A novel inherited CARD9 deficiency in an otherwise healthy woman with CNS candidiasis.

Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.

A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated enhancer clusters.

As an oncogenic transcription factor, Yin Yang 1 (YY1) regulates enhancer and promoter connection. However, gaps still exist in understanding how YY1 coordinates coactivators and chromatin enhancer elements to assemble enhancers and super-enhancers. Here, we demonstrate that a histidine cluster in YY1's transactivation domain is essential for its formation of phase separation condensates, which can be extended to additional proteins. The histidine cluster is also required for YY1-promoted cell proliferation, migration, clonogenicity and tumor growth. YY1-rich nuclear puncta contain coactivators EP300, BRD4, MED1 and active RNA polymerase II, and colocalize with histone markers of gene activation, but not that of repression. Furthermore, YY1 binds to the consensus motifs in the FOXM1 promoter to activate its expression. Wild-type YY1, but not its phase separation defective mutant, connects multiple enhancer elements and the FOXM1 promoter to form an enhancer cluster. Consistently, fluorescent in situ hybridization (FISH) assays reveal the colocalization of YY1 puncta with both the FOXM1 gene locus and its nascent RNA transcript. Overall, this study demonstrates that YY1 activates target gene expression through forming liquid-liquid phase separation condensates to compartmentalize both coactivators and enhancer elements, and the histidine cluster of YY1 plays a determinant role in this regulatory mechanism.

Pyrrolysine-Inspired in Cellulo Synthesis of an Unnatural Amino Acid for Facile Macrocyclization of Proteins.

Macrocyclization has been touted as an effective strategy to enhance the in vivo stability and efficacy of protein therapeutics. Herein, we describe a scalable and robust system based on the endogenous biosynthesis of a noncanonical amino acid coupled to the pyrrolysine translational machinery for the generation of lasso-grafted proteins. The in cellulo biosynthesis of the noncanonical amino acid d-Cys-ε-Lys was achieved by hijacking the pyrrolysine biosynthesis pathway, and then, its genetical incorporation into proteins was performed using an optimized PylRS/tRNAPyl pair and cell line. This system was then applied to the structurally inspired cyclization of a 23-mer therapeutic P16 peptide engrafted on a fusion protein, resulting in near-complete cyclization of the target cyclic subunit in under 3 h. The resulting cyclic P16 peptide fusion protein possessed much higher CDK4 binding affinity than its linear counterpart. Furthermore, a bifunctional bicyclic protein harboring a cyclic cancer cell targeting RGD motif on the one end and the cyclic P16 peptide on the other is produced and shown to be a potent cell cycle arrestor with improved serum stability.

High-Output Single-Electrode Droplet Triboelectric Nanogenerator Based on Asymmetrical Distribution Electrostatic Induction Enhancement.

Droplet-based triboelectric nanogenerators (D-TENGs) have recently gained much attention due to their great potential in harvesting energy. However, the output performance of conventional single-electrode droplet-based TENGs is limited owing to low induced electrification efficiency. The asymmetric distribution of electric fields on both sides of the electrode edge enhances the electrostatic induction process and improves the output performance of D-TENG. Herein, an induced electrification-enhanced droplet-based triboelectric nanogenerator (IED-TENG) is developed to effectively enhance the output performance by simultaneously optimizing the electrode structure and the dynamics of the water droplet. One droplet falling from a height of 30 cm results in a -70 V output voltage and -6 µA short-circuit current, which is 70 times and 20 times the full-inductive-electrode mode, respectively. The working principle and the relationship between electric signal and droplet dynamics are analyzed in detail. Moreover, the peak output voltage can reach -110 V, and the peak current can get -140 µA by using the power generation of multiple water droplets. The present protocol provides an easy and reproducibility strategy in energy harvesting and sensing areas.

Multi-nodes dissemination of stable radio frequency with 10-17 instability over 2000 km optical fiber.

To meet the demand of flexible access for high-precision synchronization frequency, we demonstrate multi-node stable radio frequency (RF) dissemination over a long-distance optical fiber. Stable radio frequency signals can be extracted at any node along the optical fiber, not just at the endpoint. The differential mixing structure (DMS) is employed to avoid the frequency harmonic leakage and enhance the precision. The phase-locked loop (PLL) provides frequency reference for the DMS while improving the signal to noise ratio (SNR) of dissemination signal. We measure the frequency instability of multi-node stable frequency dissemination system (MFDS) at different locations along the 2,000 km optical fiber. The measured short-term instability with average time of 1 s are 1.90 × 10-14 @ 500 km, 2.81 × 10-14 @ 1,000 km, 3.46 × 10-14 @ 1,500 km, and 3.84 × 10-14 @ 2,000 km respectively. The long-term instability with average time of 10,000 s are basically the same at any position of the optical fiber, which is about (6.24 ± 0.05) × 10-17. The resulting instability is sufficient for the propagation of precision active hydrogen masers.

Shape and texture analyses based on conventional MRI for the preoperative prediction of the aggressiveness of pituitary adenomas.

OBJECTIVES: Pituitary adenomas can exhibit aggressive behavior, characterized by rapid growth, resistance to conventional treatment, and early recurrence. This study aims to evaluate the clinical value of shape-related features combined with textural features based on conventional MRI in evaluating the aggressiveness of pituitary adenomas and develop the best diagnostic model. METHODS: Two hundred forty-six pituitary adenoma patients (84 aggressive, 162 non-aggressive) who underwent preoperative MRI were retrospectively reviewed. The patients were divided into training (n = 193) and testing (n = 53) sets. Clinical information, shape-related, and textural features extracted from the tumor volume on contrast-enhanced T1-weighted images (CE-T1WI), were compared between aggressive and non-aggressive groups. Variables with significant differences were enrolled into Pearson's correlation analysis to weaken multicollinearity. Logistic regression models based on the selected features were constructed to predict tumor aggressiveness under fivefold cross-validation. RESULTS: Sixty-five imaging features, including five shape-related and sixty textural features, were extracted from volumetric CE-T1WI. Forty-seven features were significantly different between aggressive and non-aggressive groups (all p values < 0.05). After feature selection, four features (SHAPE_Sphericity, SHAPE_Compacity, DISCRETIZED_Q3, and DISCRETIZED_Kurtosis) were put into logistic regression analysis. Based on the combination of these features and Knosp grade, the model yielded an area under the curve value of 0.935, with a sensitivity of 94.4% and a specificity of 82.9%, to discriminate between aggressive and non-aggressive pituitary adenomas in the testing set. CONCLUSION: The radiomic model based on tumor shape and textural features study from CE-T1WI might potentially assist in the preoperative aggressiveness diagnosis of pituitary adenomas. KEY POINTS: • Pituitary adenomas with aggressive behavior exhibit rapid growth, resistance to conventional treatment, and early recurrence despite gross resection and may require multiline treatments. • Shape-related features and texture features based on CE-T1WI were significantly correlated with the Ki-67 labeling index, mitotic count, and p53 expression, and the proposed model achieved a favorable prediction of the aggressiveness of PAs with an AUC value of 0.935. • The prediction model might provide valuable guidance for individualized treatment in patients with PAs.

Induction therapy with high-dose fluconazole plus flucytosine for human immunodeficiency virus-uninfected cryptococcal meningitis patients: Feasible or not?

BACKGROUND: Cryptococcal meningitis (CM) is increasingly recognised in human immunodeficiency virus (HIV)-uninfected patients with high mortality. The efficacy and safety profiles of induction therapy with high-dose fluconazole plus flucytosine remain unclear. METHODS: HIV-uninfected CM patients who received high-dose fluconazole (800 mg/d) for initial therapy in Huashan Hospital were included in this retrospective study from January 2013 to December 2018. Efficacy and safety of initial therapy, clinical outcomes and risk factors were evaluated. RESULTS: Twenty-seven (71.1%) patients who received high-dose fluconazole with flucytosine combination therapy and 11 (28.9%) having fluconazole alone for induction therapy were included. With a median duration of 42 days (IQR, 28-86), the successful response rate of initial therapy was 76.3% (29/38), while adverse drug reactions occurred in 14 patients (36.8%). The rate of persistently positive cerebrospinal fluid (CSF) culture results was 30.6% at 2 weeks, which was significantly associated with CSF CrAg titre >1:1280 (OR 9.56; 95% CI 1.40-103.65; p = .010) and CSF culture of Cryptococcus >3.9 log10 CFU/ml (OR 19.20; 95% CI 1.60-920.54; p = .011), and decreased to 8.6% at 4 weeks. One-year mortality was 15.8% (6/38), and low serum albumin (35 g/L) was found as an independent risk factor for 1-year mortality (HR 6.31; 95% CI 1.150-34.632; p = .034). CONCLUSIONS: Induction therapy with high-dose fluconazole (800 mg/d), combined with flucytosine, effectively treated HIV-uninfected CM and was well tolerated. Long-term fluconazole treatment with continued monitoring is beneficial for patients with persistent infection.

Diagnostic performance of noncultural methods for central nervous system aspergillosis.

BACKGROUND: Central nervous system (CNS) aspergillosis is an uncommon but fatal disease, the diagnosis of which is still difficult. OBJECTIVES: We aim to explore the diagnositic performance of noncultural methods for CNS aspergillosis. METHODS: In this retrospective study, all pathologically confirmed rhinosinusitis patients in whom cerebrospinal fluid (CSF) galactomannan (GM) test and metagenomic next-generation sequencing (mNGS) had been performed were included. We evaluated the diagnostic performances of CSF GM optical density indexes (ODI) at different cut-off values and compared performance with mNGS in patients with and without CNS aspergillosis, as well as in patients with different manifestations of CNS aspergillosis. RESULTS: Of the 21 proven and probable cases, one had positive culture result, five had positive mNGS results and 10 had a CSF GM ODI of >0.7. Sample concordance between mNGS and GM test was poor, but best diagnostic performance was achieved by combination of GM test (ODI of >0.7) and mNGS, which generated a sensitivity of 61.9% and specificity of 82.6%. Further investigation of combination diagnostic performances in different kind of CNS aspergillosis was also conducted. Lowest sensitivity (42.9%) was identified in abscess group, while increased sensitivity (60.0%) was achieved in abscess with encephalitis groups. Combination test exhibited the best performance for encephalitis patients who had only CSF abnormalities, in whom the sensitivity and specificity were 77.8% and 82.6%, respectively. CONCLUSIONS: In conclusion, combination of these two tests might be useful for diagnosis of CNS aspergillosis associated with fungal rhinosinusitis, especially in encephalitis patients.

Immune reconstitution inflammatory syndrome in non-HIV cryptococcal meningitis: Cross-talk between pathogen and host.

BACKGROUND: Cryptococcal meningitis (CM)-associated immune reconstitution inflammatory syndrome (IRIS) is associated with high mortality, the epidemiology and pathophysiology of which is poorly understood, especially in non-HIV populations. OBJECTIVES: We aim to explore the incidence, clinical risk factors, immunological profiles and potential influence of leukotriene A4 hydroxylase (LTA4H) on non-HIV CM IRIS populations. METHODS: In this observational cohort study, 101 previously untreated non-HIV CM patients were included. We obtained data for clinical variables, 27 cerebrospinal fluid (CSF) cytokines levels and LTA4H genotype frequencies. Changes of CSF cytokines levels before and at IRIS occurrence were compared. RESULTS: Immune reconstitution inflammatory syndrome was identified in 11 immunocompetent males, generating an incidence of 10.9% in non-HIV CM patients. Patients with higher CrAg titres (> 1:160) were more likely to develop IRIS, and titre of 1:1280 is the optimum level to predict IRIS occurrence. Baseline CSF cytokines were significantly higher in IRIS group, which indicated a severe host immune inflammation response. Four LTA4H SNPs (rs17525488, rs6538697, rs17525495 and rs1978331) exhibited significant genetic susceptibility to IRIS in overall non-HIV CM, while five cytokines were found to be associated with rs1978331, and baseline monocyte chemotactic protein 1 (MCP-1) became the only cytokine correlated with both IRIS and LTA4H SNPs. CONCLUSIONS: Our study suggested that non-HIV CM patients with high fungal burden and severe immune inflammation response were more likely to developed IRIS. LTA4H polymorphisms may affect the pathogenesis of IRIS by regulating the level of baseline CSF MCP-1.

Genetic polymorphisms of transient receptor potential melastatin 1 correlate with voriconazole-related visual adverse events.

BACKGROUND: Causes of voriconazole-related visual adverse events (VVAE) remained controversial. OBJECTIVES: We aimed to explore the relationship between voriconazole serum concentrations and VVAE as well as the potential influence of transient receptor potential melastatin 1 (TRPM1) on VVAE. PATIENTS/METHODS: This prospective observational cohort study was done in two stages. Patients who received voriconazole for invasive fungal diseases were consecutively enrolled. Correlations between voriconazole trough levels and VVAE were explored in 76 patients. Genotyping was further conducted for 17 tag SNPs of TRPM1 in a larger population of 137 patients. Genotype distributions were compared between patients with and without VVAE. RESULT: Of the 76 patients, a total of 229 steady-state voriconazole trough levels were evaluated, 69.9% of which were within the target range (1-5.5 mg/L). No correlations were found between voriconazole trough levels and VVAE. Of the total 137 patients, VVAE occurred in 37 (27.0%) patients, including visual hallucination (13.9%, 19/137) and visual disturbances (19.0%, 26/137). Significant difference in TRPM1 genotype distribution was only observed in patients with visual hallucination but not with visual disturbances. We found that rs890160 G/T genotype was under-presented (OR, 0.11; 95% CI, 0.01-0.84; P = .011) and rs1378847 C/C genotype was more frequently detected (OR, 8.89; 95% CI, 1.14-69.02; P = .013) in patients with visual hallucination when compared with those without. CONCLUSION: Transient receptor potential melastatin 1 was genetically associated with voriconazole-related visual hallucination. The correlation was failed to found between voriconazole trough levels and VVAE.

Structural basis of 5' flap recognition and protein-protein interactions of human flap endonuclease 1.

Human flap endonuclease 1 (hFEN1) is a structure-specific nuclease essential for DNA replication and repair processes. hFEN1 has 5' flap removal activity, as well as gap endonuclease activity that is critical for restarting stalled replication forks. Here, we report the crystal structures of wild-type and mutant hFEN1 proteins in complex with DNA substrates, followed by mutagenesis studies that provide mechanistic insight into the protein-protein interactions of hFEN1. We found that in an α-helix forming the helical gateway of hFEN1 recognizes the 5' flap prior to its threading into the active site for cleavage. We also found that the ß-pin region is rigidified into a short helix in R192F hFEN1-DNA structures, suppressing its gap endonuclease activity and cycle-dependent kinase interactions. Our findings suggest that a single mutation at the primary methylation site can alter the function of hFEN1 and provide insight into the role of the ß-pin region in hFEN1 protein interactions that are essential for DNA replication and repair.

High dose fluconazole in salvage therapy for HIV-uninfected cryptococcal meningitis.

BACKGROUND: The 2010 Infectious Diseases Society of America (IDSA) guidelines for management of cryptococcal diseases recommend high dose fluconazole (≥ 800 mg/day), either alone or with other antifungal drugs, as alternative anticryptococcal choices. But evidence for its use in the treatment of HIV-uninfected cryptococcal meningitis (CM) remains sparse. METHODS: A retrospective analysis of HIV-uninfected CM patients who received fluconazole 800 mg/day for salvage therapy from January 2011 to December 2016 at Huashan Hospital, Shanghai, China was performed. Efficacy and safety were assessed, and mortality and prognostic factors evaluated. RESULTS: A total of 44 patients were studied including 19 refractory to amphotericin B induction therapy, 8 refractory to fluconazole consolidation therapy (400 mg/d), and 17 intolerant of antifungal drugs. For salvage, 11 patients received triple therapy of high dose fluconazole, amphotericin B and flucytosine, 20 received dual therapy of high dose fluconazole and flucytosine, 13 received monotherapy of high dose fluconazole. Median duration of high dose fluconazole in salvage regimens was 136.5 days (range, 1-667 days). Clinical response rates were 72.1% (31/43) and 83.7% (36/43) when assessed at 2 weeks and the end of salvage therapy, respectively. Adverse events possibly related to high dose fluconazole occurred in 54.5% (24/44) of the patients, and all were mild or moderate. From the initiation of salvage therapy, 1-year all-cause mortality was 13.6% (6 of 44 patients) among the study population with no significant difference in refractory or intolerant patients. CONCLUSIONS: Adherence to guideline recommendations of high dose fluconazole, alone or in combination with other antifungals, was safe and often effective for salvage therapy of HIV-uninfected CM patients.

The efficacy and safety of cilostazol as an alternative to aspirin in Chinese patients with aspirin intolerance after coronary stent implantation: a combined clinical study and computational system pharmacology analysis.

Dual antiplatelet therapy (DAT) with aspirin and clopidogrel is the standard regimen to achieve rapid platelet inhibition and prevent thrombotic events. Currently, little information is available regarding alternative antiplatelet therapy in patients with an allergy or intolerance to aspirin. Although cilostazol is already a common alternative to aspirin in clinical practice in China, its efficacy and safety remain to be determined. We retrospectively analyzed 613 Chinese patients who had undergone primary percutaneous coronary intervention (PCI). Among them, 405 patients received standard DAT (aspirin plus clopidogrel) and 205 patients were identified with intolerance to aspirin and received alternative DAT (cilostazol plus clopidogrel). There were no significant differences between the two groups in their baseline clinical characteristics. The main outcomes of the study included major adverse cardiac events (MACEs) and bleeding events during 12 months of follow-up. The MACEs endpoint was reached in 10 of 205 patients treated with cilostazol (4.9%) and in 34 of 408 patients treated with aspirin (8.3%). No statistically significant difference was observed in MACEs between the two groups. However, patients in the cilostazol group had less restenosis than did patients in the aspirin group (1.5% vs 4.9%, P=0.035). The occurrence of bleeding events tended to be lower in the cilostazol group (0.49% vs 2.7%, P=0.063). These clinical observations were further analyzed using network system pharmacology analysis, and the outcomes were consistent with clinical observations and preclinical data reports. We conclude that in Chinese patients with aspirin intolerance undergoing coronary stent implantation, the combination of clopidogrel with cilostazol may be an efficacious and safe alternative to the standard DAT regimen.

Characterization and role of a 2',3'-cyclic phosphodiesterase from Deinococcus radiodurans.

OBJECTIVES: A 2',3'-cyclic phosphodiesterase gene (drCPDase) has been characterized from Deinococcus radiodurans and is involved in the robust resistance of this organism. RESULTS: Cells lacking 2',3'-cyclic phosphodiesterase gene (drCPDase) showed modest growth defects and displayed increased sensitivities to high doses of various DNA-damaging agents including ionizing radiation, mitomycin C, UV and H2O2. The transcriptional level of drCPDase increased after H2O2 treatment. Additional nucleotide monophosphate partially recovered the phenotype of drCPDase knockout cells. Complementation of E. coli with drCPDase resulted in enhanced H2O2 resistance. CONCLUSIONS: The 2',3'-cyclic phosphodiesterase (drCPDase) contributes to the extreme resistance of D. radiodurans and is presumably involved in damaged nucleotide detoxification.

RRM2B-Mediated Regulation of Mitochondrial Activity and Inflammation under Oxidative Stress.

RRM2B is a critical ribonucleotide reductase (RR) subunit that exists as p53-inducible and p53-dependent molecule. The p53-independent regulation of RRM2B has been recently studied, and FOXO3 was identified as a novel regulator of RRM2B. However, the p53-independent regulation of RRM2B, particularly under oxidative stress, remains largely unknown. In this study, we investigated the role of RRM2B underoxidative stress-induced DNA damage and further examined the regulation of mitochondrial and inflammatory genes by RRM2B. Our study is the first to report the critical role of RRM2B in mitochondrial homeostasis and the inflammation signaling pathway in a p53-independent manner. Furthermore, our study provides novel insights into the role of the RR in inflammatory diseases.

Measuring Technical Efficiency and Productivity of Secondary Maternal and Child Health Hospitals in Hubei, China: Some Evidences from Hubei Province of China 2019 to 2021.

Environmental factors like COVID-19 can have significant impact on technical efficiency (TE) and total factor productivity (TFP) of health services provided. In this study, focusing on Maternal and Child Health (MCH) hospitals in Hubei Province of China in 2019 to 2021, we aimed to measure their TE and TFP, identify some influential environmental factors, and propose some policy recommendations. Altogether 62 secondary MCH hospitals were selected as the study sample. Four input indicators, 3 output indicators, and 4 environmental indicators were selected to analyze the panel data from 2019 to 2021. Three-stage Data Envelopment Analysis (DEA) and Malmquist Productivity Index (MPI) model were employed to estimate the TE and TFP of these hospitals. During 2019 to 2021, the inputs of the sample hospitals had increased, while the outputs had decreased. The inputs redundancy was negatively associated with birth rate, number of residents, and GDP per capita (P < .05). It was positively associated with number of COVID-19 infections (P < .05). The adjusted TE scores in 2019 to 2021 were 0.822, 0.784, and 0.803, respectively. The TFP declined in 2020 and 2021 compared to 2019, with scores being 0.845 and 0.762. The technical efficiency change (TEC) scores from 2019 to 2021 were 0.926 and 1.063. The technological change (TC) scores from 2019 to 2021 were 0.912 and 0.716. During 2019 to 2021, the operation of sample hospitals had been significantly influenced by environmental factors like COVID-19 pandemic, low birth rate, number of residents, and GDP per capita. The inputs had increased but outputs had decreased, leading to an increase in inputs redundancy and a decline in TE. The TFP showed a downward trend, with TC and SEC being the priority directions for improvement. Some recommendations are made for both hospitals and government to continuously improve the TE and TFP.

Comparison of Microbial Diversity of Two Typical Volcanic Soils in Wudalianchi, China.

Volcanic lava is an excellent model of primary succession, in which basalt-associated microorganisms drive the cycling of different elements such as nitrogen, carbon, and other nutrients. Microbial communities in volcanic soils are of particular interest for study on the emergence and evolution of life within special and extreme conditions. The initial processes of colonization and subsequent rock weathering by microbial communities are still poorly understood. We analyzed the soil bacterial and fungal communities and diversities associated with lava (LBL) and kipuka (BK) sites in Wudalianchi using 16S and ITS rRNA Illumina Miseq sequencing techniques. The results showed that soil physical and chemical properties (pH, MC, TOC, TN, TP, AP, DOC, and DON) significantly differed between LBL and BK. The Shannon, Ace, and Pd indexes of fungi in the two sites showed a significant difference (p < 0.05). The dominant bacterial phyla forming communities at LBL and BK sites were Acidobacteria, Proteobacteria, Actinobacteria, and Basidiomycota, and their differences were driven by Gemmatimonadetes and Verrucomicrobia. The dominant fungal phyla of LBL and BK sites were Ascomycota, Zygomycota, and Rozellomcota, which differed significantly between the two sites. The microbial communities showed extremely significant differences (p < 0.05), with MC, pH, and nitrogen being the main influencing factors according to RDA/CCA and correlation analysis. Microbial functional prediction analysis across the two sites showed that the relative abundance of advantageous functional groups was significantly different (p < 0.05). The combined results drive us to conclude that the volcanic soil differences in the deposits appear to be the main factor shaping the microbial communities in Wudalianchi (WDLC) volcanic ecosystems.

Fast Bacterial Succession Associated with the Decomposition of Larix gmelinii Litter in Wudalianchi Volcano.

In order to understand the role of microorganisms in litter decomposition and the nutrient cycle in volcanic forest ecosystems, the dominant forest species Larix gmelinii in the volcanic lava plateau of the Wudalianchi volcano was considered as the research object. We analyzed the response of bacterial community structure and diversity to litter decomposition for 1 year, with an in situ decomposition experimental design using litter bags and Illumina MiSeq high-throughput sequencing. The results showed that after 365 days, the litter quality residual rate of Larix gmelinii was 77.57%, and the litter N, P, C:N, C:P, and N:P showed significant differences during the decomposition period (p < 0.05). The phyla Cyanobacteria and the genus unclassified_o_Chloroplast were the most dominant groups in early decomposition (January and April). The phyla Proteobacteria, Actinobacteriota, and Acidobacteriota and the genera Massilia, Pseudomonas, and Sphingomona were higher in July and October. The microbial communities showed extremely significant differences during the decomposition period (p < 0.05), with PCoa, RDA, and litter QRR, C:P, and N as the main factors driving litter bacteria succession. Microbial functional prediction analysis showed that Chloroplasts were the major functional group in January and April. Achemoheterotrophy and aerobic chemoheterotrophy showed a significant decrease as litter decomposition progressed.

Platelet-to-lymphocyte ratios as a haematological marker of synovitis in rheumatoid arthritis with normal acute phase reactant level.

BACKGROUND: Although normal acute phase reactants (APRs) play an important role in assessing disease activity of rheumatoid arthritis (RA), some studies pointed out the discordance between disease activity and APR level. Neutrophil-to-lymphocyte ratios (NLRs), platelet-to-lymphocyte ratios (PLRs) and lymphocyte-to-monocyte ratios (LMRs) have been reported to be sensitive measures of inflammatory reaction. This study aims to explore the value of these haematological makers in assessment of APR-negative RA patients. METHODS: Out of a cohort of 418 consecutive patients with RA, we enrolled 135 patients with normal APR for this study. We performed ultrasound assessments to evaluate synovitis and bone erosion in the affected joints. Synovitis was evaluated by ultrasound grey scale (GS) and power Doppler (PD) with semi-quantitative scoring (0-3). Demographic, clinical and laboratory data were collected from the patients. Disease Activity Score-28 joints (DAS28), NLR, MLR and PLR were calculated. RESULTS: In RA patients with normal APR, PLR exhibited a positive correlation with ultrasound-detected synovitis and bone erosion, whereas NLR, MLR showed no significant correlation with ultrasonography parameters. The area under the ROC curve (AUC) for identifying synovitis with a GS grade ≥2 based on a PLR cutoff value of ≥159.6 was 0.7868 (sensitivity: 80.95%, specificity: 74.24%). For synovitis with a PD grade ≥2, the AUC was 0.7690, using a PLR cutoff value of ≥166.1 (sensitivity: 68.0%, specificity: 83.87%). CONCLUSIONS: Our findings suggested that PLR might be a reliable and cost-effective marker for identifying moderate-to-severe synovitis in RA patients with normal APR.

G-quadruplexes promote the motility in MAZ phase-separated condensates to activate CCND1 expression and contribute to hepatocarcinogenesis.

G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel the motility in MAZ phase-separated condensates and subsequently activate CCND1 transcription. Zinc finger (ZF) 2 of MAZ is a responsible for G4 binding, while ZF3-5, but not a highly disordered region, is critical for MAZ condensation. MAZ nuclear puncta overlaps with signals of G4s and various coactivators including BRD4, MED1, CDK9 and active RNA polymerase II, as well as gene activation histone markers. MAZ mutants lacking either G4 binding or phase separation ability did not form nuclear puncta, and showed deficiencies in promoting hepatocellular carcinoma cell proliferation and xenograft tumor formation. Overall, we unveiled that G4s recruit MAZ to the CCND1 promoter and facilitate the motility in MAZ condensates that compartmentalize coactivators to activate CCND1 expression and subsequently exacerbate hepatocarcinogenesis.