Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Structure of the interleukin-5 receptor complex exemplifies the organizing principle of common beta cytokine signaling.

Cytokines regulate immune responses by binding to cell surface receptors, including the common subunit beta (ßc), which mediates signaling for GM-CSF, IL-3, and IL-5. Despite known roles in inflammation, the structural basis of IL-5 receptor activation remains unclear. We present the cryo-EM structure of the human IL-5 ternary receptor complex, revealing architectural principles for IL-5, GM-CSF, and IL-3. In mammalian cell culture, single-molecule imaging confirms hexameric IL-5 complex formation on cell surfaces. Engineered chimeric receptors show that IL-5 signaling, as well as IL-3 and GM-CSF, can occur through receptor heterodimerization, obviating the need for higher-order assemblies of ßc dimers. These findings provide insights into IL-5 and ßc receptor family signaling mechanisms, aiding in the development of therapies for diseases involving deranged ßc signaling.

Two-factor authentication underpins the precision of the piRNA pathway.

The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young, active transposons during germline development in male mice1. piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript, resulting in DNA methylation through SPOCD1 (refs. 2-5). Transposon methylation requires great precision: every copy needs to be methylated but off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 interacts directly with SPIN1 (SPINDLIN1), a chromatin reader that primarily binds to H3K4me3-K9me3 (ref. 6). The prevailing assumption is that all the molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. We find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1 copies, but not old ones, are marked by H3K4me3, H3K9me3 and SPIN1 before the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the interaction between SPOCD1 and SPIN1 is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that piRNA-directed LINE1 DNA methylation requires a developmentally timed two-factor authentication process. The first authentication is the recruitment of SPIN1-SPOCD1 to the young LINE1 promoter, and the second is MIWI2 engagement with the nascent transcript. In summary, independent authentication events underpin the precision of piRNA-directed LINE1 DNA methylation.

Organizing structural principles of the IL-17 ligand-receptor axis.

The IL-17 family of cytokines and receptors have central roles in host defence against infection and development of inflammatory diseases1. The compositions and structures of functional IL-17 family ligand-receptor signalling assemblies remain unclear. IL-17E (also known as IL-25) is a key regulator of type 2 immune responses and driver of inflammatory diseases, such as allergic asthma, and requires both IL-17 receptor A (IL-17RA) and IL-17RB to elicit functional responses2. Here we studied IL-25-IL-17RB binary and IL-25-IL-17RB-IL-17RA ternary complexes using a combination of cryo-electron microscopy, single-molecule imaging and cell-based signalling approaches. The IL-25-IL-17RB-IL-17RA ternary signalling assembly is a C2-symmetric complex in which the IL-25-IL-17RB homodimer is flanked by two 'wing-like' IL-17RA co-receptors through a 'tip-to-tip' geometry that is the key receptor-receptor interaction required for initiation of signal transduction. IL-25 interacts solely with IL-17RB to allosterically promote the formation of the IL-17RB-IL-17RA tip-to-tip interface. The resulting large separation between the receptors at the membrane-proximal level may reflect proximity constraints imposed by the intracellular domains for signalling. Cryo-electron microscopy structures of IL-17A-IL-17RA and IL-17A-IL-17RA-IL-17RC complexes reveal that this tip-to-tip architecture is a key organizing principle of the IL-17 receptor family. Furthermore, these studies reveal dual actions for IL-17RA sharing among IL-17 cytokine complexes, by either directly engaging IL-17 cytokines or alternatively functioning as a co-receptor.

Emphysematous pyelonephritis caused by Raoultella ornithinolytica: a case report.

BACKGROUND: Emphysematous pyelonephritis is a rare and severe urinary tract infection that is potentially life-threatening and easily progresses to septic shock. In this report, we present a unique case of emphysematous pyelonephritis caused by Raoultella ornithinolytica. CASE PRESENTATION: An 86-year-old man presented with severe back pain of 3 days' duration. He had a history of hypertension and diabetes for more than 20 years, and his infection indicators and serum creatinine were elevated. Abdominal computed tomography revealed an abnormal gas shadow around his right kidney and the anterior edge of his right psoas muscle. Consequently, he was initially diagnosed with emphysematous pyelonephritis. There was no evidence of nephrolithiasis or other anatomical or structural abnormalities that could have precipitated this focal renal infection. Both blood and drainage fluid cultures revealed R. ornithinolytica. After early anti-infection treatment, percutaneous drainage and moderate control of blood glucose, the patient gradually recovered. CONCLUSIONS: Emphysematous pyelonephritis caused by R. ornithinolytica is rare but has a high drug resistance rate potentially and may cause severe infections. Early diagnosis, prompt use of antibiotics that are sensitive to the organism, and decompression drainage could be the key to treatment.

Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity of the wild-type G6PD. The crystal structure of G6PD reveals these mutations are located away from the active site, concentrating around the noncatalytic NADP+-binding site and the dimer interface. However, the molecular mechanisms of class I mutant dysfunction have remained elusive, hindering the development of efficient therapies. To resolve this, we performed integral structural characterization of five G6PD mutants, including four class I mutants, associated with the noncatalytic NADP+ and dimerization, using crystallography, small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and biophysical analyses. Comparisons with the structure and properties of the wild-type enzyme, together with molecular dynamics simulations, bring forward a universal mechanism for this severe G6PD deficiency due to the class I mutations. We highlight the role of the noncatalytic NADP+-binding site that is crucial for stabilization and ordering two ß-strands in the dimer interface, which together communicate these distant structural aberrations to the active site through a network of additional interactions. This understanding elucidates potential paths for drug development targeting G6PD deficiency.

Crystal structure and functional analysis of mycobacterial erythromycin resistance methyltransferase Erm38 reveals its RNA-binding site.

Erythromycin resistance methyltransferases (Erms) confer resistance to macrolide, lincosamide, and streptogramin antibiotics in Gram-positive bacteria and mycobacteria. Although structural information for ErmAM, ErmC, and ErmE exists from Gram-positive bacteria, little is known about the Erms in mycobacteria, as there are limited biochemical data and no structures available. Here, we present crystal structures of Erm38 from Mycobacterium smegmatis in apoprotein and cofactor-bound forms. Based on structural analysis and mutagenesis, we identified several catalytically critical, positively charged residues at a putative RNA-binding site. We found that mutation of any of these sites is sufficient to abolish methylation activity, whereas the corresponding RNA-binding affinity of Erm38 remains unchanged. The methylation reaction thus appears to require a precise ensemble of amino acids to accurately position the RNA substrate, such that the target nucleotide can be methylated. In addition, we computationally constructed a model of Erm38 in complex with a 32-mer RNA substrate. This model shows the RNA substrate stably bound to Erm38 by a patch of positively charged residues. Furthermore, a π-π stacking interaction between a key aromatic residue of Erm38 and a target adenine of the RNA substrate forms a critical interaction needed for methylation. Taken together, these data provide valuable insights into Erm-RNA interactions, which will aid subsequent structure-based drug design efforts.

Viral long non-coding RNA regulates virus life-cycle and pathogenicity.

Viral infection is still a serious global health problem that kills hundreds of thousands of people annually. Understanding the mechanism by which virus replicates, packages, and infects the host cells can provide new strategies to control viral infection. Long non-coding RNAs (lncRNAs) have been identified as critical regulators involved in viral infection process and antiviral response. A lot of host lncRNAs have been identified and shown to be involved in antiviral immune response during viral infection. However, our knowledge about lncRNAs expressed by viruses is still at its infancy. LncRNAs expressed by viruses are involved in the whole viral life cycle, including promoting genome replication, regulating gene expression, involvement in genome packaging, assembling new viruses and releasing virions to the host cells. Furthermore, they enhance the pathogenicity of viral infections by down-regulating the host cell's antiviral immune response and maintain the viral latency through a refined procedure of genome integration. This review focuses on the regulatory roles of viral lncRNA in the life-cycle and pathogenicity of viruses. It gives an insight into the viral lncRNAs that can be utilized as therapeutic targets against viral diseases, and future researches aimed to identify and explore new viral lncRNAs and the mechanisms of their involvement in viral infection is encouraged.

All-yarn triboelectric nanogenerator and supercapacitor based self-charging power cloth for wearable applications.

Despite rapid developments, multifunctional wearable electronics are still not significant in practical applications as compared to portable and stretchable power devices. In this paper, we present the flexible and easy large-scale production of single-electrode mode triboelectric nanogenerator (TENG) and supercapacitor yarn-based self-charging power fabric, for simultaneously converting and storing biomechanical energy. Fabricated using traditional knitting technologies, the self-charging power fabric can adapt to complex mechanical deformations owing to its high flexibility and stretchability. Additionally, the output characteristics of the TENG fabric were systematically investigated with the purpose of energy generation. The TENG fabric can generate a maximum peak power density of ∼90 mW·m-2using nylon as the contact material, with an operating frequency of 4 Hz. The as-prepared yarn-based supercapacitor exhibited high capacitance, good cycling stability, and flexibility, making it an appropriate wearable energy-storage device. Moreover, the proposed design uses energy harvested from biomechanical motions to sustainably power portable electronic devices. The results of this study indicate that the proposed design is a promising sustainable power source for wearable electronic devices.

GSB: GNGS and SAG-BiGRU network for malware dynamic detection.

With the rapid development of the Internet, the continuous increase of malware and its variants have brought greatly challenges for cyber security. Due to the imbalance of the data distribution, the research on malware detection focuses on the accuracy of the whole data sample, while ignoring the detection rate of the minority categories' malware. In the dataset sample, the normal data samples account for the majority, while the attacks' malware accounts for the minority. However, the minority categories' attacks will bring great losses to countries, enterprises, or individuals. For solving the problem, this study proposed the GNGS algorithm to construct a new balance dataset for the model algorithm to pay more attention to the feature learning of the minority attacks' malware to improve the detection rate of attacks' malware. The traditional malware detection method is highly dependent on professional knowledge and static analysis, so we used the Self-Attention with Gate mechanism (SAG) based on the Transformer to carry out feature extraction between the local and global features and filter irrelevant noise information, then extracted the long-distance dependency temporal sequence features by the BiGRU network, and obtained the classification results through the SoftMax classifier. In the study, we used the Alibaba Cloud dataset for malware multi-classification. Compared the GSB deep learning network model with other current studies, the experimental results showed that the Gaussian noise generation strategy (GNGS) could solve the unbalanced distribution of minority categories' malware and the SAG-BiGRU algorithm obtained the accuracy rate of 88.7% on the eight-classification, which has better performance than other existing algorithms, and the GSB model also has a good effect on the NSL-KDD dataset, which showed the GSB model is effective for other network intrusion detection.

Targeted isolation, identification, and antioxidant evaluation of aromatic polyketides from a plant-derived fungus Ophiobolus cirsii LZU-1509.

There are >350 species of the Ophiobolus genus, which is not yet very well-known and lacks research reports on secondary metabolites. Three new 3,4-benzofuran polyketides 1-3, a new 3,4-benzofuran polyketide racemate 4, two new pairs of polyketide enantiomers (±)-5 and (±)-7, two new acetophenone derivatives 6 and 8, and three novel 1,4-dioxane aromatic polyketides 9-11, were isolated from a fungus Ophiobolus cirsii LZU-1509 derived from an important medicinal and economic crop Anaphalis lactea. The isolation was guided by LC-MS/MS-based GNPS molecular networking analysis. The planar structures and relative configurations were mainly elucidated by NMR and HR-ESI-MS data. Their absolute configurations were determined by using X-ray diffraction analysis and via comparing computational and experimental ECD, NMR, and specific optical rotation data. 9 possesses an unreported 5/6/6/6/5 five-ring framework with a 1,4-dioxane, and 10 and 11 feature unprecedented 6/6/6/5 and 6/6/5/6 four-ring frames containing a 1,4-dioxane. The biosynthetic pathways of 9-11 were proposed. 1-11 were nontoxic in HT-1080 and HepG2 tumor cells at a concentration of 20 µM, whereas 3 and 5 exerted higher antioxidant properties in the hydrogen peroxide-stimulated model in the neuron-like PC12 cells. They could be potential antioxidant agents for neuroprotection.

Isolation and Identification of Novel Antioxidant Polyketides from an Endophytic Fungus Ophiobolus cirsii LZU-1509.

Sixteen new polyketides, ophicirsins A-P (1-16), including four novel carbon skeletons (5-9, 14, 15, and 16), were isolated from the extract of an endophytic fungus Ophiobolus cirsii LZU-1509. The unique frameworks of ophicirsin N (14) and O (15) feature a different cyclic ether connected with an aromatic ring system. Ophicirsin P (16) is characterized by the unprecedented heterozygote of a polyketide and an alkaloid. The absolute stereochemistries of those polyketides were characterized via single-crystal X-ray diffraction analysis and the experimental and computational electric circular dichroism spectra comparison. Theoretical reaction pathways in the fermentation to generate different novel skeletons starting from acetyl CoA and malonyl CoA helped to assign their structures. Compounds 1-16 appear almost nontoxic in HepG2 and HT-1080 tumor cells. Their antioxidant effects were further evaluated, and 15 exhibits an excellent protection activity in hydrogen peroxide-stimulated oxidative damage in neuron-like PC12 cells via screening all compounds. Moreover, 15 displays a greater ability to scavenge the 2,2-diphenyl-1-picrylhydrazyl free radicals than resveratrol. Taken together, these findings suggest that the novel polyketides could serve as potential antioxidant agents for neuroprotection.

Early versus delayed enteral nutrition for neonatal hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia: a randomized controlled trial.

BACKGROUND: The practice of therapeutic hypothermia (TH) is widely used for neonatal hypoxic-ischemic encephalopathy (HIE) despite its corresponding feeding strategies are still controversial. This randomized controlled trial (RCT) demonstrated to evaluate the effect of early vs. delayed enteral nutrition on the incidence of feeding intolerance (FI) and other association during TH. METHODS: This single center, parallel-group, and no-blinded RCT was processed in a level III, and academic neonatal intensive care unit. Infants who were diagnosed with HIE and undertaken TH from September 2020 to August 2021 were enrolled. Participants were randomized to receive enteral nutrition either during TH/rewarming (early enteral nutrition, EEN) or after TH (delayed enteral nutrition, DEN) according to a recommend enteral feeding protocol. All data were analyzed using SPSS 26.0 software with a p-value< 0.05 was considered statistically significant. RESULTS: Ninety-two infants were enrolled after randomization, but 12 (13.04%) cases including 3 (3.26%) deaths were excluded from eventually analyzed, who did not initiate or discontinue the intervention. 80 cases (42 and 38 in the EEN and DEN group, respectively) who completed the interventions were eventually analyzed. Besides initial time of enteral feeds, two groups had processed the same feeding method. Total 23 (25.0%) cases developed FI, and no difference of morbidity was found between two groups (23.4% vs 26.7%, p = 0.595; Log Rank, p = 0.803). There was no case died or developed late-onset bloodstream and no difference of the incidence of hypoglycemia or weight gain was found (p > 0.05). The percentage of infants who had not reaching the goal of full enteral feeding volume between the two groups was similar (21.43% vs 23.68%, p = 0.809). The average time of parenteral nutrition, reaching full enteral feeds and hospital stay were shorter in the EEN group compared with the DEN group with significant differences (8.81 ± 1.67 vs 10.61 ± 2.06 days, p < 0.001; 9.91 ± 1.88 vs 12.24 ± 2.50 days, p < 0.001; 12.55 ± 4.57 vs 16.47 ± 5.27 days, p = 0.001 respectively). CONCLUSIONS: Compared with delayed enteral nutrition, introduction of early enteral nutrition according to a recommend feeding strategy for neonatal HIE undergoing TH may be feasible and safe.FI is frequent in this high-risk group of infants which should not be ignored during feeding process. TRIAL REGISTRATION: The Chinese Clinical Trial Registry,ChiCTR2000038193, 2020-9-13, https://www.chictr.org.cn .

Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections.

Germ cells are essential to pass DNA from one generation to the next. In human reproduction, germ cell development begins with the specification of primordial germ cells (PGCs) and a failure to specify PGCs leads to human infertility. Recent studies have revealed that the transcription factor network required for PGC specification has diverged in mammals, and this has a significant impact on our understanding of human reproduction. Here, we reveal that the Hominidae-specific Transposable Elements (TEs) LTR5Hs, may serve as TEENhancers (TE Embedded eNhancers) to facilitate PGC specification. LTR5Hs TEENhancers become transcriptionally active during PGC specification both in vivo and in vitro with epigenetic reprogramming leading to increased chromatin accessibility, localized DNA demethylation, enrichment of H3K27ac, and occupation of key hPGC transcription factors. Inactivation of LTR5Hs TEENhancers with KRAB mediated CRISPRi has a significant impact on germ cell specification. In summary, our data reveals the essential role of Hominidae-specific LTR5Hs TEENhancers in human germ cell development.

Krüppel-like factor 5 rewires NANOG regulatory network to activate human naive pluripotency specific LTR7Ys and promote naive pluripotency.

Endogenous retroviruses (ERVs) have been reported to participate in pre-implantation development of mammalian embryos. In early human embryogenesis, different ERV sub-families are activated in a highly stage-specific manner. How the specificity of ERV activation is achieved remains largely unknown. Here, we demonstrate the mechanism of how LTR7Ys, the human morula-blastocyst-specific HERVH long terminal repeats, are activated by the naive pluripotency transcription network. We find that KLF5 interacts with and rewires NANOG to bind and regulate LTR7Ys; in contrast, the primed-specific LTR7s are preferentially bound by NANOG in the absence of KLF5. The specific activation of LTR7Ys by KLF5 and NANOG in pluripotent stem cells contributes to human-specific naive pluripotency regulation. KLF5-LTR7Y axis also promotes the expression of trophectoderm genes and contributes to the expanded cell potential toward extra-embryonic lineage. Our study suggests that HERVs are activated by cell-state-specific transcription machinery and promote stage-specific transcription network and cell potency.

Ursodeoxycholic Acid at 18-22 mg/kg/d Showed a Promising Capacity for Treating Refractory Primary Biliary Cholangitis.

Aim: To compare the response between the current recommended dosage 13-15 mg/kg/d and 20 mg/kg/d dose of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) patients who do not respond completely to a standard dose of UDCA. Methods: We included 73 patients with poor response and randomized them into two groups to investigate whether increasing the dosage of UDCA was beneficial to nonresponders. Patients assigned to the 13-15 mg/kg/d group continued with standard therapy, and participants in the 18-22 mg/kg/d group switched to the higher dosage (18-22 mg/kg/d), with a follow-up of 12 months for both groups. The primary endpoints were the rate of response at 6 months and drug side effects. Results: According to the Paris 2 criteria, patients receiving 18-22 mg/kg/d UDCA achieved a response rate of 59.4% compared with 36.1% in the standard dosage group (P=0.046) at 6 months, respectively. At 12 months, the high-UDCA-dosage group achieved a response rate of 59.4% compared with 47.2% in the standard dosage group (P=0.295), respectively. Additionally, the risk score predicted by the UK-PBC model was lower in high-dosage UDCA-treated patients than in the standard dosage group (all P < 0.05). Side effects include diarrhea, nausea and vomiting, rash, and newly developed high blood pressure, which were mild and tolerated. Conclusions: Patients treated with the high UDCA dosage showed some advantages over those who continued the standard dosage in terms of biochemical remission and disease progression, indicating that standard therapy with UDCA for 6 months and then another 1 year with high UDCA dosage for nonresponders could be a treatment option before second-line therapy is recommended.

Early-Stage Primary Anti-inflammatory Therapy Enhances the Regenerative Efficacy of Platelet-Rich Plasma in a Rabbit Achilles Tendinopathy Model.

BACKGROUND: Tendinopathy is a pervasive clinical problem that afflicts both athletes and the general public. Although the inflammatory changes in tendinopathy are well characterized, how the therapeutic effects of platelet-rich plasma (PRP) on tendinopathy are being modulated by the inflammatory environment is not well defined. PURPOSE/HYPOTHESIS: In this study, we aimed to compare the therapeutic effects of PRP alone versus a combination of PRP with a primary glucocorticoid (GC) injection at the early stage of tendinopathy. We hypothesized that PRP treatment could promote better tendon regeneration through the suppression of inflammation with GC. STUDY DESIGN: Controlled laboratory study. METHODS: The gene expression profile of tendon stem/progenitor cells (TSPCs) cultured with PRP was analyzed with RNA sequencing. To evaluate the cell viability, senescence, and apoptosis of TSPCs under different conditions, TSPCs were treated with 0.1 mg/mL triamcinolone acetonide (TA) and/or 10% PRP in an IL1B-induced inflammatory environment. To further verify the effects of the sequential therapy of GCs and PRP, an early tendinopathy animal model was established through a local injection of collagenase in the rabbit Achilles tendon. The tendinopathy model was then treated with isopycnic normal saline (NS group), TA (TA group), PRP (PRP group), or TA and PRP successively (TA+PRP group). At 8 weeks after treatment, the tendons were assessed with magnetic resonance imaging (MRI), histological examination, transmission electron microscopy (TEM), and mechanical testing. RESULTS: Gene Ontology enrichment analysis indicated that PRP treatment of TPSCs induced an inflammatory response, regulated cell migration, and remodeled the extracellular matrix. Compared with the sole use of PRP, successive treatment with TA followed by PRP yielded similar results in cell viability and senescence but less cell apoptosis in vitro. In vivo experiments demonstrated that the TA+PRP group achieved significantly better tendon regeneration, as confirmed by MRI, histological examination, TEM, and mechanical testing. CONCLUSION: This study showed that the primary use of GCs did not exert any obvious deleterious side effects on the treated tendon but instead enhanced the regenerative effects of PRP in early inflammatory tendinopathy. CLINICAL RELEVANCE: The sequential therapy of GCs followed by PRP provides a promising treatment strategy for tendinopathy in clinical practice. PRP combined with the primary use of GCs appears to promote tendon regeneration in early inflammatory tendinopathy.

MicroRNAs in autoimmune liver diseases: from diagnosis to potential therapeutic targets.

Autoimmune liver diseases (AILDs) are a group of liver disorders composed of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) characterized by chronic hepatic and biliary inflammation. Although several genetic factors, such as HLA alleles, TNFA, and CTLA-4, have been reported in the pathogenesis of AILDs, many details remain unknown. In recent years, microRNAs (miRNAs) have emerged as crucial components in the diagnosis and therapeutic applications of various autoimmune diseases, including systemic lupus erythematosus (SLE), glomerulonephritis, and AILDs. MiRNAs comprise a class of small, noncoding molecules of 19--25 nucleotides that modulate multiple genes by suppressing or degrading target mRNAs. Altered miRNA profiles have been identified in serum, immune cells, and live tissues from AILD patients. Elevated serum miR-21 and miR-122 levels in AIH patients as well as decreased miR-200c levels in PSC patients indicate their diagnostic utility. Highly expressed miR-122 and miR-378f as well as downregulated miR-4311 and miR-4714-3p in serum samples from refractory PBC patients suggest their potential to evaluate treatment efficacy. Moreover, miRNAs have been reported to participate in AILD development. Increased miR-506 levels may impair bile secretion in PBC by inhibiting Cl-/HCO3-anion exchanger 2 (AE2) and type III inositol 1,4,5-trisphosphate receptor-3 (InsP3R3). Additionally, different miRNA mimics or antagonists, such as atagomiR-155 and miR-223 mimics, have been widely applied in experimental AILD murine models with great efficacy. Here, we provide an overview of miRNAs in AILDs, aiming to summarize their potential roles in diagnosis and therapeutic interventions, and we discuss the challenges and future applications of miRNAs in clinical practice.

Brain-Derived Neurotrophic Factor Regulates Ishikawa Cell Proliferation through the TrkB-ERK1/2 Signaling Pathway.

(1) Background: Endometrial regulation is a necessary condition for maintaining normal uterine physiology, which is driven by many growth factors. Growth factors produced in the endometrium are thought to be related to the proliferation of endometrial cells induced by estradiol-17ß (E2). In this study, we found that E2 can induce the secretion of brain-derived neurotrophic factor (BDNF) in Ishikawa cells (the cells of an endometrial cell line). Furthermore, Ishikawa cells were used in exploring the regulatory role of BDNF in endometrial cells and to clarify the potential mechanism. (2) Methods: Ishikawa cells were treated with different concentrations of BDNF (100, 200, 300, 400, and 500 ng/mL). The mRNA expression levels of various proliferation-related genes were detected through quantitative reverse transcription polymerase chain reaction, and the expression of various proliferation-related genes was detected by knocking out BDNF or inhibiting the binding of BDNF to its receptor TrkB. The expression levels of various proliferation-related genes were detected by performing Western blotting on the TrkB-ERK1/2 signaling pathway. (3) Results: Exogenous BDNF promoted the growth of the Ishikawa cells, but the knocking down of BDNF or the inhibition of TrkB reduced their growth. Meanwhile, BDNF enhanced cell viability and increased the expression of proliferation-related genes, including cyclin D1 and cyclin E2. More importantly, the BDNF-induced proliferation of the Ishikawa cells involved the ERK1/2 signaling pathway. (4) Conclusions: The stimulating effect of exogenous E2 on the expression of BDNF in the uterus and the action of BDNF promoted the proliferation of the Ishikawa cells through the TrkB-ERK1/2 signal pathway.