scGRN: a comprehensive single-cell gene regulatory network platform of human and mouse.

Gene regulatory networks (GRNs) are interpretable graph models encompassing the regulatory interactions between transcription factors (TFs) and their downstream target genes. Making sense of the topology and dynamics of GRNs is fundamental to interpreting the mechanisms of disease etiology and translating corresponding findings into novel therapies. Recent advances in single-cell multi-omics techniques have prompted the computational inference of GRNs from single-cell transcriptomic and epigenomic data at an unprecedented resolution. Here, we present scGRN (https://bio.liclab.net/scGRN/), a comprehensive single-cell multi-omics gene regulatory network platform of human and mouse. The current version of scGRN catalogs 237 051 cell type-specific GRNs (62 999 692 TF-target gene pairs), covering 160 tissues/cell lines and 1324 single-cell samples. scGRN is the first resource documenting large-scale cell type-specific GRN information of diverse human and mouse conditions inferred from single-cell multi-omics data. We have implemented multiple online tools for effective GRN analysis, including differential TF-target network analysis, TF enrichment analysis, and pathway downstream analysis. We also provided details about TF binding to promoters, super-enhancers and typical enhancers of target genes in GRNs. Taken together, scGRN is an integrative and useful platform for searching, browsing, analyzing, visualizing and downloading GRNs of interest, enabling insight into the differences in regulatory mechanisms across diverse conditions.

LncSEA 2.0: an updated platform for long non-coding RNA related sets and enrichment analysis.

Long non-coding RNAs (lncRNAs) possess a wide range of biological functions, and research has demonstrated their significance in regulating major biological processes such as development, differentiation, and immune response. The accelerating accumulation of lncRNA research has greatly expanded our understanding of lncRNA functions. Here, we introduce LncSEA 2.0 (http://bio.liclab.net/LncSEA/index.php), aiming to provide a more comprehensive set of functional lncRNAs and enhanced enrichment analysis capabilities. Compared with LncSEA 1.0, we have made the following improvements: (i) We updated the lncRNA sets for 11 categories and extremely expanded the lncRNA scopes for each set. (ii) We newly introduced 15 functional lncRNA categories from multiple resources. This update not only included a significant amount of downstream regulatory data for lncRNAs, but also covered numerous epigenetic regulatory data sets, including lncRNA-related transcription co-factor binding, chromatin regulator binding, and chromatin interaction data. (iii) We incorporated two new lncRNA set enrichment analysis functions based on GSEA and GSVA. (iv) We adopted the snakemake analysis pipeline to track data processing and analysis. In summary, LncSEA 2.0 offers a more comprehensive collection of lncRNA sets and a greater variety of enrichment analysis modules, assisting researchers in a more comprehensive study of the functional mechanisms of lncRNAs.

Two Calcium Sensor-Activated Kinases Function in Root Hair Growth.

Plant pollen tubes and root hairs typical polarized tip growth. It is well established that calcium ions (Ca2+) play essential roles in maintaining cell polarity and guiding cell growth orientation. Ca2+ signals are encoded by Ca2+ channels and transporters and are decoded by a variety of Ca2+-binding proteins often called Ca2+ sensors, in which calcineurin B-like protein (CBL) proteins function by interacting with and activating a group of kinases, activate CBL-interacting protein kinases (CIPKs). Some CBL-CIPK complexes, such as CBL2/3-CIPK12/19, act as crucial regulators of pollen tube growth. Whether these calcium decoding components regulate the growth of root hairs, another type of plant cell featuring Ca2+-regulated polarized growth, remains unknown. In this study, we identified CIPK13 and CIPK18 as genes specifically expressed in Arabidopsis (Arabidopsis thaliana) root hairs. The cipk13 cipk18 double mutants showed reduced root hair length and lower growth rates. The calcium oscillations at the root hair tip were attenuated in the cipk13 cipk18 mutants as compared to the wild-type plants. Through yeast two-hybrid screens, CBL2 and CBL3 were identified as interacting with CIPK13 and CIPK18. cbl2 cbl3 displayed a shortened root hair phenotype similar to cipk13 cipk18. This genetic analysis, together with biochemical assays showing activation of CIPK13/18 by CBL2/3, supported the conclusion that CBL2/3 and CIPK13/18 may work as Ca2+-decoding modules in controlling root hair growth. Thus, the findings that CIPK12/19 and CIPK13/18 function in pollen tube and root hair growth, respectively, illustrate a molecular mechanism in which the same CBLs recruit distinct CIPKs in regulating polarized tip growth in different types of plant cells.

Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling.

Asthma is a heterogeneous disease characterized by chronic airway inflammation, reversible airflow limitation, and airway remodeling. Eosinophil peroxidase (EPX) is the most abundant secondary granule protein unique to activated eosinophils. In this study, we aimed to illustrate the effect of EPX on the epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Our research found that both EPX and ADAM33 were negatively correlated with FEV1/FVC and FEV1%pred, and positively correlated with IL-5 levels. Asthma patients had relatively higher levels of ADAM33 and EPX compared to the healthy control group. The expression of TSLP, TGF-ß1 and ADAM33 in the EPX intervention group was significantly higher. Moreover, EPX could promote the proliferation, migration and EMT of BEAS-2B cells, and the effect of EPX on various factors was significantly improved by the PI3K inhibitor LY294002. The findings from this study could potentially offer a novel therapeutic target for addressing airway remodeling in bronchial asthma, particularly focusing on EMT.

Baicalein promotes KDM4E to induce BICD1 and inhibit triple-negative breast cancer progression by blocking PAR1 signaling.

Baicalein has been implicated in the chemotherapy overcoming triple-negative breast cancer (TNBC). However, many unanswered questions remain regarding its role in treating TNBC. Here, we sought to demonstrate the molecular pathway mediated by baicalein in TNBC. Lysine-specific demethylase 4E (KDM4E), reduced in TNBC cells, was identified as a target protein of baicalein, and baicalein enhanced the protein expression and stability of KDM4E in TNBC cells. Knockdown of KDM4E attenuated the inhibitory effect of baicalein on TNBC cell activity, as demonstrated by intensified mobility, viability, and apoptosis resistance in TNBC cells. KDM4E activated protein bicaudal D homolog 1 (BICD1) expression by reducing the deposition of histone H3 lysine 9 trimethylation (H3K9me3) in its promoter, whereas BICD1 promoted protease-activated receptor-1 (PAR1) endocytosis and blocked PAR1 signaling through physical interaction with PAR1. Knockdown of KDM4E strengthened the PAR1-dependent activity of TNBC cells in response to thrombin activation, whereas TNBC progression activated by PAR1 signaling was blocked by combined overexpression of BICD1. Taken together, our data indicate that baicalein-promoted KDM4E enhanced the expression of BICD1 and activated the inhibitory effect of BICD1 on PAR1 signaling, thereby inhibiting TNBC progression.

Prevalence of Late-Stage Parkinson's Disease in the US Healthcare System: Insights from TriNetX.

BACKGROUND: Patients in late-stage Parkinson's disease (PDLS) are caregiver-dependent, have low quality of life, and higher healthcare costs. OBJECTIVE: To estimate the prevalence of PDLS patients in the current US healthcare system. METHODS: We downloaded the 2010-2022 data from the TriNetX Diamond claims network that consists of 92 US healthcare sites. PD was identified using standard diagnosis codes, and PDLS was identified by the usage of wheelchair dependence, personal care assistance, and/or presence of diagnoses of dementia. Age of PDLS identification and survival information were obtained and stratified by demographic and the disability subgroups. RESULTS: We identified 1,031,377 PD patients in the TriNetX database. Of these, 18.8% fitted our definition of PDLS (n = 194,297), and 10.2% met two or more late-stage criteria. Among all PDLS, the mean age of PDLS identification was 78.1 (±7.7) years, and 49% were already reported as deceased. PDLS patients were predominantly male (58.5%) with similar distribution across PDLS subgroups. The majority did not have race (71%) or ethnicity (69%) information, but for the available information >90% (n = 53,162) were White, 8.2% (n = 5121) Hispanic/Latino, 7.8% (n = 4557) Black, and <0.01% (n = 408) Asian. Of the PDLS cohort, 71.6% identified with dementia, 12.9% had personal care assistance, and 4.8% were wheelchair-bound. CONCLUSIONS: Late-stage patients are a significant part of the PD landscape in the current US healthcare system, and largely missed by traditional motor-based disability staging. It is imperative to include this population as a clinical, social, and research priority. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

TF-Marker: a comprehensive manually curated database for transcription factors and related markers in specific cell and tissue types in human.

Transcription factors (TFs) play key roles in biological processes and are usually used as cell markers. The emerging importance of TFs and related markers in identifying specific cell types in human diseases increases the need for a comprehensive collection of human TFs and related markers sets. Here, we developed the TF-Marker database (TF-Marker, http://bio.liclab.net/TF-Marker/), aiming to provide cell/tissue-specific TFs and related markers for human. By manually curating thousands of published literature, 5905 entries including information about TFs and related markers were classified into five types according to their functions: (i) TF: TFs which regulate expression of the markers; (ii) T Marker: markers which are regulated by the TF; (iii) I Marker: markers which influence the activity of TFs; (iv) TFMarker: TFs which play roles as markers and (v) TF Pmarker: TFs which play roles as potential markers. The 5905 entries of TF-Marker include 1316 TFs, 1092 T Markers, 473 I Markers, 1600 TFMarkers and 1424 TF Pmarkers, involving 383 cell types and 95 tissue types in human. TF-Marker further provides a user-friendly interface to browse, query and visualize the detailed information about TFs and related markers. We believe TF-Marker will become a valuable resource to understand the regulation patterns of different tissues and cells.

An intelligent grasper to provide real-time force feedback to shorten the learning curve in laparoscopic training.

BACKGROUND: A lack of force feedback in laparoscopic surgery often leads to a steep learning curve to the novices and traditional training system equipped with force feedback need a high educational cost. This study aimed to use a laparoscopic grasper providing force feedback in laparoscopic training which can assist in controlling of gripping forces and improve the learning processing of the novices. METHODS: Firstly, we conducted a pre-experiment to verify the role of force feedback in gripping operations and establish the safe gripping force threshold for the tasks. Following this, we proceeded with a four-week training program. Unlike the novices without feedback (Group A2), the novices receiving feedback (Group B2) underwent training that included force feedback. Finally, we completed a follow-up period without providing force feedback to assess the training effect under different conditions. Real-time force parameters were recorded and compared. RESULTS: In the pre-experiment, we set the gripping force threshold for the tasks based on the experienced surgeons' performance. This is reasonable as the experienced surgeons have obtained adequate skill of handling grasper. The thresholds for task 1, 2, and 3 were set as 0.731 N, 1.203 N and 0.938 N, respectively. With force feedback, the gripping force applied by the novices with feedback (Group B1) was lower than that of the novices without feedback (Group A1) (p < 0.005). During the training period, the Group B2 takes 6 trails to achieve gripping force of 0.635 N, which is lower than the threshold line, whereas the Group A2 needs 11 trails, meaning that the learning curve of Group B2 was significantly shorter than that of Group A2. Additionally, during the follow-up period, there was no significant decline in force learning, and Group B2 demonstrated better control of gripping operations. The training with force feedback received positive evaluations. CONCLUSION: Our study shows that using a grasper providing force feedback in laparoscopic training can help to control the gripping force and shorten the learning curve. It is anticipated that the laparoscopic grasper equipped with FBG sensor is promising to provide force feedback during laparoscopic training, which ultimately shows great potential in laparoscopic surgery.

High-Yield α-Synuclein Purification and Ionic Strength Modification Pivotal to Seed Amplification Assay Performance and Reproducibility.

Alpha-synuclein seed amplification assays (αSyn-SAAs) have emerged as promising diagnostic tools for Parkinson's disease (PD) by detecting misfolded αSyn and amplifying the signal through cyclic shaking and resting in vitro. Recently, our group and others have shown that multiple biospecimens, including CSF, skin, and submandibular glands (SMGs), can be used to seed the aggregation reaction and robustly distinguish between patients with PD and non-disease controls. The ultrasensitivity of the assay affords the ability to detect minute quantities of αSyn in peripheral tissues, but it also produces various technical challenges of variability. To address the problem of variability, we present a high-yield αSyn protein purification protocol for the efficient production of monomers with a low propensity for self-aggregation. We expressed wild-type αSyn in BL21 Escherichia coli, lysed the cells using osmotic shock, and isolated αSyn using acid precipitation and fast protein liquid chromatography (FPLC). Following purification, we optimized the ionic strength of the reaction buffer to distinguish the fluorescence maximum (Fmax) separation between disease and healthy control tissues for enhanced assay performance. Our protein purification protocol yielded high quantities of αSyn (average: 68.7 mg/mL per 1 L of culture) and showed highly precise and robust αSyn-SAA results using brain, skin, and SMGs with inter-lab validation.

Effects of asiaticoside on the model of gestational diabetes mellitus in HTR-8/svneo cells via PI3K/AKT pathway.

BACKGROUND: Asiaticoside (AS) has been reported to improve the changes induced by high glucose stimulation, and it may have potential therapeutic effects on gestational diabetes mellitus (GDM). This study aims to explore the effect of AS on the cell model of GDM and the action mechanism of the PI3K/AKT pathway. METHODS: The GDM model was established in HTR-8/Svneo cells with a high glucose (HG) medium. After the cytotoxicity assay of AS, cells were divided into the control group, HG group and HG + AS group to conduct control experiment in cells. The cell proliferation and migration were detected by CCK-8 assay and scratch test, respectively. The mRNA levels of PI3K, AKT2, mTORC1, and GLUT4 in PI3K/AKT signalling pathway were measured by RT-PCR, and the protein expressions of these signalling molecules were monitored by western blot. RESULTS: AS showed a promotion effect on the cell proliferation rate of HTR-8/Svneo cells, and 80 µmol/L AS with a treatment time of 48 h had no cytotoxicity. The cell proliferation rate, migration rate, mRNA levels and protein expressions of PI3K, AKT2, mTORC1, and GLUT4 in the HG group were significantly lower than those in the control group, which were significantly increased in the HG + AS group (p < 0.05). CONCLUSIONS: AS can facilitate the cell proliferation and migration in the cell model of GDM, and might play a role in GDM treatment via PI3K/AKT pathway.

Asiaticoside possesses various pharmacological effects and has been reported to show a beneficial effect on the treatment of diabetes mellitus. This research firstly investigated the effect and mechanism of asiaticoside on gestational diabetes mellitus, and found that asiaticoside could facilitate the cell proliferation and migration of HTR-8/Svneo cells treated with high glucose, and affect the signalling molecules of PI3K/AKT pathway. Therefore, asiaticoside may be a novel useful therapeutic drug in the treatment of gestational diabetes mellitus.

Biochemistry and Protein Interactions of the CYREN Microprotein.

Over the past decade, advances in genomics have identified thousands of additional protein-coding small open reading frames (smORFs) missed by traditional gene finding approaches. These smORFs encode peptides and small proteins, commonly termed micropeptides or microproteins. Several of these newly discovered microproteins have biological functions and operate through interactions with proteins and protein complexes within the cell. CYREN1 is a characterized microprotein that regulates double-strand break repair in mammalian cells through interaction with Ku70/80 heterodimer. Ku70/80 binds to and stabilizes double-strand breaks and recruits the machinery needed for nonhomologous end join repair. In this study, we examined the biochemical properties of CYREN1 to better understand and explain its cellular protein interactions. Our findings support that CYREN1 is an intrinsically disordered microprotein and this disordered structure allows it to enriches several proteins, including a newly discovered interaction with SF3B1 via a distinct short linear motif (SLiMs) on CYREN1. Since many microproteins are predicted to be disordered, CYREN1 is an exemplar of how microproteins interact with other proteins and reveals an unknown scaffolding function of this microprotein that may link NHEJ and splicing.

Natural Carrier-Free Binary Small Molecule Self-Assembled Hydrogel Synergize Antibacterial Effects and Promote Wound Healing by Inhibiting Virulence Factors and Alleviating the Inflammatory Response.

Methicillin-resistant Staphylococcus aureus (MRSA)-infected skin wounds have caused a variety of diseases and seriously endanger global public health. Therefore, multidimensional strategies are urgently to find antibacterial dressings to combat bacterial infections. Antibacterial hydrogels are considered potential wound dressing, while their clinical translation is limited due to the unpredictable risks and high costs of carrier excipients. it is found that the natural star antibacterial and anti-inflammatory phytochemicals baicalin (BA) and sanguinarine (SAN) can directly self-assemble through non-covalent bonds such as electrostatic attraction, π-π stacking, and hydrogen bonding to form carrier-free binary small molecule hydrogel. In addition, BA-SAN gel exhibited a synergistic inhibitory effect on MRSA. And its plasticity and injectability allowed it to be applied as a wound dressing. Due to the matched physicochemical properties and synergistic therapeutic effects, BA-SAN gel can inhibit bacterial virulence factors, alleviate wound inflammation, promote wound healing, and has good biocompatibility. The current study not only provided an antibacterial hydrogel with clinical value but also opened up new prospects that carrier-free hydrogels can be designed and originated from clinically used small-molecule phytochemicals.

Vascular and pulmonary effects of ibuprofen on neonatal lung development.

BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). METHODS: We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. RESULTS: Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. CONCLUSIONS: In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

Susceptibility Magnetic Resonance Imaging Correlates with Glial Density and Tau in the Substantia Nigra Pars Compacta.

BACKGROUND: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration. OBJECTIVE: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden. METHODS: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression. RESULTS: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden. CONCLUSIONS: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.

Thyrotropin receptor autoantibody (TRAb) enhance the expression of thyrotropin receptor on mouse brain vascular endothelial cells: in vivo and in vitro.

The possibility that thyrotropin receptor (TSHR) expression in non-thyroid tissue is well-documented. However, there is insufficient data on the expression of TSHR in medulla oblongata regions, particularly when focusing on the background of encephalopathy associated with hyperthyroidism. In this study, we explored the expression of the functional TSHR in Graves' disease (GD) mouse cerebral vascular endothelial cells and the effects of thyrotropin receptor autoantibody (TRAb) on its expression. A mouse model of GD was constructed with an adenovirus overexpressing TSHR289. The location and expression of the TSHR gene and protein in vivo were determined via RT-qPCR, Western blot, and immunofluorescence techniques. The effect of TRAb on the expression of functional TSHR in vitro was investigated using bEnd.3 cells. Our results show that medulla oblongata vascular endothelial cells from GD mice expressed higher levels of TSHR compared to control mice. In an in vitro experiment, novel results demonstrated that after treatment with a monoclonal TSHR-specific agonistic antibody (M22), the expression of TSHR on the bEnd.3 cells increased at both the protein and mRNA levels. Furthermore, compared with bEnd.3 cells were treated with IBMX only, those treated with M22 showed increased cAMP production. This study suggested that TSHR is expressed and functionally active in the mouse medulla oblongata and in vitro-cultured bEnd.3 cells and TRAb (M22) increased the expression of TSHR on bEnd.3 cells.

Association of Ureaplasma infection pattern and azithromycin treatment effect with bronchopulmonary dysplasia in Ureaplasma positive infants: a cohort study.

BACKGROUND: It is unclear whether Ureaplasma-associated pneumonia and azithromycin treatment affect the risk for bronchopulmonary dysplasia (BPD). METHODS: A retrospective cohort study was performed in very low birth weight (VLBW) infants who tested positive for Ureaplasma within 72 h after birth in a tertiary unit. Chest X-ray (CXR) and laboratory test were performed before and after azithromycin treatment. Multivariate logistic regression analysis was used to identify the independent association between BPD and Ureaplasma-associated pneumonia, as well as BPD and effective azithromycin treatment. RESULTS: A total of 118 infants were included in the current study, of whom 36 developed BPD (defined as supplemental oxygen needed at postmenstrual age 36 weeks or discharge). The rate of BPD was significantly higher in infants with Ureaplasma-associated pneumonia (44.6%) compared to infants with Ureaplasma colonization (17.7%, P = 0.002). After adjusting for confounders, an effective azithromycin treatment was significantly associated with reduced risk of BPD [odd ratio (OR) 0.011; 95% confidence interval (CI): 0.000-0.250), whereas Ureaplasma-associated pneumonia was not significantly associated with BPD (OR 1.835; 95% CI: 0.548-6.147). CONCLUSION: Effective Azithromycin treatment in Ureaplasma positive VLBW infants was associated with a reduced risk of BPD.

Structural features on quantitative chest computed tomography of patients with maximal mid-expiratory flow impairment in a normal lung function population.

BACKGROUND: Maximal mid-expiratory flow (MMEF) is an earlier predictor of chronic obstructive pulmonary disease (COPD) development than forced expiratory volume in 1 s (FEV1). Changes of lung structure in patients with MMEF impairment only is still not clear. Therefore, this study aimed to investigate the structural features of patients with decreased MMEF by quantitative computed tomography (QCT) and develop a predictive model for predicting patients with reduced MMEF in normal lung function population. METHODS: In this study, 131 patients with normal spirometry results and available volumetric chest CT images were enrolled and divided into the reduced MMEF group (FEV1/forced expiratory vital capacity (FEV1/FVC) > 0.7, FEV1% predictive values (FEV1%pred) > 80%, MMEF%pred < 80%, n = 52) and the normal MMEF group (FEV1/FVC > 0.7, FEV1%pred > 80%, MMEF%pred ≥ 80%, n = 79). The emphysema, small airway disease and medium-size airway parameters were measured by a commercial software. The differences were investigated in clinical features, spirometrical parameters and QCT parameters between the two groups. A nomogram model was constructed based on the results of the multivariable logistic regression model. Spearman's correlation coefficients were calculated between QCT measurements and spirometrical parameters. RESULTS: There were more males in reduced MMEF group than normal group (P < 0.05). Lung parenchyma parameter (PRMEmph) and airway-related parameters (functional small airway disease (PRMfSAD), luminal area of fifth- and sixth- generation airway (LA5, LA6) were significantly different between the reduced MMEF group and the normal group (20.2 ± 17.4 vs 9.4 ± 6.7, 3.4 ± 3.5 vs 1.9 ± 2.0, 12.2 ± 2.5 vs 13.7 ± 3.4, 7.7 ± 2.4 vs 8.9 ± 2.8, respectively, all P < 0.01). After multivariable logistical regression, only sex (odds ratio [OR]: 2.777; 95% confidence interval [CI]:1.123-3.867), PRMfSAD (OR:1.102, 95%CI:1.045-1.162) and LA6 (OR:0.650, 95%CI:0.528-0.799) had significant differences between the two groups (P < 0.05) and a model incorporating with the three indicators was constructed (area under curve, 0.836). Correlation analysis showed MMEF%pred had mild to moderate correlation with airway-related measurements. CONCLUSION: In normal lung function population, patients with reduced MMEF have potential medium-size and small airway changes, and MMEF%pred is significantly associated with airway-related CT parameters. The nomogram incorporating with sex, PRMfSAD and LA6 has good predictive value and offers more objective evidences in a group with reduced MMEF.

Asiaticoside hampers epithelial-mesenchymal transition by promoting PPARG expression and suppressing P2RX7-mediated TGF-ß/Smad signaling in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes because of its high propensity to develop metastases. Here, the anticancer effects of asiaticoside (AC) against TNBC and the possible underlying mechanism were examined. We found that AC inhibited the TGF-ß1 expression and the SMAD2/3 phosphorylation in TNBC cells, thereby impairing the TGF-ß/SMAD signaling. AC inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of TNBC cells by suppressing the TGF-ß/SMAD signaling. Meanwhile, AC inhibited the lung metastasis of TNBC cells in vivo and the expression of p-SMAD2/3 and vimentin, and increased the expression of E-cadherin and ZO-1 in the lung. Peroxisome proliferator activated receptor gamma (PPARG) was identified as a potential target of AC. AC increased PPARG expression, while PPARG knockdown attenuated the therapeutic effect of AC. AC-mediated PPARG overexpression suppressed the transcription of P2X purinoceptor 7 (P2RX7). The restoration of P2RX7 reversed the therapeutic effect of AC. These results suggested that AC blocked P2RX7-mediated TGF-ß/SMAD signaling by increasing PPARG expression, thereby suppressing EMT in TNBC.

Kinase SnRK1.1 regulates nitrate channel SLAH3 engaged in nitrate-dependent alleviation of ammonium toxicity.

Nitrate (NO3-) and ammonium (NH4+) are major inorganic nitrogen (N) supplies for plants, but NH4+ as the sole or dominant N source causes growth inhibition in many plants, known as ammonium toxicity. Small amounts of NO3- can significantly mitigate ammonium toxicity, and the anion channel SLAC1 homolog 3 (SLAH3) is involved in this process, but the mechanistic detail of how SLAH3 regulates nitrate-dependent alleviation of ammonium toxicity is still largely unknown. In this study, we identified SnRK1.1, a central regulator involved in energy homeostasis, and various stress responses, as a SLAH3 interactor in Arabidopsis (Arabidopsis thaliana). Our results suggest that SNF1-related protein kinase 1 (SnRK1.1) functions as a negative regulator of SLAH3. Kinase assays indicate SnRK1.1 strongly phosphorylates the C-terminal of SLAH3 at the site S601. Under high-NH4+/low-pH condition, phospho-mimetic and phospho-dead mutations in SLAH3 S601 result in barely rescued phenotypes and fully complemented phenotypes in slah3. Furthermore, SnRK1.1 migrates from cytoplasm to nucleus under high-NH4+/low-pH conditions. The translocation of SnRK1.1 from cytosol to nucleus under high-ammonium stress releases the inhibition on SLAH3, which allows SLAH3-mediated NO3- efflux leading to alleviation of high-NH4+/low-pH stress. Our study reveals that the C-terminal phosphorylation also plays important role in SLAH3 regulation and provides additional insights into nitrate-dependent alleviation of ammonium toxicity in plants.

Subtyping preserved ratio impaired spirometry (PRISm) by using quantitative HRCT imaging characteristics.

BACKGROUND: Preserved Ratio Impaired Spirometry (PRISm) is defined as FEV1/FVC ≥ 70% and FEV1 < 80%pred by pulmonary function test (PFT). It has highly prevalence and is associated with increased respiratory symptoms, systemic inflammation, and mortality. However, there are few radiological studies related to PRISm. The purpose of this study was to investigate the quantitative high-resolution computed tomography (HRCT) characteristics of PRISm and to evaluate the correlation between quantitative HRCT parameters and pulmonary function parameters, with the goal of establishing a nomogram model for predicting PRISm based on quantitative HRCT. METHODS: A prospective and continuous study was performed in 488 respiratory outpatients from February 2020 to February 2021. All patients underwent both deep inspiratory and expiratory CT examinations, and received pulmonary function test (PFT) within 1 month. According to the exclusion criteria and Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification standard, 94 cases of normal pulmonary function, 51 cases of PRISm and 48 cases of mild to moderate chronic obstructive lung disease (COPD) were included in the study. The lung parenchyma, parametric response mapping (PRM), airway and vessel parameters were measured by automatic segmentation software (Aview). One-way analysis of variance (ANOVA) was used to compare the differences in clinical features, pulmonary function parameters and quantitative CT parameters. Spearman rank correlation analysis was used to evaluate the correlation between CT quantitative index and pulmonary function parameters. The predictors were obtained by binary logistics regression analysis respectively in normal and PRISm as well as PRISm and mild to moderate COPD, and the nomogram model was established. RESULTS: There were significant differences in pulmonary function parameters among the three groups (P < 0.001). The differences in pulmonary parenchyma parameters such as emphysema index (EI), pixel indices-1 (PI-1) and PI-15 were mainly between mild to moderate COPD and the other two groups. The differences of airway parameters and pulmonary vascular parameters were mainly between normal and the other two groups, but were not found between PRISm and mild to moderate COPD. Especially there were significant differences in mean lung density (MLD) and the percent of normal in PRM (PRMNormal) among the three groups. Most of the pulmonary quantitative CT parameters had mild to moderate correlation with pulmonary function parameters. The predictors of the nomogram model using binary logistics regression analysis to distinguish normal from PRISm were smoking, MLD, the percent of functional small airways disease (fSAD) in PRM (PRMfSAD) and Lumen area. It had a good goodness of fit (χ2 = 0.31, P < 0.001) with the area under curve (AUC) value of 0.786. The predictor of distinguishing PRISm from mild to moderate COPD were PRMEmph (P < 0.001, AUC = 0.852). CONCLUSIONS: PRISm was significantly different from subjects with normal pulmonary function in small airway and vessel lesions, which was more inclined to mild to moderate COPD, but there was no increase in pulmonary parenchymal attenuation. The nomogram based on quantitative HRCT parameters has good predictive value and provide more objective evidence for the early screening of PRISm.