Fragmentomics of plasma mitochondrial and nuclear DNA inform prognosis in COVID-19 patients with critical symptoms.

BACKGROUND: The mortality rate of COVID-19 patients with critical symptoms is reported to be 40.5%. Early identification of patients with poor progression in the critical cohort is essential to timely clinical intervention and reduction of mortality. Although older age, chronic diseases, have been recognized as risk factors for COVID-19 mortality, we still lack an accurate prediction method for every patient. This study aimed to delve into the cell-free DNA fragmentomics of critically ill patients, and develop new promising biomarkers for identifying the patients with high mortality risk. METHODS: We utilized whole genome sequencing on the plasma cell-free DNA (cfDNA) from 33 COVID-19 patients with critical symptoms, whose outcomes were classified as survival (n = 16) and death (n = 17). Mitochondrial DNA (mtDNA) abundance and fragmentomic properties of cfDNA, including size profiles, ends motif and promoter coverages were interrogated and compared between survival and death groups. RESULTS: Significantly decreased abundance (~ 76% reduction) and dramatically shorter fragment size of cell-free mtDNA were observed in deceased patients. Likewise, the deceased patients exhibited distinct end-motif patterns of cfDNA with an enhanced preference for "CC" started motifs, which are related to the activity of nuclease DNASE1L3. Several dysregulated genes involved in the COVID-19 progression-related pathways were further inferred from promoter coverages. These informative cfDNA features enabled a high PPV of 83.3% in predicting deceased patients in the critical cohort. CONCLUSION: The dysregulated biological processes observed in COVID-19 patients with fatal outcomes may contribute to abnormal release and modifications of plasma cfDNA. Our findings provided the feasibility of plasma cfDNA as a promising biomarker in the prognosis prediction in critically ill COVID-19 patients in clinical practice.

Prediction of Unexplained Recurrent Miscarriages Using Thromboelastography.

Objective: This study investigates the thromboelastography (TEG) changes in patients with unexplained recurrent spontaneous abortion (URSA) to identify effective diagnostic markers for URSA. Methods: We retrospectively analyzed 160 URSA patients from the Gynecology Department of the First People's Hospital of Lianyungang (June 2017 - June 2020) and compared them with 190 healthy, fertile women without adverse pregnancy histories (control group). TEG parameters were assessed using logistic regression, applying stepwise selection for model optimization. Model performance was evaluated using Receiver Operating Characteristic (ROC) curves, determining sensitivity and specificity. The Youden index identified optimal cut points for predictive probabilities. Results: Significant differences were observed between the URSA and control groups in coagulation reaction time (R), clot formation time (K), clot formation rate (Angle-α), and maximum clot strength (MA) (P<0.05). Multivariable logistic regression identified R, Angle-α, and MA as independent URSA risk factors. The model demonstrated excellent discrimination (AUC: 0.940; 95% CI: 0.918-0.962). The optimal cut point of predictive probability (Youden index) was P=0.355, yielding a sensitivity of 0.925 and specificity of 0.795. Conclusion: URSA patients exhibit a hypercoagulable state even when not pregnant. More research is needed to validate our findings and explore the potential clinical implications of anticoagulants in treating URSA.

The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis.

BACKGROUND AND AIMS: The Hippo signaling has emerged as a crucial regulator of tissue homeostasis, regeneration, and tumorigenesis, representing a promising therapeutic target. Neurofibromin 2 (NF2), a component of Hippo signaling, is directly linked to human cancers but has been overlooked as a target for cancer therapy. APPROACH AND RESULTS: Through a high-content RNA interference genome-wide screen, the actin-binding protein Drebrin (DBN1) has been identified as a novel modulator of YAP localization. Further investigations have revealed that DBN1 directly interacts with NF2, disrupting the activation of large tumor suppressor kinases (LATS1/2) by competing with LATS kinases for NF2 binding. Consequently, DBN1 knockout considerably promotes YAP nuclear exclusion and repression of target gene expression, thereby preventing cell proliferation and liver tumorigenesis. We identified three lysine residues (K238, K248, and K252) essential for DBN1-NF2 interaction and developed a mutant DBN1 (DBN1-3Kmut) that is defective in NF2 binding and incompetent to trigger NF2-dependent YAP activation and tumorigenesis both in vitro and in vivo. Furthermore, BTP2, a DBN1 inhibitor, successfully restored NF2-LATS kinase binding and elicited potent antitumor activity. The combination of sorafenib and BTP2 exerted synergistic inhibitory effects against HCC. CONCLUSIONS: Our study identifies a novel DBN1-NF2-LATS axis, and pharmacological inhibition of DBN1 represents a promising alternative intervention targeting the Hippo pathway in cancer treatment.

SIRT7 remodels the cytoskeleton via RAC1 to enhance host resistance to Mycobacterium tuberculosis.

Phagocytosis of Mycobacterium tuberculosis (Mtb) followed by its integration into the matured lysosome is critical in the host defense against tuberculosis. How Mtb escapes this immune attack remains elusive. In this study, we unveiled a novel regulatory mechanism by which SIRT7 regulates cytoskeletal remodeling by modulating RAC1 activation. We discovered that SIRT7 expression was significantly reduced in CD14+ monocytes of TB patients. Mtb infection diminished SIRT7 expression by macrophages at both the mRNA and protein levels. SIRT7 deficiency impaired actin cytoskeleton-dependent macrophage phagocytosis, LC3II expression, and bactericidal activity. In a murine tuberculosis model, SIRT7 deficiency detrimentally impacted host resistance to Mtb, while Sirt7 overexpression significantly increased the host defense against Mtb, as determined by bacterial burden and inflammatory-histopathological damage in the lung. Mechanistically, we demonstrated that SIRT7 limits Mtb infection by directly interacting with and activating RAC1, through which cytoskeletal remodeling is modulated. Therefore, we concluded that SIRT7, in its role regulating cytoskeletal remodeling through RAC1, is critical for host responses during Mtb infection and proposes a potential target for tuberculosis treatment.IMPORTANCETuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant global health issue. Critical to macrophages' defense against Mtb is phagocytosis, governed by the actin cytoskeleton. Previous research has revealed that Mtb manipulates and disrupts the host's actin network, though the specific mechanisms have been elusive. Our study identifies a pivotal role for SIRT7 in this context: Mtb infection leads to reduced SIRT7 expression, which, in turn, diminishes RAC1 activation and consequently impairs actin-dependent phagocytosis. The significance of our research is that SIRT7 directly engages with and activates Rac Family Small GTPase 1 (RAC1), thus promoting effective phagocytosis and the elimination of Mtb. This insight into the dynamic between host and pathogen in TB not only broadens our understanding but also opens new avenues for therapeutic development.

TUDCA inhibits EV71 replication by regulating ER stress signaling pathway and suppressing autophagy.

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that alleviates endoplasmic reticulum (ER) stress and inhibits apoptosis, thereby protecting cells. Previous studies have shown that enterovirus 71 (EV71) infection modulates ER stress and induces autophagy to assist viral replication. This study observed the effects of TUDCA pretreatment on HeLa and Vero cells infected with EV71, finding that TUDCA inhibits EV71 replication in TUDCA pretreated HeLa and Vero cells in a dose-dependent manner. We found that TUDCA pretreatment inhibited EV71 replication by regulating three branches of UPR, that is up-regulated ATF6, down-regulated both PERK and IRE1. The results also indicated that autophagy which is downstream of UPR, was inhibited either. The results indicate that TUDCA inhibits EV71 replication by regulating UPR sensor proteins and autophagy following ER stress.

A segmentation-based algorithm for classification of benign and malignancy Thyroid nodules with multi-feature information.

The aim of this study is to propose a new diagnostic model based on "segmentation + classification" to improve the routine screening of Thyroid nodule ultrasonography by utilizing the key domain knowledge of medical diagnostic tasks. A Multi-scale segmentation network based on a pyramidal pooling structure of multi-parallel void spaces is proposed. First, in the segmentation network, the exact information of the underlying feature space is obtained by an Attention Gate. Second, the inflated convolutional part of Atrous Spatial Pyramid Pooling (ASPP) is cascaded for multiple downsampling. Finally, a three-branch classification network combined with expert knowledge is designed, drawing on doctors' clinical diagnosis experience, to extract features from the original image of the nodule, the regional image of the nodule, and the edge image of the nodule, respectively, and to improve the classification accuracy of the model by utilizing the Coordinate attention (CA) mechanism and cross-level feature fusion. The Multi-scale segmentation network achieves 94.27%, 93.90% and 88.85% of mean precision (mPA), Dice value (Dice) and mean joint intersection (MIoU), respectively, and the accuracy, specificity and sensitivity of the classification network reaches 86.07%, 81.34% and 90.19%, respectively. Comparison tests show that this method outperforms the U-Net, AGU-Net and DeepLab V3+ classical models as well as the nnU-Net, Swin UNetr and MedFormer models that have emerged in recent years. This algorithm, as an auxiliary diagnostic tool, can help physicians more accurately assess the benign or malignant nature of Thyroid nodules. It can provide objective quantitative indicators, reduce the bias of subjective judgment, and improve the consistency and accuracy of diagnosis. Codes and models are available at https://github.com/enheliang/Thyroid-Segmentation-Network.git.

Self-shedding MOF-nanocarriers modulated CdS/MoSe2 heterojunction activity through in-situ ion exchange: An enhanced split-type photoelectrochemical sensor for deoxynivalenol.

Deoxynivalenol (DON), a mycotoxin produced by Fusarium, poses a significant risk to human health and the environment. Therefore, the development of a highly sensitive and accurate detection method is essential to monitor the pollution situation. In response to this imperative, we have devised an advanced split-type photoelectrochemical (PEC) sensor for DON analysis, which leverages self-shedding MOF-nanocarriers to modulate the photoelectric response ability of PEC substrate. The PEC sensing interface was constructed using CdS/MoSe2 heterostructures, while the self-shedding copper peroxide nanodots@ZIF-8 (CPNs@ZIF-8) served as the Cu2+ source for the in-situ ion exchange reaction, which generated a target-related signal reduction. The constructed PEC sensor exhibited a broad linear range of 0.1 pg mL-1 to 500 ng mL-1 with a low detection limit of 0.038 pg mL-1, demonstrating high stability, selectivity, and proactivity. This work not only introduces innovative ideas for the design of photosensitive materials, but also presents novel sensing strategies for detecting various environmental pollutants.

Axial Compression Behavior of Circular Seawater and Sea Sand Concrete Columns Reinforced with Hybrid GFRP-Stainless Steel Bars.

The ductility of FRP-reinforced concrete structures is reduced by the brittleness of FRP bars. To address this issue, this study employs the hybrid reinforcement of stainless steel (SS) and GFRP bars to enhance the ductility of concrete columns. A total of 21 axially compressed seawater and sea sand concrete (SWSSC) circular columns are fabricated, including 15 hybrid GFRP and SS bar-reinforced SWSSC (GFRP-SS-SWSSC) columns, 3 GFRP bar-reinforced SWSSC (GFRP-SWSSC) columns, and 3 SS bar-reinforced SWSSC (SS-SWSSC) columns. The test results are analyzed in terms of failure mode, load-axial displacement curve, bearing capacity, and ductility. Results show that GFRP-SWSSC columns suffer brittle failure, while GFRP-SS-SWSSC columns and SS-SWSSC columns demonstrate ductile failure characteristics. Furthermore, the hybrid reinforcement contributes to an improvement in the bearing capacity of the columns. A calculation equation for the bearing capacity of axially compressed columns was established, providing reasonable predictions of bearing capacities, with a design compressive strain of 2000 µÎµ for GFRP bars. It was found that hybrid reinforcement enhanced the ductility of GFRP-SWSSC columns. In addition, when the percentage of the SS reinforcement ratio reaches 50%, the ductility indexes of the GFRP-SS-SWSSC columns closely approach those of the SS-SWSSC columns.

miR-324-3p Suppresses Hepatic Stellate Cell Activation and Hepatic Fibrosis Via Regulating SMAD4 Signaling Pathway.

In hepatic fibrosis (HF), hepatic stellate cells (HSCs) form the extracellular matrix (ECM), and the pathological accumulation of ECM in the liver leads to inflammation. Our previous research found that miR-324-3p was down-regulated in culture-activated human HSCs. However, the precise effect of miR-324-3p on HF has not been elucidated. In this study, the HF mouse models were induced through directly injecting carbon tetrachloride (CCl4) into mice; the HF cell models were constructed using TGF-ß1-treated LX-2 cells. Next, real-time-quantitative polymerase chain reaction (RT-qPCR), western blot (WB) and immunohistochemistry (IHC) were applied to assess the expression levels of miR-324-3p, α-smooth muscle actin (α-SMA), Vimentin or SMAD4; hematoxylin and eosin (H&E), Masson' s trichrome and Sirius red staining to evaluate the liver injury; luciferase reporter assay to verify the targeting relationship between miR-324-3p and SMAD4; enzyme-linked immunosorbent assay (ELISA) to determine the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and cell counting kit-8 (CCK-8) and flow cytometry to evaluate the effects of miR-324-3p on cell proliferation and cycle/apoptosis, respectively. The experimental results showed a reduction in miR-324-3p level in CCl4-induced HF mice as well as transforming growth factor (TGF)-ß1-activated HSCs. Interestingly, the miR-324-3p level was rescued following the HF recovery process. In HF mice induced by CCl4, miR-324-3p overexpression inhibited liver tissue damage, decreased serum ALT and AST levels, and inhibited fibrosis-related biomarkers (α-SMA, Vimentin) expression, thereby inhibiting HF. Similarly, miR-324-3p overexpression up-regulated α-SMA and Vimentin levels in HF cells, while knockdown of miR-324-3p had the opposite effect. Besides, miR-324-3p played an antifibrotic role through inhibiting the proliferation of hepatocytes. Further experiments confirmed that miR-324-3p targeted and down-regulated SMAD4 expression. SMAD4 was highly expressed in HF cells, and silencing SMAD4 significantly decreased the α-SMA and Vimentin levels in HF cells. Collectively, the miR-324-3p may suppress the activation of HSCs and HF by targeting SMAD4. Therefore, miR-324-3p is identified as a potential and novel therapeutic target for HF.

Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

[Clinical phenotype and genetic analysis of a fetus with recombinant chromosome 8 syndrome].

OBJECTIVE: To explore the clinical characteristics and molecular genetic mechanism of a fetus with recombinant chromosome 8 (Rec8) syndrome. METHODS: A fetus who was diagnosed with Rec8 syndrome at the Provincial Hospital Affiliated to Shandong First Medical University on July 20, 2021 due to high risk for sex chromosomal aneuploidy indicated by non-invasive prenatal testing (NIPT) (at 21st gestational week) was selected as the study subject. Clinical data of the fetus was collected. G-banded karyotyping and chromosomal microarray analysis (CMA) were carried out on the amniotic fluid sample. Peripheral blood samples of the couple were also subjected to G banded karyotyping analysis. RESULTS: Prenatal ultrasonography at 23rd gestational week revealed hypertelorism, thick lips, renal pelvis separation, intrahepatic echogenic foci, and ventricular septal defect. The karyotype of amniotic fluid was 46,XX,rec(8)(qter→q22.3::p23.1→qter), and CMA was arr[GRCh37]8p23.3p23.1(158049_6793322)×1, 8q22.3q24.3(101712402_146295771)×3. The karyotype of the pregnant woman was 46,XX,inv(8)(p23.1q22.3), whilst that of her husband was normal. CONCLUSION: The Rec8 syndrome in the fetus may be attributed to the pericentric inversion of chromosome 8 in its mother. Molecular testing revealed that the breakpoints of this Rec8 have differed from previously reported ones.

The role of long noncoding RNAs in liquid-liquid phase separation.

Long noncoding RNAs (lncRNAs), which are among the most well-characterized noncoding RNAs, have attracted much attention due to their regulatory functions and potential therapeutic options in many types of disease. Liquid-liquid phase separation (LLPS), the formation of droplet condensates, is involved in various cellular processes, but the molecular interactions of lncRNAs in LLPS are unclear. In this review, we describe the research development on LLPS, including descriptions of various methods established to identify LLPS, summarize the physiological and pathological functions of LLPS, identify the molecular interactions of lncRNAs in LLPS, and present the potential applications of leveraging LLPS in the clinic. The aim of this review is to update the knowledge on the association between LLPS and lncRNAs, which might provide a new direction for the treatment of LLPS-mediated disease.

The complete and fully-phased diploid genome of a male Han Chinese.

Since the release of the complete human genome, the priority of human genomic study has now been shifting towards closing gaps in ethnic diversity. Here, we present a fully phased and well-annotated diploid human genome from a Han Chinese male individual (CN1), in which the assemblies of both haploids achieve the telomere-to-telomere (T2T) level. Comparison of this diploid genome with the CHM13 haploid T2T genome revealed significant variations in the centromere. Outside the centromere, we discovered 11,413 structural variations, including numerous novel ones. We also detected thousands of CN1 alleles that have accumulated high substitution rates and a few that have been under positive selection in the East Asian population. Further, we found that CN1 outperforms CHM13 as a reference genome in mapping and variant calling for the East Asian population owing to the distinct structural variants of the two references. Comparison of SNP calling for a large cohort of 8869 Chinese genomes using CN1 and CHM13 as reference respectively showed that the reference bias profoundly impacts rare SNP calling, with nearly 2 million rare SNPs miss-called with different reference genomes. Finally, applying the CN1 as a reference, we discovered 5.80 Mb and 4.21 Mb putative introgression sequences from Neanderthal and Denisovan, respectively, including many East Asian specific ones undetected using CHM13 as the reference. Our analyses reveal the advances of using CN1 as a reference for population genomic studies and paleo-genomic studies. This complete genome will serve as an alternative reference for future genomic studies on the East Asian population.

Constitutively active autophagy in macrophages dampens inflammation through metabolic and post-transcriptional regulation of cytokine production.

Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine the impact of autophagic modulation in the context of inflammatory conditions are lacking. Here, using mice with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production during a model of macrophage activation syndrome and in adherent-invasive Escherichia coli (AIEC) infection. Moreover, loss of functional autophagy through conditional deletion of Beclin1 in myeloid cells significantly enhances innate immunity in these contexts. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.

N6-methyladenosine-modified circIRF2, identified by YTHDF2, suppresses liver fibrosis via facilitating FOXO3 nuclear translocation.

Circular RNA (circRNA) has been implicated in liver fibrosis and modulated by multiple elusive molecular mechanisms, while the effects of N6-methyladenosine (m6A) modification on circRNA are still elusive. Herein, we identify circIRF2 from our circRNA sequencing data, which decreased in liver fibrogenesis stage and restored in resolution stage, indicating that dysregulated circIRF2 may be closely associated with liver fibrosis. Gain/loss-of-function analysis was performed to evaluate the effects of circIRF2 on liver fibrosis at both the fibrogenesis and resolution in vivo. Ectopic expression of circIRF2 attenuated liver fibrogenesis and HSCs activation at the fibrogenesis stage, whereas downregulation of circIRF2 impaired mouse liver injury repair and inflammation resolution. Mechanistically, YTHDF2 recognized m6A-modified circIRF2 and diminished circIRF2 stability, partly accounting for the decreased circIRF2 in liver fibrosis. Microarray was applied to investigate miRNAs regulated by circIRF2, our data elucidate cytoplasmic circIRF2 may directly harbor miR-29b-1-5p and competitively relieve its inhibitory effect on FOXO3, inducing FOXO3 nuclear translocation and accumulation. Clinically, circIRF2 downregulation was prevalent in liver fibrosis patients compared with healthy individuals. In summary, our findings offer a novel insight into m6A modification-mediated regulation of circRNA and suggest that circIRF2 may be an exploitable prognostic marker and/or therapeutic target for liver fibrosis.

Nanozyme-assisted ratiometric photoelectrochemical aptasensor over Cu2O nanocubes mediated photocurrent-polarity-switching based on S-scheme FeCdS@FeIn2S4 heterostructure.

The controllable modulation of the response mode is highly attractive for the construction of photoelectrochemical (PEC) sensors with improved sensitivity and anti-interference ability in complex real samples matrix. Here, we present a charming proof-of-concept ratiometric PEC aptasensor of enrofloxacin (ENR) analysis via the controllable signal transduction. Different with the traditional sensing mechanism, this ratiometric PEC aptasensor integrates the anodic PEC signal induced by PtCuCo nanozyme-catalyzed precipitation reaction and the polarity-switching cathodic PEC response mediated by Cu2O nanocubes on S-scheme FeCdS@FeIn2S4 heterostructure. Taking advantages of the photocurrent-polarity-switching signal response model and the superior performance of the photoactive substrate material, the proposed ratiometric PEC aptasensor displays a good detection linear range for ENR analysis from 0.01 pg mL-1 to 10 ng mL-1, with a detection limit of 3.3 fg mL-1. This study provides a general platform for detecting interested trace analytes in real samples and expands the diversity of sensing strategy design.

Mycobacterium tuberculosis-Induced Prostaglandin J2 and 15-Deoxy-Prostaglandin J2 Inhibit Inflammatory Signals in Human M1 Macrophages via a Negative Feedback Loop.

Tuberculosis caused by Mycobacterium tuberculosis is a leading cause of death globally and a major health concern. In humans, macrophages are the first line invaded by M. tuberculosis. Upon infection, macrophages upregulate cyclooxygenase-2 (COX-2) expression and consequently elevate the formation of PGs, including PGE2 and PGD2. Although the role of proinflammatory PGE2 in M. tuberculosis infection has been reported, the roles of PGJ2 and 15-deoxy-PGJ2 (collectively named J2-PGs), the metabolites of PGD2 with anti-inflammatory features, remain elusive. In this study, we show that M. tuberculosis (H37Rv strain)-conditioned medium stimulates human monocyte-derived macrophages (MDMs) to elevate COX-2 expression along with robust generation of PGJ2, exceeding PGD2 formation, and to a minor extent also of 15-deoxy-PGJ2. Of interest, in M1-MDM phenotypes, PGJ2 and 15-deoxy-PGJ2 decreased M. tuberculosis (H37Rv strain)-conditioned medium-induced COX-2 expression and related PG formation by a negative feedback loop. Moreover, these J2-PGs downregulated the expression of the proinflammatory cytokines IL-6, IL-1ß, and IFN-γ, but elevated the anti-inflammatory cytokine IL-10 and the M2 markers arginase-1 and CD163. These anti-inflammatory effects of J2-PGs in M1-MDM correlated with impaired activation of TGF-ß-activated kinase 1/NF-κB/MAPK pathways. Finally, we found that J2-PGs regulate COX-2 expression, at least partially, via PGD2 receptor (DP1) and chemoattractant receptor homologue expressed on Th2 cells/DP2 receptors, but independent of the J2-PG receptor peroxisome proliferator-activated receptor-γ. Together, our findings reveal that M. tuberculosis induces COX-2 expression in human M1-MDMs, along with robust formation of J2-PGs that mediates anti-inflammatory effects via a negative feedback loop.

Plasma cell-free DNA promise monitoring and tissue injury assessment of COVID-19.

Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.

Renal histopathological manifestations of IgA vasculitis nephritis in children and adults.

BACKGROUND: IgA vasculitis nephritis (IgAVN) is a common form of secondary glomerulonephritis and can occur in patients of any age. Our study was designed to reveal renal histopathological manifestations of children and adults with IgAVN and to explore the potential pathogenesis of IgAVN. METHODS: Sixty-one pediatric and seventy adult patients with IgAVN were enrolled altogether, and all of them underwent kidney biopsies. General information, laboratory parameters, and renal histopathological manifestations of all patients were analyzed. RESULTS: (1) Diabetes, hypertension, and various levels of proteinuria made no difference between children and adults. (2) Global sclerosis and tubular atrophy/interstitial fibrosis occurred more commonly in adults than in children (24.29 % vs 8.20 %, 65.71 % vs 9.84 %, respectively) (P < 0.05). (3) The immunofluorescence deposition of complement C3 was more apparent in adults (P < 0.05). (4) The deposition of IgA, IgG, IgM, and C3 in kidneys was unrelated to the pathological types. (5) The deposition of IgG or IgM was related to the deposition of IgA or C3 in children and adults (P < 0.05). CONCLUSIONS: Chronic kidney injury occurred more commonly in adult IgAVN patients compared to pediatric IgAVN patients. Immunoglobulin and complement deposits in kidneys were independent of the types of renal pathological injury. Additionally, IgG and IgM were probably involved in IgAVN pathogenesis.

Impaired intracranial venous outflow profiles are associated with poor outcome in stroke after reperfusion therapy: A hypoperfusion-matched intracranial venous scale.

PURPOSE: Arterial blood flow provided prognostic information in acute ischemic stroke (AIS). However, part of the patients with favorable arterial blood flow still suffered from poor outcomes after reperfusion therapy. We aimed to verify the hypothesis that intracranial venous outflow profiles (both cortical and deep) within the hypoperfusion area were associated with clinical outcome in AIS patients who received reperfusion therapy. METHOD: We performed a retrospective analysis of prospectively collected data from anterior circulation AIS patients. All patients underwent pretreatment CTP and received reperfusion therapy. We constructed a 5-point hypoperfusion-matched Intracranial Venous Scale (hypo-IVS) from the sum of the contrast enhancement degree (1, attenuated contrast enhancement; 0, complete contrast enhancement) of 4 typical veins (superficial middle cerebral vein, vein of Labbé, vein of Trolard, and internal cerebral vein) whose outflow territories had matched hypoperfusion. Logistic and ordinal regression were used to analyze the association between hypo-IVS and clinical outcome. RESULTS: A total of 751 patients were included. Higher Hypo-IVS was significantly associated with poor outcome (3-month mRS of >2; OR = 1.194; 95 % CI: 1.014-1.407; p = 0.033). The adjusted ORs for poor outcome and high 24-hour NIHSS were 1.172 (95 %CI: 1.035-1.328; p = 0.012) and 1.176 (95 %CI: 1.030-1.330; p = 0.010) in ordinal regression, respectively. Hypo-IVS > 2 was an independent risk factor of poor outcome (75.2 % vs 40.8 %; OR = 1.932; 95 %CI: 1.158-3.224; p = 0.012). CONCLUSIONS: Intracranial venous outflow profiles deliver prognostic information in AIS and the hypo-IVS is a helpful tool to predict clinical outcomes after reperfusion therapy.