoraceae, and Pteridaceae. The classification and phylogenetic relationships among these eleven genera have been poorly understood. To explore the deep relationships within suborder Dennstaedtiineae and estimate the early diversification of this morphologically heterogeneous group, we analyzed complete plastomes of 57 samples representing all eleven genera of suborder Dennstaedtiineae using maximum likelihood and Bayesian inference., Results: The phylogenetic relationships of all the lineages in the bracken fern family Dennstaedtiaceae were well resolved with strong support values. All six genera of Hypolepidoideae were recovered as forming a monophyletic group with full support, and Pteridium was fully supported as sister to all the other genera in Hypolepidoideae. Dennstaedtioideae (Dennstaedtia s.l.) fell into four clades with full support: the Microlepia clade, the northern Dennstaedtia clade, the Dennstaedtia globulifera clade, and the Dennstaedtia s.s. clade. Monachosorum was strongly resolved as sister to all the remaining genera of suborder Dennstaedtiineae. Based on the well resolved relationships among genera, the divergence between Monachosorum and other groups of suborder Dennstaedtiineae was estimated to have occurred in the Early Cretaceous, and all extant genera (and clades) in Dennstaedtiineae, were inferred to have diversified since the Late Oligocene., Conclusion: This study supports reinstating a previously published family Monachosoraceae as a segregate from Dennstaedtiaceae, based on unique morphological evidence, the shady habitat, and the deep evolutionary divergence from its closest relatives., (© 2022. The Author(s).)

Background: The study aims to evaluate the accuracy of the generative adversarial networks (GAN) for reconstructing bony midfacial defects., Methods: According to anatomy, the bony midface was divided into five subunit structural regions and artificial defects are manually created on the corresponding CT images. GAN is trained to reconstruct artificial defects to their previous normal shape and tested. The clinical defects are reconstructed by the trained GAN, where the midspan defects were used for qualitative evaluation and the unilateral defects were used for quantitative evaluation. The cosine similarity and the mean error are used to evaluate the accuracy of reconstruction. The Mann-Whitney U test is used to detect whether reconstruction errors were consistent in artificial and unilateral clinical defects., Results: This study included 518 normal CT data, with 415 in training set and 103 in testing set, and 17 real patient data, with 2 midspan defects and 15 unilateral defects. Reconstruction of midspan clinical defects assessed by experts is acceptable. The cosine similarity in the reconstruction of artificial defects and unilateral clinical defects is 0.97 ± 0.01 and 0.96 ± 0.01, P = 0.695. The mean error in the reconstruction of artificial defects and unilateral clinical defects is 0.59 ± 0.31 mm and 0.48 ± 0.08 mm, P = 0.09., Conclusion: GAN-based virtual reconstruction technology has reached a high accuracy in testing set, and statistical tests suggest that it can achieve similar results in real patient data. This study has preliminarily solved the problem of bony midfacial defect without reference., (© 2022. The Author(s).)

Background: Members of the genus Novius Mulsant, 1846 (= Rodolia Mulsant, 1850) (Coleoptera, Coccinellidae), play important roles in the biological control of cotton cushion scale pests, especially those belonging to Icerya. Since the best-known species, the vedalia beetle Novius cardinalis (Mulsant, 1850) was introduced into California from Australia, more than a century of successful use in classical biological control, some species of Novius have begun to exhibit some field adaptations to novel but related prey species. Despite their economic importance, relatively little is known about the underlying genetic adaptations associated with their feeding habits. Knowledge of the genome sequence of Novius is a major step towards further understanding its biology and potential applications in pest control., Results: We report the first high-quality genome sequence for Novius pumilus (Weise, 1892), a representative specialist of Novius. Computational Analysis of gene Family Evolution (CAFE) analysis showed that several orthogroups encoding chemosensors, digestive, and immunity-related enzymes were significantly expanded (P < 0.05) in N. pumilus compared to the published genomes of other four ladybirds. Furthermore, some of these orthogroups were under significant positive selection pressure (P < 0.05). Notably, transcriptome profiling demonstrated that many genes among the significantly expanded and positively selected orthogroups, as well as genes related to detoxification were differentially expressed, when N. pumilus feeding on the nature prey Icerya compared with the no feeding set. We speculate that these genes are vital in the Icerya adaptation of Novius species., Conclusions: We report the first Novius genome thus far. In addition, we provide comprehensive transcriptomic resources for N. pumilus. The results from this study may be helpful for understanding the association of the evolution of genes related to chemosensing, digestion, detoxification and immunity with the prey adaptation of insect predators. This will provide a reference for future research and utilization of Novius in biological control programs. Moreover, understanding the possible molecular mechanisms of prey adaptation also inform mass rearing of N. pumilus and other Novius, which may benefit pest control., (© 2022. The Author(s).)

Background: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, and its diagnosis depends mainly on renal biopsy. However, there is no specific treatment for IgAN. Moreover, its causes and underlying molecular events require further exploration., Methods: The expression profiles of GSE64306 and GSE93798 were downloaded from the Gene Expression Omnibus (GEO) database and used to identify the differential expression of miRNAs and genes, respectively. The StarBase and TransmiR databases were employed to predict target genes and transcription factors of the differentially expressed miRNAs (DE-miRNAs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to predict biological functions. A comprehensive analysis of the miRNA-mRNA regulatory network was constructed, and protein-protein interaction (PPI) networks and hub genes were identified. CIBERSORT was used to examine the immune cells in IgAN, and correlation analyses were performed between the hub genes and infiltrating immune cells., Results: Four downregulated miRNAs and 16 upregulated miRNAs were identified. Forty-five and twelve target genes were identified for the upregulated and downregulated DE-miRNAs, respectively. CDKN1A, CDC23, EGR1, HIF1A, and TRIM28 were the hub genes with the highest degrees of connectivity. CIBERSORT revealed increases in the numbers of activated NK cells, M1 and M2 macrophages, CD4 naive T cells, and regulatory T cells in IgAN. Additionally, HIF1A, CDC23, TRIM28, and CDKN1A in IgAN patients were associated with immune cell infiltration., Conclusions: A potential miRNA-mRNA regulatory network contributing to IgAN onset and progression was successfully established. The results of the present study may facilitate the diagnosis and treatment of IgAN by targeting established miRNA-mRNA interaction networks. Infiltrating immune cells may play significant roles in IgAN pathogenesis. Future studies on these immune cells may help guide immunotherapy for IgAN patients., (© 2021. The Author(s).)

Background: Horizontal gene transfer (HGT) has been documented in many herbivorous insects, conferring the ability to digest plant material and promoting their remarkable ecological diversification. Previous reports suggest HGT of antibacterial enzymes may have contributed to the insect immune response and limit bacterial growth. Carnivorous insects also display many evolutionary successful lineages, but in contrast to the plant feeders, the potential role of HGTs has been less well-studied., Results: Using genomic and transcriptomic data from 38 species of ladybird beetles, we identified a set of bacterial cell wall hydrolase (cwh) genes acquired by this group of beetles. Infection with Bacillus subtilis led to upregulated expression of these ladybird cwh genes, and their recombinantly produced proteins limited bacterial proliferation. Moreover, RNAi-mediated cwh knockdown led to downregulation of other antibacterial genes, indicating a role in antibacterial immune defense. cwh genes are rare in eukaryotes, but have been maintained in all tested Coccinellinae species, suggesting that this putative immune-related HGT event played a role in the evolution of this speciose subfamily of predominant predatory ladybirds., Conclusion: Our work demonstrates that, in a manner analogous to HGT-facilitated plant feeding, enhanced immunity through HGT might have played a key role in the prey adaptation and niche expansion that promoted the diversification of carnivorous beetle lineages. We believe that this represents the first example of immune-related HGT in carnivorous insects with an association with a subsequent successful species radiation.

Background: Ladybird beetles (Coleoptera, Coccinellidae) are highly diverse in their feeding habits. Most of them are specialist feeders, while some can have a broad spectrum of prey. As a representative group of generalists, the tribe Coccinellini includes many aphidophagous species, but members of this tribe also feed on other hemipterous insects including coccids, psyllids and whiteflies. As a result, several species are effective biological control agents or invasive species with serious non-target effects. Despite their economic importance, relatively little is known about how they adapt to new prey., Results: In this study, comparisons of the life history traits and transcriptomes of ladybirds fed initial (aphids) and alternative prey (mealybugs) were performed in three Coccinellini species. The use of alternative prey greatly decreased performance, implied by the significantly prolonged development time and decreased survival rate and adult weight. Prey shifts resulted in a set of differentially expressed genes encoding chemosensory proteins and digestive and detoxifying enzymes., Conclusions: Our results suggest that these generalists do not perform well when they use alternative prey as the sole nutrition source. Although their capacity for predation might have created an opportunity to use varied prey, they must adapt to physiological obstacles including chemosensing, digestion and detoxification in response to a prey shift. These findings challenge the effect of Coccinellini predators on the biological control of non-aphid pests and suggest the possibility of non-target attacks by so-called specialists.

Background: Bilateral hands including proximal interphalangeal joints (PIPJs) are recommended on physical, X-ray radiographic, or ultrasonographic examination by clinical guidelines of rheumatoid arthritis (RA), but MRI still tends to examine unilateral wrists and/or MCPJs. We aimed to demonstrate the advantages of MRI examination on bilateral hands including PIPJs for disease assessment in early RA patients., Methods: Active early RA patients received 3.0T whole-body MRI examination with contrast-enhanced imaging on bilateral wrists, MCPJs, and PIPJs. MRI features were scored referring to the updated RAMRIS. Clinical assessments were conducted on the day of MRI examination., Results: The mean time of MRI examination was 24 ± 3 min. MRI bone erosion in MCPJs would be missed-diagnosed in 23% of patients if non-dominant MCPJs were scanned unilaterally, while osteitis in MCPJs would be missed-diagnosed in 16% of patients if dominant MCPJs were scanned unilaterally. MRI synovitis severity was also asymmetric: 21% of patients showing severe synovitis unilaterally in non-dominant MCPJs/PIPJs and other 20% showing severe synovitis unilaterally in dominant MCPJs/PIPJs. Among these early RA patients, MRI tenosynovitis occurred the most frequently in wrist extensor compartment I, while MRI examination on bilateral hands demonstrated no overuse influence present. However, overuse should be considered in dominant PIPJ2, PIPJ4, and IPJ of thumb of which MRI tenosynovitis prevalence was respectively 18%, 17%, or 16% higher than the non-dominant counterparts. Early MRI abnormality of nervus medianus secondary to severe tenosynovitis occurred either in dominant or non-dominant wrists; MRI of unilateral hands would take a risk of missed-diagnosis. Common MRI findings in PIPJs were synovitis and tenosynovitis, respectively in 87% and 69% of patients. MRI tenosynovitis prevalence in IPJ of thumb or PIPJ5 was much higher than the continued wrist flexor compartments. MRI synovitis or tenosynovitis in PIPJs independently increased more than twice probability of joint tenderness (OR = 2.09 or 2.83, both p < 0.001)., Conclusions: In consideration of asymmetric MRI features in early RA, potential overuse influence for certain tenosynovitis in dominant hands, and high prevalence of MRI findings in PIPJs, MRI examination on bilateral hands including PIPJs is deserved for disease assessment in early RA patients.

Background: To validate the clinical value of simple rules in distinguishing malignant adnexal masses from benign ones and to explore the effect of simple rules for experienced and less-experienced sonographers., Methods: Patients with persistent adnexal masses were enrolled between November 2013 and December 2015. All masses were proven through histological examinations. Five sets of diagnoses were made and compared with one another. Diagnosis 1 was made, according to the simple rules, by a trainee with little clinical diagnostic experience. Diagnoses 2 and 3 were made by experienced and less-experienced sonographers, respectively, according to their clinical experiences. With diagnosis 1 as a reference, the two sonographers were asked to provide a second diagnosis, which were diagnoses 4 and 5. The efficiency of the five sets of diagnoses was compared using ROC curves., Results: In total, 75 malignant (37.7%) and 124 benign lesions (62.3%) were enrolled in this study. The mean diameter of the benign masses was obviously smaller than that of the malignant ones (6.8 ± 3.4 cm vs. 9.3 ± 4.9 cm, p < 0.01). The malignant ratio in postmenopausal women was much higher (66.1%) than that in the premenopausal population (25.7%) (p < 0.0001). Totally, 156 of the 199 cases (79.4%) resulted in conclusive diagnoses. Sensitivity and specificity were 98.4% and 73.9%, respectively, among the conclusive cases. The area under the ROC curve (Az) for the simple rule diagnosis was significantly lower than that for the experienced sonographer diagnosis (0.85 vs. 0.96, p < 0.0001); compared with the less-experienced sonographer, this difference was not significant (0.85 vs. 0.86, p = 0.9776). No significant difference was found in the comparison between the diagnoses made by the experienced sonographer before and after referencing the simple rule diagnosis (Az, 0.96 vs. 0.97, p = 0.2055). Using diagnosis 1 as a reference, the diagnostic performance of the less-experienced sonographer increased (from 0.86 to 0.92, p = 0.012); however, it was still lower than that of the experienced sonographer (Az, 96% vs. 92%, p = 0.0241)., Conclusions: The simple rules was an appealing method for discriminating malignant masses from benign ones, particularly for a less-experienced sonographer.

Background: Schizophrenia is a widespread and debilitating mental disorder. However, the underlying molecular mechanism of schizophrenia remains largely unknown and no objective laboratory tests are available to diagnose this disorder. The aim of the present study was to characterize the alternations of glucose metabolites and identify potential diagnostic biomarkers for schizophrenia., Methods: Gas chromatography/mass spectrometry based targeted metabolomic method was used to quantify the levels of 13 glucose metabolites in peripheral blood mononuclear cells (PBMCs) derived from healthy controls, schizophrenia and major depression subjects (n = 55 for each group)., Results: The majority (84.6%) of glucose metabolites were significantly disturbed in schizophrenia subjects, while only two (15.4%) glucose metabolites were differently expressed in depression subjects relative to healthy controls in both training set (n = 35/group) and test set (n = 20/group). Antipsychotics had only a subtle effect on glucose metabolism pathway. Moreover, ribose 5-phosphate in PBMCs showed a high diagnostic performance for first-episode drug-naïve schizophrenia subjects., Conclusion: These findings suggested disturbance of glucose metabolism may be implicated in onset of schizophrenia and could aid in development of diagnostic tool for this disorder.

Background: C-src is an evolutionarily conserved proto-oncogene that regulates cell proliferation, differentiation and apoptosis. In our previous studies, we have reported that another proto-oncogene, c-erbB2, plays an important role in primordial follicle activation and development. We also found that c-src was expressed in mammalian ovaries, but its functions in primordial follicle activation remain unclear. The objective of this study is to investigate the role and mechanism of c-src during the growth of primordial follicles., Methods: Ovaries from 2-day-old rats were cultured in vitro for 8 days. Three c-src-targeting and one negative control siRNA were designed and used in the present study. PCR, Western blotting and primordial follicle development were assessed for the silencing efficiency of the lentivirus c-src siRNA and its effect on primordial follicle onset. The expression of c-src mRNA and protein in primordial follicle growth were examined using the PCR method and immunohistochemical staining. Furthermore, the MAPK inhibitor PD98059, the PKC inhibitor Calphostin and the PI3K inhibitor LY294002 were used to explore the possible signaling pathways of c-src in primordial folliculogenesis., Results: The results showed that Src protein was distributed in the ooplasmic membrane and the granulosa cell membrane in the primordial follicles, and c-src expression level increased with the growth of primordial follicle. The c-src -targeting lentivirus siRNAs had a silencing effect on c-src mRNA and protein expression. Eight days after transfection of rat ovaries with c-src siRNA, the GFP fluorescence in frozen ovarian sections was clearly discernible under a fluorescence microscope, and its relative expression level was 5-fold higher than that in the control group. Furthermore, the c-src-targeting lentivirus siRNAs lowered its relative expression level 1.96 times. We also found that the development of cultured primordial follicles was completely arrested after c-src siRNA knockdown of c-src expression. Furthermore, our studies demonstrated that folliculogenesis onset was inhibited by Calphostin, PD98059 or LY294002 treatment,but none of them down-regulated c-src expression. In contrast, the expression levels of p-PKC, p-ERK1/2 and p-PI3K in the follicles were clearly decreased by c-src siRNA transfection. Correspondingly, both Calphostin and LY294002 treatment resulted in a decrease in the p-PKC level in follicles, but no change was observed in the PD98059 group. Finally, LY294002 treatment decreased the p-PI3K expression level in the follicles, but no changes were observed in the PD98059 and Calphostin groups., Conclusions: C-src plays an important role in regulating primordial follicle activation and growth via the PI3K-PKC- ERK1/2 pathway.