Na3V2(PO4)3-decorated Na3V2(PO4)2F3 as a high-rate and cycle-stable cathode material for sodium ion batteries.

Since Na3V2(PO4)3 (NVP) possesses modest volume deformation and three-dimensional ion diffusion channels, it is a potential sodium-ion battery cathode material that has been extensively researched. Nonetheless, NVP still endures the consequences of poor electronic conductivity and low voltage platforms, which need to be further improved. On this basis, a high voltage platform Na3V2(PO4)2F3 was introduced to form a composite with NVP to increase the energy density. In this study, the sol-gel technique was successfully used to synthesize a Na3V2(PO4)2.75F0.75/C (NVPF·3NVP/C) composite cathode material. The citric acid-derived carbon layer was utilized to construct three-dimensional conducting networks to effectively promote ion and electron diffusion. Furthermore, the composites' synergistic effect accelerates the quick ionic migration and improves the kinetic reaction. In particular, NVP as the dominant phase enhanced the structural stability and significantly increased the capacitive contribution. Therefore, at 0.1C, the discharge capacity of the modified NVPF·3NVP/C composite is 120.7 mA h g-1, which is greater than the theoretical discharge capacity of pure NVP (118 mA h g-1). It discharged 110.9 mA h g-1 of reversible capacity even at an elevated multiplicity of 10C, and after 200 cycles, it retained 64.1% of its capacity. Thus, the effort produced an optimized NVPF·3NVP/C composite cathode material that may be used in the sodium ion cathode.

Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript.

Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family. Methods: A comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient's condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro. Results: The patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154-6 C > G in the WDR62 intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons. Conclusion: This study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2.

CGG repeat expansion in LOC642361/NUTM2B-AS1 typically presents as oculopharyngodistal myopathy.

CGG repeat expansions in LOC642361/NUTM2B-AS1 have recently been identified as a cause of oculopharyngeal myopathy with leukoencephalopathy. However, since only three patients from a single family were reported, it remains unknown whether their clinicopathological features are typical for CGG repeat expansions in LOC642361/NUTM2B-AS1. Here, using repeat-primed-polymerase chain reaction and long-read sequencing, we identify 12 individuals from 3 unrelated families with CGG repeat expansions in LOC642361/NUTM2B-AS1, typically presenting with oculopharyngodistal myopathy. The CGG repeat expansions range from 161 to 669 repeat units. Most of the patients present with ptosis, restricted eye movements, dysphagia, dysarthria, and diffuse limb muscle weakness. Only one patient shows T2-weighted hyperintensity in the cerebellar white matter surrounding the deep cerebellar nuclei on brain magnetic resonance imaging. Muscle biopsies from three patients show a myopathic pattern and rimmed vacuoles. Analyses of muscle biopsies suggest that CGG repeat expansions in LOC642361/NUTM2B-AS1 may deleteriously affect aggrephagic capacity, suggesting that RNA toxicity and mitochondrial dysfunction may contribute to pathogenesis. Our study thus expands the phenotypic spectrum for the CGG repeat expansion of LOC642361/NUTM2B-AS1 and indicates that this genetic variant typically manifests as oculopharyngodistal myopathy with chronic myopathic changes with rimmed vacuoles and filamentous intranuclear inclusions in muscle fibers.

Effects of rainfall amount and frequencies on soil net nitrogen mineralization in Gahai wet meadow in the Qinghai-Tibetan Plateau.

Global climate change has led to a significant increase in the frequency of extreme rainfall events in the Qinghai-Tibetan Plateau (QTP), thus potentially increasing the annual rainfall amounts and, consequently, affecting the net soil nitrogen (N) mineralization process. However, few studies on the responses of the soil net N mineralization rates to the increases in rainfall amounts and frequencies in alpine wet meadows have been carried out. Therefore, the present study aims to assess the effects of rainfall frequency and amount changes on the N fixation capacity of wet meadow soils by varying the rainfall frequency and amount in the Gahai wet meadow in the northeastern margin of the QTP during the plant-growing season in 2019. The treatment scenarios consisted of ambient rain (CK) and supplementary irrigation at a rate of 25 mm, with different irrigation frequencies, namely weekly (DF1), biweekly (DF2), every three weeks (DF3), and every four weeks (DF4). According to the obtained results, the increased rainfall frequency and amount decreased the soil mineral N stock and increased the aboveground vegetation biomass (AB) amounts and soil water contents in the wet meadows of the QTP. Ammonium (NH4+-N) and nitrate N (NO3--N) contributed similarly to the mineral N contents. However, the ammonification process played a major role in the soil mineralization process. The effects of increasing rainfall amount and frequency on N mineralization showed seasonal variations. The N mineralization rate showed a single-peaked curve with increasing soil temperature during the rapid vegetation growth phase, reaching the highest value in August. In addition, the N mineralization rates showed significant positive correlations with soil temperatures and NH4+-N contents and a significant negative correlation with AB (P < 0.05). The results of this study demonstrated the key role of low extreme rainfall event frequencies in increasing the net soil N mineralization rates in the vegetation growing season, which is detrimental to soil N accumulation, thereby affecting the effectiveness of soil N contents.

A Network Landscape of HPVOPC Reveals Methylation Alterations as Significant Drivers of Gene Expression via an Immune-Mediated GPCR Signal.

HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16-human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor-immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting.

Side-Chain-Dependent Functional Intercalations in Graphene Oxide Membranes for Selective Water and Ion Transport.

Subnanometer interlayer space in graphene oxide (GO) laminates is desirable for use as permselective membrane nanochannels. Although the facile modification of the local structure of GO enables various nanochannel functionalizations, precisely controlling nanochannel space is still a challenge, and the roles of confined nanochannel chemistry in selective water/ion separation have not been clearly defined. In this study, macrocyclic molecules with consistent basal plane but varying side groups were used to conjunct with GO for modified nanochannels in laminates. We demonstrated the side-group dependence of both the angstrom-precision tunability for channel free space and the energy barrier setting for ion transport, which challenges the permeability-selectivity trade-off with a slightly decreased permeance from 1.1 to 0.9 L m-2 h-1 bar-1 but an increased salt rejection from 85% to 95%. This study provides insights into the functional-group-dependent intercalation modifications of GO laminates for understanding laminate structural control and nanochannel design.

On-line multi-gas component measurement in the mud logging process based on Raman spectroscopy combined with a CNN-LSTM-AM hybrid model.

The qualitative and quantitative analysis of gas components extracted from drilling fluids during mud logging is essential for identifying drilling anomalies, reservoir characteristics, and hydrocarbon properties during oilfield recovery. Gas chromatography (GC) and gas mass spectrometers (GMS) are currently used for the online analysis of gases throughout the mud logging process. Nevertheless, these methods have limitations, including expensive equipment, high maintenance costs, and lengthy detection periods. Raman spectroscopy can be applied to the online quantification of gases at mud logging sites due to its in-situ analysis, high resolution, and rapid detection. However, laser power fluctuations, field vibrations, and the overlapping of characteristic peaks of different gases in the existing online detection system of Raman spectroscopy can affect the quantitative accuracy of the model. For these reasons, a gas Raman spectroscopy system with a high reliability, low detection limits, and increased sensitivity has been designed and applied to the online quantification of gases in the mud logging process. The near-concentric cavity structure is used to improve the signal acquisition module in the gas Raman spectroscopic system, thus enhancing the Raman spectral signal of the gases. One-dimensional convolutional neural networks (1D-CNN) combined with long- and short-term memory networks (LSTM) are applied to construct quantitative models based on the continuous acquisition of Raman spectra of gas mixtures. In addition, the attention mechanism is used to futher improve the quantitative model performance. The results indicated that our proposed method has the capability to continuously on-line detect 10 hydrocarbon and non-hydrocarbon gases in the mud logging process. The limitation of detection (LOD) for different gas components based on the proposed method are in the range of 0.0035%-0.0223%. Based on the proposed CNN-LSTM-AM model, the average detection errors of different gas components range from 0.899% to 3.521%, and their maximum detection errors range from 2.532% to 11.922%. These results demonstrate that our proposed method has a high accuracy, low deviation, and good stability and can be applied to the on-line gas analysis process in the mud logging field.

A Novel Hypomorphic Apex1 Mouse Model Implicates Apurinic/Apyrimidinic Endonuclease 1 in Oxidative DNA Damage Repair in Gastric Epithelial Cells.

Aims: Though best known for its role in oxidative DNA damage repair, apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that regulates multiple host responses during oxidative stress, including the reductive activation of transcription factors. As knockout of the APE1-encoding gene, Apex1, is embryonically lethal, we sought to create a viable model with generalized inhibition of APE1 expression. Results: A hypomorphic (HM) mouse with decreased APE1 expression throughout the body was generated using a construct containing a neomycin resistance (NeoR) cassette knocked into the Apex1 site. Offspring were assessed for APE1 expression, breeding efficiency, and morphology with a focused examination of DNA damage in the stomach. Heterozygotic breeding pairs yielded 50% fewer HM mice than predicted by Mendelian genetics. APE1 expression was reduced up to 90% in the lungs, heart, stomach, and spleen. The HM offspring were typically smaller, and most had a malformed tail. Oxidative DNA damage was increased spontaneously in the stomachs of HM mice. Further, all changes were reversed when the NeoR cassette was removed. Primary gastric epithelial cells from HM mice differentiated more quickly and had more evidence of oxidative DNA damage after stimulation with Helicobacter pylori or a chemical carcinogen than control lines from wildtype mice. Innovation: A HM mouse with decreased APE1 expression throughout the body was generated and extensively characterized. Conclusion: The results suggest that HM mice enable studies of APE1's multiple functions throughout the body. The detailed characterization of the stomach showed that gastric epithelial cells from HM were more susceptible to DNA damage. Antioxid. Redox Signal. 38, 183-197.

Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. RESULTS: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

Chromatin Accessibility and Transcriptional Differences in Human Stem Cell-Derived Early-Stage Retinal Organoids.

Retinogenesis involves the specification of retinal cell types during early vertebrate development. While model organisms have been critical for determining the role of dynamic chromatin and cell-type specific transcriptional networks during this process, an enhanced understanding of the developing human retina has been more elusive due to the requirement for human fetal tissue. Pluripotent stem cell (PSC) derived retinal organoids offer an experimentally accessible solution for investigating the developing human retina. To investigate cellular and molecular changes in developing early retinal organoids, we developed SIX6-GFP and VSX2-tdTomato (or VSX2-h2b-mRuby3) dual fluorescent reporters. When differentiated as 3D organoids these expressed GFP at day 15 and tdTomato (or mRuby3) at day 25, respectively. This enabled us to explore transcriptional and chromatin related changes using RNA-seq and ATAC-seq from pluripotency through early retina specification. Pathway analysis of developing organoids revealed a stepwise loss of pluripotency, while optic vesicle and retina pathways became progressively more prevalent. Correlating gene transcription with chromatin accessibility in early eye field development showed that retinal cells underwent a clear change in chromatin landscape, as well as gene expression profiles. While each dataset alone provided valuable information, considering both in parallel provided an informative glimpse into the molecular nature eye development.

GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.

OBJECTIVE: Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ptosis, dysarthria, ophthalmoplegia, and distal muscle weakness. Recent studies revealed that GGC repeat expansions in 5'-UTR of LRP12, GIPC1, and NOTCH2NLC are associated with OPDM. Despite these advances, approximately 30% of OPDM patients remain genetically undiagnosed. Herein, we aim to investigate the genetic basis for undiagnosed OPDM patients in two unrelated Chinese Han families. METHODS: Parametric linkage analysis was performed. Long-read sequencing followed by repeat-primed polymerase chain reaction and amplicon length polymerase chain reaction were used to determine the genetic cause. Targeted methylation sequencing was implemented to detect epigenetic changes. The possible pathogenesis mechanism was investigated by quantitative polymerase chain reaction, immunoblotting, RNA fluorescence in situ hybridization, and immunofluorescence staining of muscle biopsy samples. RESULTS: The disease locus was mapped to 12q24.3. Subsequently, GGC repeat expansion in the promoter region of RILPL1 was identified in six OPDM patients from two families, findings consistent with a founder effect, designated as OPDM type 4. Targeted methylation sequencing revealed hypermethylation at the RILPL1 locus in unaffected individuals with ultralong expansion. Analysis of muscle samples showed no significant differences in RILPL1 mRNA or RILPL1 protein levels between patients and controls. Public CAGE-seq data indicated that alternative transcription start sites exist upstream of the RefSeq-annotated RILPL1 transcription start site. Strand-specific RNA-seq data revealed bidirectional transcription from the RILPL1 locus. Finally, fluorescence in situ hybridization/immunofluorescence staining showed that both sense and antisense transcripts formed RNA foci, and were co-localized with hnRNPA2B1 and p62 in the intranuclear inclusions of OPDM type 4 patients. INTERPRETATION: Our findings implicate abnormal GGC repeat expansions in the promoter region of RILPL1 as a novel genetic cause for OPDM, and suggest a methylation mechanism and a potential RNA toxicity mechanism are involved in OPDM type 4 pathogenesis. ANN NEUROL 2022;92:512-526.

Effects of conservation tillage strategies on soil physicochemical indicators and N2O emission under spring wheat monocropping system conditions.

As one of the important greenhouse gas, nitrous oxide (N2O) has attracted much attention globally under climate change context. Agricultural practices are the main sources of greenhouse gas emissions. Nevertheless, scarcity of literature is available on the effects of different tillage measures on soil N2O emission under spring wheat (Triticum aestivum L.) ecosystem in the semi-arid area of the Loess Plateau. The main objective of the experimental study was to explore the influence of conservation tillage techniques on soil physicochemical properties, nitrous oxide emission and yield in the Northern semi-arid Dingxi region of China. Four treatments viz., conventional tillage (CT), no tillage (NT), straw mulch with conventional tillage (TS) and stubble-return with no-till (NTS) were evaluated under randomized complete block design with three replications. Our results depicted that compared with conventional tillage, bulk density and water content of topsoil was increased and soil pH value was reduced under conservation tillage techniques. Conservation tillage NT, TS and NTS increased organic carbon, TN, MBN and NH4+-N and reduced the accumulation of NO3-N. Additionally, although the N2O emission under NT, TS and NTS was 8.95, 41.90 and 21.05% respectively higher than under T treatment, the corresponding wheat yield was 15.40, 31.97 and 63.21% higher than T treatment. Moreover, correlation analysis showed that soil moisture and temperature were the most significant factors affecting soil N2O emission. The NTS treatment pointedly increased crop yield without significantly increasing soil N2O emission. Consequently, based on economic and environmental benefits and considering N2O emission and crop yield, we suggest that NTS technique is the best conservation tillage strategy in the semi-arid environmental zone of the Loess Plateau of Dingxi China.

Anti-ganglioside Antibodies in Guillain-Barre Syndrome: A Novel Immunoblotting-Panel Assay.

Objective: This study aimed to determine the diagnostic efficiency of a novel immunoblotting detection assay for anti-ganglioside antibodies (AGAs) in the Guillain-Barre syndrome (GBS). Method: Serum immunoglobulin (IgG and IgM) of AGAs were measured in 121 participants from a registered cohort study of immune-mediated neuropathies and 29 healthy controls by immunoblotting panel assay. Sensitivity, specificity, and positive predictive value (PPV) of the assay were compared to calculate the diagnostic accuracy. Result: In our cohort, any of the AGAs were positive in 42.4% of the GBS patients. The sensitivity and specificity of AGAs (both IgG and IgM) in the diagnosis of GSB were 42 and 76% while for IgG-AGAs were 35 and 87%. AGAs positivity had a significant association with the AMAN subtype (P = 0.0004), and the sensitivity, specificity of AGAs in AMAN were 86, 69%, respectively with high (AUC = 0.78, p = 0.002) discriminative powers. GM1-IgG AGA was more common and specific to AMAN patients than other GBS forms (p = 0.008). Conclusion: Our novel immunoblotting detection assay could complement GBS diagnosis. IgG-AGAs were more likely to be detected in GBS, and GM1-IgG AGA could assist AMAN diagnosis.

Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription.

PURPOSE: Human papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood. EXPERIMENTAL DESIGN: Forty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets. RESULTS: Our analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human-viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition. CONCLUSIONS: Nonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.

Progress and Perspectives of Desalination in China.

In recent decades, the ever-growing demands for clean water in households and industries have urged researchers to take every possible step to deal with the global water crisis. Seawater desalination has turned out to be the most promising and efficient way to provide clean water. Owing to the advancement of synthetic chemistries and technologies, great success has been achieved in the desalination and utilization of seawater worldwide. China, with the world's largest population, has pushed the development of desalination and multipurpose utilization of seawater further in respect of materials, technologies and services, etc. This review reports recent progress of desalination technologies accomplished in China, from the viewpoints of facilities and equipment, collaborations, technologies, applications, research abilities, services, and standard systems. Inspired by the Fourteenth Five-year Plan, it also proposes future perspectives of desalination in China.

Serum Uric Acid Levels Predict Mortality Risk in Male Amyotrophic Lateral Sclerosis Patients.

Objective: To explore the associations between serum uric acid levels with survival in male and female ALS patients. Methods: A longitudinal cohort study was carried out including 313 sporadic and 16 familial ALS patients with repeated serum uric acid measurements. Multivariate Cox regression models were used to evaluate the survival-related factors. Results: There were 207 male and 122 female, and the mean age of onset was 55.7 ± 11.2 years old. The male patients had significantly higher baseline uric acid levels than that in female patients (342.4 ± 91.4 vs. 279.3 ± 71.4 µmol/L; p < 0.0001). The uric acid levels were inversely associated with the decline rate of ALSFRS-R per month (ΔALSFRS-R). After multivariate Cox regression analysis, a survival advantage was found in male, but not female, with higher serum uric acid levels. In males, a shorter diagnostic delay (≤10 m), lower BMI at baseline (≤18.70 kg/m2), faster disease progression (ΔALSFRS-R > 0.63), and lower baseline uric acid levels (≤292 µmol/L, HR: 1.936; 95% CI: 1.334-2.810) were associated with a shorter survival. During follow-up, the serum uric acid levels were not significantly altered over time. Conclusion: There is an inverse correlation between baseline serum uric acid levels and risk of death, prominently in male ALS patients.

Dust-mite-derived protein disulfide isomerase suppresses airway allergy by inducing tolerogenic dendritic cells.

House dust mites (HDMs) are a potent allergen source that are commonly found in human living environments. While HDMs are known to induce allergic diseases in humans, such as asthma, its other biological activities related to human health are less understood. Our laboratory recently purified the HDM protein PDI (protein disulfide isomerase). In this study, we assess the role of PDI in contributing to immune regulation. Using mass spectrometry, we analyzed the complexes of DEC205 and HDM extracts, and the role of PDI in the induction of tolerogenic dendritic cells (DCs) was assessed in human cell culture experiments and verified in a murine model. We found that more than 20 HDM-derived proteins, including PDI, bound to DCs by forming complexes with DEC205. Additionally, DEC205-mediated the endocytosis of PDI. HDM-derived PDI (HDM-PDI) promoted Foxp3 expression in DCs. HDM-PDI-primed DCs also showed tolerogenic properties that induced regulatory T cell development, indicating that the primed DCs were tolerogenic DCs. Our results suggested that the PDI/DEC205/TIEG1/Foxp3 signal pathway activation was involved in the HDM-PDI-induced Foxp3 expression in DCs. Finally, we found that HDM-PDI competitively counteracted the Th2 cytokines to restore DC's tolerogenicity, and administration of HDM-PDI could suppress experimental asthma. In conclusion, our data suggest that HDM-PDI contributes to immune regulation by inducing tolerogenic DC development. Administration of HDM-PDI can alleviate experimental asthma. These findings demonstrate that HDM-PDI has translational potential to be used in the treatment of immune disorders such as asthma.

Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.

Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3ß isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.