A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.

Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.

A signalling pathway for transcriptional regulation of sleep amount in mice.

In mice and humans, sleep quantity is governed by genetic factors and exhibits age-dependent variation1-3. However, the core molecular pathways and effector mechanisms that regulate sleep duration in mammals remain unclear. Here, we characterize a major signalling pathway for the transcriptional regulation of sleep in mice using adeno-associated virus-mediated somatic genetics analysis4. Chimeric knockout of LKB1 kinase-an activator of AMPK-related protein kinase SIK35-7-in adult mouse brain markedly reduces the amount and delta power-a measure of sleep depth-of non-rapid eye movement sleep (NREMS). Downstream of the LKB1-SIK3 pathway, gain or loss-of-function of the histone deacetylases HDAC4 and HDAC5 in adult brain neurons causes bidirectional changes of NREMS amount and delta power. Moreover, phosphorylation of HDAC4 and HDAC5 is associated with increased sleep need, and HDAC4 specifically regulates NREMS amount in posterior hypothalamus. Genetic and transcriptomic studies reveal that HDAC4 cooperates with CREB in both transcriptional and sleep regulation. These findings introduce the concept of signalling pathways targeting transcription modulators to regulate daily sleep amount and demonstrate the power of somatic genetics in mouse sleep research.

Mechanochemical C-H Arylation and Alkylation of Indoles Using 3 d Transition Metal and Zero-Valent Magnesium.

Although the 3 d transition-metal catalyzed C-H functionalization have been extensively employed to promote the formation of valuable carbon-carbon bonds, the persistent problems, including the use of sensitive Grignard reagents and the rigorous operations (solvent-drying, inert gas protection, metal pre-activation and RMgX addition rate control), still leave great room for further development of sustainable methodologies. Herein, we report a mechanochemical technology toward in-situ preparation of highly sensitive organomagnesium reagents, and thus building two general 3 d transition-metal catalytic platforms that enables regioselective arylation and alkylation of indoles with a wide variety of halides (including those containing post transformable functionalities and heteroaromatic rings). This mechanochemical strategy also brings unique reactivity and high step-economy in producing functionalized N-free indole products.

Clinical manifestations, antimicrobial resistance and genomic feature analysis of multidrug-resistant Elizabethkingia strains.

BACKGROUND: Elizabethkingia is emerging as an opportunistic pathogen in humans. The aim of this study was to investigate the clinical epidemiology, antimicrobial susceptibility, virulence factors, and genome features of Elizabethkingia spp. METHODS: Clinical data from 71 patients who were diagnosed with Elizabethkingia-induced pneumonia and bacteremia between August 2019 and September 2021 were analyzed. Whole-genome sequencing was performed on seven isolates, and the results were compared with a dataset of 83 available Elizabethkingia genomes. Genomic features, Kyoto Encyclopedia of Genes and Genomes (KEGG) results and clusters of orthologous groups (COGs) were analyzed. RESULTS: The mean age of the patients was 56.9 ± 20.7 years, and the in-hospital mortality rate was 29.6% (21/71). Elizabethkingia strains were obtained mainly from intensive care units (36.6%, 26/71) and emergency departments (32.4%, 23/71). The majority of the strains were isolated from respiratory tract specimens (85.9%, 61/71). All patients had a history of broad-spectrum antimicrobial exposure. Hospitalization for invasive mechanical ventilation or catheter insertion was found to be a risk factor for infection. The isolates displayed a high rate of resistance to cephalosporins and carbapenems, but all were susceptible to minocycline and colistin. Genomic analysis identified five ß-lactamase genes (blaGOB, blaBlaB, blaCME, blaOXA, and blaTEM) responsible for ß-lactam resistance and virulence genes involved in stress adaptation (ureB/G, katA/B, and clpP), adherence (groEL, tufA, and htpB) and immune modulation (gmd, tviB, cps4J, wbtIL, cap8E/D/G, and rfbC). Functional analysis of the COGs revealed that "metabolism" constituted the largest category within the core genome, while "information storage and processing" was predominant in both the accessory and unique genomes. The unique genes in our 7 strains were mostly enriched in KEGG pathways related to microRNAs in cancer, drug resistance (ß-lactam and vancomycin), ABC transporters, biological metabolism and biosynthesis, and nucleotide excision repair mechanisms. CONCLUSION: The Elizabethkingia genus exhibits multidrug resistance and carries carbapenemase genes. This study presents a comparative genomic analysis of Elizabethkingia, providing knowledge that facilitates a better understanding of this microorganism.

Recent Progress on Cyclic Peptides' Assembly and Biomedical Applications.

Cyclic peptides are important building blocks for forming functional structures and have been applied in various fields. Considering the significant structural and functional roles of cyclic peptides in materials science and the attributed biophysical advantages, we provide an overview of cyclic peptide types that can self-assemble to form nanotubes, recent progress in stimuli-triggered cyclic peptide assembly, and methods to construct peptide and polymer conjugates based on cyclic peptides with alternative chirality. Specifically, we highlight the roles that stimuli-triggered cyclic peptides and their conjugates play in biomedical applications. Recent progress in other cyclic peptides acting as gelators in drug delivery and biomedicine are also summarized. These cyclic peptides with self-assembly properties are expected to act as adaptive systems for drug delivery and selective disease targeting.

Role and application of chemokine CXCL13 in central nervous system lymphoma.

Chemokine ligand 13 (CXCL13) and its chemokine receptor 5 (CXCR5) both play significant roles in the tumor microenvironment (TME). CXCL13 in cerebrospinal fluid (CSF) has recently been found to have significant diagnostic and prognostic value in primary and secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL), and the CXCL13-CXCR5 axis has been shown to play an important chemotactic role in the TME of CNS-DLBCL. In this review, we first describe the clinical value of CXCL13 in CSF as a prognostic and diagnostic biomarker for CNS-DLBCL. In addition, this review also discusses the specific mechanisms associated with the CXCL13-CXCR5 axis in tumor immunity of primary diffuse large B cell lymphoma of the central nervous system (PCNS-DLBCL) by reviewing the specific mechanisms of this axis in the immune microenvironment of DLBCL and CNS inflammation, as well as the prospects for the use of CXCL13-CXCR5 axis in immunotherapy in PCNS-DLBCL.

Chromosomal-level genome and metabolome analyses of highly heterozygous allohexaploid Dendrocalamus brandisii elucidate shoot quality and developmental characteristics.

Dendrocalamus brandisii (Munro) Kurz is a sympodial bamboo species with inimitable taste and flavorful shoots. Its rapid growth and use as high-quality material make this bamboo species highly valued for both food processing and wood applications. However, genome information for D. brandisii is lacking, primarily due to its polyploidy and large genome size. Here, we assembled a high-quality genome for hexaploid D. brandisii, which comprises 70 chromosomes with a total size of 2,756 Mb, using long-read HiFi sequencing. Furthermore, we accurately separated the genome into its three constituent subgenomes. We used Oxford Nanopore Technologies long reads to construct a transcriptomic dataset covering 15 tissues for gene annotation to complement our genome assembly, revealing differential gene expression and post-transcriptional regulation. By integrating metabolome analysis, we unveiled that well-balanced lignin formation, as well as abundant flavonoid and fructose contents, contribute to the superior quality of D. brandisii shoots. Integrating genomic, transcriptomic, and metabolomic datasets provided a solid foundation for enhancing bamboo shoot quality and developing efficient gene-editing techniques. This study should facilitate research on D. brandisii and enhance its use as a food source and wood material by providing crucial genomic resources.

[Application of Rapid Detection Method Based on NG-Test® CARBA 5 in Bloodstream Infections Associated With Carbapenem-Resistant Enterobacterales].

Objective: To compare the consistency and accuracy of a rapid test method and a traditional test method for pathogen identification, antimicrobial susceptibility and carbapenemase type identification of positive blood culture samples. Methods: A total of 51 positive blood culture samples of bloodstream infection (BSI) were collected between March 2022 and May 2022. All samples were found to be "positive for Gram-negative bacilli" according to the blood smear results. The rapid method was adopted to perform rapid antimicrobial susceptibility test (RAST) and analysis of the positive blood culture samples. According to the RAST result interpretation standards, NG-Test® CARBA 5 was used for rapid carbapenemase detection of the imipenem-resistant strains and the results were confirmed by PCR. In addition, mass spectrometry, VITEK 2 Compact drug sensitivity analysis, and carbapenemase type identification were performed with the colonies cultured with positive samples according to the traditional method. Results: In the identification of bacteria, the rapid method and the traditional method had 100% consistency rate in the identification results of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. In the antimicrobial susceptibility test, the consistency rate between the results of the two methods was high and the consistency rate for results for susceptibility to imipenem was 100%. In the identification of carbapenemase type, 18 serinase-producing strains and 3 metal-ß-lactamase-producing strains of Enterobacterales were detected by the traditional method. With the rapid method, 18 Klebsiella pneumoniae carbapenemase (KPC)-producing strains, 2 New Delhi metallo-betalactamase (NDM)-producing strains, and 1 imipenem enzyme (IMP)-producing strain were identified in the blood culture samples by using a testing kit. Compared with the PCR results, the sensitivity and specificity of the rapid test for determining carbapenemase types were 100%. In this study, we investigated a rapid method for bacteria and carbapenemase type identification of positive blood culture specimens and found that the turnaround time (TAT) of the rapid method was reduced by 1.94 days on average in comparison with the TAT of the traditional method. Conclusion: The rapid method established in the study can effectively shorten the TAT for pathogenic microorganism identification and antimicrobial susceptibility test of blood culture samples, and the joint report of colloidal gold carbapenemase type identification results can provide a reference for clinicians to use antibiotics appropriately and accurately manage multi-drug resistant bacterial infections.

Dynamic Control of Cyclic Peptide Assembly to Form Higher-Order Assemblies.

Chirality correction, asymmetry, ring-chain tautomerism and hierarchical assemblies are fundamental phenomena in nature. They are geometrically related and may impact the biological roles of a protein or other supermolecules. It is challenging to study those behaviors within an artificial system due to the complexity of displaying these features. Herein, we design an alternating D,L peptide to recreate and validate the naturally occurring chirality inversion prior to cyclization in water. The resulting asymmetrical cyclic peptide containing a 4-imidazolidinone ring provides an excellent platform to study the ring-chain tautomerism, thermostability and dynamic assembly of the nanostructures. Different from traditional cyclic D,L peptides, the formation of 4-imidazolidinone promotes the formation of intertwined nanostructures. Analysis of the nanostructures confirmed the left-handedness, representing chirality induced self-assembly. This proves that a rationally designed peptide can mimic multiple natural phenomena and could promote the development of functional biomaterials, catalysts, antibiotics, and supermolecules.

Cutaneous Phaeohyphomycosis of the Right Hand Caused by Exophiala jeanselmei: A Case Report and Literature Review.

Exophiala spp. is increasingly reported as a pathogen causing the cutaneous, subcutaneous or invasive infection. In this report, we present a case of cutaneous phaeohyphomycosis due to E. jeanselmei on the right hand of a farmer, who suffered from this disease three years ago which had not been definitely diagnosed until he was admitted to our hospital. In our hospital, a potential fungal pathogen was observed by histopathological examination, and then was recovered and identified as E. jeanselmei by sequencing its internal transcribed spacer region. After 4 weeks of antifungal treatment, his hand recovered very well. To investigate the in vitro susceptibility of E. jeanselmei isolates to antifungal agents and compare the characteristics of their related infections among immunocompetent and immunocompromised patients, we reviewed 84 cases published in PubMed database between 1980 and 2020.

[Sources of Klebsiella pneumoniae Isolated in a Hospital in the Past Decade and Trends and Changes of in vitro Drug Susceptibility].

Objective: To investigate the source of Klebsiella pneumoniae (KP) isolated in a hospital in the past decade and the in vitro drug susceptibility, and to provide clinical references for the treatment of KP-associated infection. Methods: The detection rate, the sources of the specimens, and in vitro susceptibility to antimicrobial agents of KP isolated from clinical specimens in a hospital between January 2012 and December 2021 were retrospectively analyzed. Resistance rate of the extended-spectrum ß-lactamases-producing isolates vs. that of the non-enzyme-producing ones, and the resistance rate of imipenem-resistant strains vs. that of imipenem-susceptible ones were compared and analyzed. Carbapenase inhibitor enhancement test was used to identify the types of the carbapenemases. Results: In total, 34 573 strains of KP were isolated from 1 684 668 clinical specimens, accounting for 14.6% of bacterial isolates. There were 16 888 non-repeated strains of KP. The main specimen sources of the isolates were sputum (10 274/16 888, 60.8%), blood (1 913/16 888, 11.3%) and urine (1 876/16 888, 11.1%). The proportion of extended-spectrum ß-lactamases-producing isolates increased from 29.6% (409/1 382) in 2012 to 38.9% (967/2 487) in 2021, and the resistance rate to antimicrobial agents was higher than that of non-enzyme-producing ones ( P<0.05). The proportion of imipenem-resistant strains increased from 3.2% (44/1 382) in 2012 to 23.4% (583/2 487) in 2021, and the resistance rate to antimicrobial agents was higher than that of imipenem-susceptible strains ( P<0.05). Serine carbapenase-producing strains accounted for 91.1% (920/1010). Conclusion: The resistance to antimicrobial agents of KP strains isolated from clinical specimens increased. It is necessary to monitor the in vitro drug susceptibility and the type of the carbapenemases of the isolates in order to provide guidance for the clinical usage of antibiotics.

Correlation analysis of long non-coding RNA TUG1 with disease risk, clinical characteristics, treatment response, and survival profiles of adult Ph- Acute lymphoblastic leukemia.

BACKGROUND: Long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) is reported to be involved in the progression and development of several malignancies; however, its role in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) is unknown. The present study aimed to explore the correlation of lncRNA TUG1 with disease risk, disease condition, and prognosis of adult Ph- ALL. METHODS: Total 101 adult Ph- ALL patients and 40 bone marrow (BM) donors were included, followed by detection of BM monocyte cell lncRNA TUG1 expression by reverse transcription-quantitative polymerase chain reaction. According to the quantiles of lncRNA TUG1 expression in Ph- ALL patients, these patients were divided into four tiers: tier 1 (ranked in 0%~25%), tier 2 (ranked in 25%~50%), tier 3 (ranked in 50%~75%), and tier 4 (ranked in 75%~100%). RESULTS: LncRNA TUG1 was upregulated in Ph- ALL patients compared with healthy donors. Further analysis indicated that in Ph- ALL patients, higher lncRNA TUG1 tier was correlated with the presence of central nervous system leukemia, increased white blood cell level, and bone marrow blasts. Furthermore, higher lncRNA TUG1 tier was negatively associated with complete remission (CR) within 4 weeks, total CR, and allogeneic hematopoietic stem cell transplant achievement. In addition, higher lncRNA TUG1 tier was associated with decreased disease-free survival and overall survival, which was further verified to be an independent factor by Cox's regression analysis. CONCLUSION: lncRNA TUG1 presents potential to be a novel biomarker for disease risk assessment and survival surveillance in Ph- ALL management.

Sperm miRNAs- potential mediators of bull age and early embryo development.

BACKGROUND: Sperm miRNAs were reported to regulate spermatogenesis and early embryonic development in some mammals including bovine. The dairy cattle breeding industry now tends to collect semen from younger bulls under high selection pressure at a time when semen quality may be suboptimal compared to adult bulls. Whether the patterns of spermatic miRNAs are affected by paternal age and/or impact early embryogenesis is not clear. Hence, we generated small non-coding RNA libraries of sperm collected from same bulls at 10, 12, and 16 months of age, using 16 months as control for differential expression and functional analysis. RESULTS: We firstly excluded all miRNAs present in measurable quantity in oocytes according to the literature. Of the remaining miRNAs, ten sperm-borne miRNAs were significantly differentially expressed in younger bulls (four in the 10 vs 16 months contrast and six in the 12 vs 16 months contrast). Targets of miRNAs were identified and compared to the transcriptomic database of two-cell embryos, to genes related to two-cell competence, and to the transcriptomic database of blastocysts. Ingenuity pathway analysis of the targets of these miRNAs suggested potential influence on the developmental competence of two-cell embryos and on metabolism and protein synthesis in blastocysts. CONCLUSIONS: The results showed that miRNA patterns in sperm are affected by the age of the bull and may mediate the effects of paternal age on early embryonic development.

Palladium-Catalyzed C-H/C-H Cross-Coupling by Mechanochemistry: Direct Alkenylation and Heteroarylation of N1-Protected 1H-Indazoles.

C3-alkenylated and C3-(hetero)arylated 1H-indazoles are privileged structural motifs in numerous pharmaceuticals. Direct C3-alkenylation and C3-(hetero)arylation of 1H-indazoles have been significantly challenging because of the inert nature of this carbon center. Herein, we present an efficient mechanochemical strategy for palladium-catalyzed C-H/C-H cross-coupling to construct C3-alkenylated and C3-heteroarylated 1H-indazoles using low-cost copper oxidants with satisfactory product yields and broad functional group tolerance. The robustness of the developed protocols was further demonstrated by the unprecedented total mechanosynthesis of the intermediate of PLK4 inhibitor CFI-400945 and HIF-1α inhibitor YC-1.

A Novel Long-Range n to π* Interaction Secures the Smallest known α-Helix in Water.

The introduction of an amide bond linking side chains of the first and fifth amino acids forms a cyclic pentapeptide that optimally stabilizes the smallest known α-helix in water. The origin of the stabilization is unclear. The observed dependence of α-helicity on the solvent and cyclization linker led us to discover a novel long-range n to π* interaction between a main-chain amide oxygen and a uniquely positioned carbonyl group in the linker of cyclic pentapeptides. CD and NMR spectra, NMR and X-ray structures, modelling, and MD simulations reveal that this first example of a synthetically incorporated long-range n to π* CO⋅⋅⋅Cγ =Ο interaction uniquely enforces an almost perfect and remarkably stable peptide α-helix in water but not in DMSO. This unusual interaction with a covalent amide bond outside the helical backbone suggests new approaches to synthetically stabilize peptide structures in water.

Identification of a 35S U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP) complex intermediate in spliceosome assembly.

The de novo assembly and post-splicing reassembly of the U4/U6.U5 tri-snRNP remain to be investigated. We report here that ZIP, a protein containing a CCCH-type zinc finger and a G-patch domain, as characterized by us previously, regulates pre-mRNA splicing independent of RNA binding. We found that ZIP physically associates with the U4/U6.U5 tri-small nuclear ribonucleoprotein (tri-snRNP). Remarkably, the ZIP-containing tri-snRNP, which has a sedimentation coefficient of ∼35S, is a tri-snRNP that has not been described previously. We also found that the 35S tri-snRNP contains hPrp24, indicative of a state in which the U4/U6 di-snRNP is integrating with the U5 snRNP. We found that the 35S tri-snRNP is enriched in the Cajal body, indicating that it is an assembly intermediate during 25S tri-snRNP maturation. We showed that the 35S tri-snRNP also contains hPrp43, in which ATPase/RNA helicase activities are stimulated by ZIP. Our study identified, for the first time, a tri-snRNP intermediate, shedding new light on the de novo assembly and recycling of the U4/U6.U5 tri-snRNP.

In Vitro Study on the Dynamics of Blood Flow Impelled by an Alternating Current Magnetohydrodynamic Blood Pump.

Artificial hearts are effective devices to treat heart failure in clinical practice and can be divided into two categories: artificial hearts and ventricular assist devices. The goal of this work was to investigate the fluidity and biological changes of in vitro sheep blood using a novel alternating current (AC) magnetohydrodynamic blood pump (central magnetic intensity: 0.9 T, alternating current frequency of the electric motor: 0-80 Hz). Blood samples were collected from five sheep and were divided into two groups: the control group (no exposure to an external magnetic field) and the exposed group (3 h of exposure to an alternating magnetic field). The blood cell counts, changes in blood viscosity, and ultrastructural changes of the blood cells under transmission electron microscopy were investigated. This study demonstrated several findings: (i) Continuous sheep blood flow can be achieved; (ii) The blood cell counts remained unchanged after 3 h of exposure to an alternating magnetic field; (iii) Compared with the control group, the high- and low-shear viscosities of the whole blood from the sheep significantly decreased after 3 h of exposure to an alternating magnetic field (P < 0.05 and P < 0.01, respectively). Plasma viscosity was significantly reduced after exposure to high-intensity alternating magnetic fields (P < 0.001); (iv) The cytoplasm of blood cells (especially erythrocytes) became lighter in color in the exposure group compared to the control group, and "beads-on-string" aggregations of black particles appeared. This work provides detailed and reliable scientific research data for the development of this type of blood pump, which may serve as a transition to the clinical artificial heart.

The Structure of ampG Gene in Pseudomonas aeruginosa and Its Effect on Drug Resistance.

In order to study the relationship between the structure and function of AmpG, structure, site-specific mutation, and gene complementary experiments have been performed against the clinical isolates of Pseudomonas aeruginosa. We found that there are 51 nucleotide variations at 34 loci over the ampG genes from 24 of 35 P. aeruginosa strains detected, of which 7 nucleotide variations resulted in amino acid change. The ampG variants with the changed nucleotides (amino acids) could complement the function of ampG deleted PA01 (PA01ΔG). The ampicillin minimum inhibitory concentration (MIC) of PA01ΔG complemented with 32 ampG variants was up to 512 µg/ml, similar to the original PA01 (P. aeruginosa PA01). Furthermore, site-directed mutation of two conservative amino acids (I53 and W90) showed that when I53 was mutated to 53S or 53T (I53S or I53T), the ampicillin MIC level dropped drastically, and the activity of AmpC ß-lactamase decreased as well. By contrast, the ampicillin MIC and the activity of AmpC ß-lactamase remained unchanged for W90R and W90S mutants. Our studies demonstrated that although nucleotide variations occurred in most of the ampG genes, the structure of AmpG protein in clinical isolates is stable, and conservative amino acid is necessary to maintain normal function of AmpG.

Europium-Labeled Synthetic C3a Protein as a Novel Fluorescent Probe for Human Complement C3a Receptor.

Measuring ligand affinity for a G protein-coupled receptor is often a crucial step in drug discovery. It has been traditionally determined by binding putative new ligands in competition with native ligand labeled with a radioisotope of finite lifetime. Competing instead with a lanthanide-based fluorescent ligand is more attractive due to greater longevity, stability, and safety. Here, we have chemically synthesized the 77 residue human C3a protein and conjugated its N-terminus to europium diethylenetriaminepentaacetate to produce a novel fluorescent protein (Eu-DTPA-hC3a). Time-resolved fluorescence analysis has demonstrated that Eu-DTPA-hC3a binds selectively to its cognate G protein-coupled receptor C3aR with full agonist activity and similar potency and selectivity as native C3a in inducing calcium mobilization and phosphorylation of extracellular signal-regulated kinases in HEK293 cells that stably expressed C3aR. Time-resolved fluorescence analysis for saturation and competitive binding gave a dissociation constant (Kd) of 8.7 ± 1.4 nM for Eu-DTPA-hC3a and binding affinities for hC3a (pKi of 8.6 ± 0.2 and Ki of 2.5 nM) and C3aR ligands TR16 (pKi of 6.8 ± 0.1 and Ki of 138 nM), BR103 (pKi of 6.7 ± 0.1 and Ki of 185 nM), BR111 (pKi of 6.3 ± 0.2 and Ki of 544 nM) and SB290157 (pKi of 6.3 ± 0.1 and Ki of 517 nM) via displacement of Eu-DTPA-hC3a from hC3aR. The macromolecular conjugate Eu-DTPA-hC3a is a novel nonradioactive probe suitable for studying ligand-C3aR interactions with potential value in accelerating drug development for human C3aR in physiology and disease.

Prognostic Significance of Monocytes and Monocytic Myeloid-Derived Suppressor Cells in Diffuse Large B-Cell Lymphoma Treated with R-CHOP.

BACKGROUND/AIMS: To evaluate the prognostic significance of monocytes and monocytic myeloid-derived suppressor cells (M-MDSCs) for patients with diffuse large B-cell lymphoma (DLBCL) under R-CHOP chemotherapy. METHODS: Flow cytometry (FCM) was applied to measure M-MDSCs (CD14+ HLA-DRlow/- M-MDSCs). RESULTS: Analysis of 144 patients with DLBCL under R-CHOP treatment showed that the 5-year overall survival rate was 61.09% (95% CI: 43.72%-72.56%) and the average survival time of patients with monocytes (%) ≥ 8% was shorter than those with monocytes (%) < 8% (P = 0.0036). Further stratified analysis suggested that the average survival time of patients with monocytes (%) ≥ 8% was shorter than patients with monocytes (%) < 8% in the moderate outcome group (R-IPI = 1, 2) (P = 0.0168) and in the poorest outcome group (R-IPI > 2) (P = 0.0397), meanwhile, there was no significant difference in survival of patients with monocytes (%) ≥ 8% compared to patients with monocytes (%) < 8% in the best outcome group (R-IPI = 0) (P = 0.3106). Both of monocytes (%) and M-MDSCs were decreased in different R-IPI groups after 4-course of R-CHOP chemotherapy (P < 0.05). CONCLUSION: Our results indicated that monocytes (%) and M-MDSCs combined with R-IPI may be a simple and efficient immunological index to evaluate prognosis.