Impaired immunosuppressive effect of bone marrow mesenchymal stem cell-derived exosomes on T cells in aplastic anemia.

BACKGROUND: Previous studies have verified the dysfunction of mesenchymal stem cells (MSCs) for immunoregulation in acquired aplastic anemia (AA) patients. Exosomes derived from MSCs can partially substitute MSCs acting as immune regulator. Dysfunction of exosomes (Exos) derived from AA-MSC (AA-Exos) may play a key role in immunologic dissonance. METHOD: In this study, CD3 + T cells were collected and cocultured with AA-Exos and exosomes derived from HD-MSC (HD-Exos). The proliferation, differentiation and activation of CD3 + T cells were detected to compare the immunosuppressive effects between AA-Exos and HD-Exos. An immune-mediated murine model of AA was structured to compare the therapeutic effect of AA-Exos and HD-Exos. Furthermore, total RNA including miRNA from exosomes we purified and total RNA of CD3 + T cells were extracted for RNA-seq in order to construct the miRNA-mRNA network for interactions and functional analysis. RESULTS: AA-Exos had impaired inhibition effects on CD3 + T cells in terms of cell proliferation, activation and differentiation compared with exosomes from HD-Exos. HD-Exos showed a more effective rescue of AA mice compared to AA-Exos. Importantly, we found some differentially expressed miRNA involved in immune response, such as miR-199, miR-128 and miR-486. The Gene Ontology analysis of differentially expressed genes (DEGs) revealed involvement of various cellular processes, such as lymphocyte chemotaxis, lymphocyte migration and response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes analysis illustrated upregulation of critical pathways associated with T cell function after coculturing with AA-Exos compared with HD-Exos, such as graft-versus-host disease, Th17 cell differentiation and JAK-STAT signaling pathway. A miRNA-mRNA network was established to visualize the interaction between them. CONCLUSION: In summary, AA-Exos had impaired immunosuppressive effect on T cells, less ability to rescue AA mice and differently expressed miRNA profile, which might partly account for the pathogenesis of AA as well as provide a new target of AA treatment.

Regioselective Synthesis of N-Vinyl Pyrazoles from Vinyl Sulfonium Salts with Diazo Compounds.

Herein, we develop a base-promoted regioselective synthesis of N-vinyl pyrazoles from vinyl sulfonium salts with diazo compounds. This metal-free synthetic protocol provides an efficient and practical approach to diverse N-vinyl pyrazoles in good to excellent yields under mild conditions. The reaction appears to experience a [3 + 2] annulation of vinyl sulfonium salts and diazo anions rather than diazo compounds, followed by N-vinylation.

[Deciphering Hypoplastic Myelodysplastic Syndrome and Aplastic Anemia via In-Depth Analysis of Lymphocyte Subsets].

OBJECTIVE: To explore the difference of lymphocyte subsets in peripheral blood (PB) between aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (hypo-MDS) patients, meanwhile to compare the clinical parameters obtained from PB and bone marrow (BM). METHODS: The lymphocyte subsets in hypo-MDS (n=25) and AA (n=33) patients were investigated by flow cytometry. Meanwhile, the differences in PB cell counts, biochemical indicators, BM cell counts and abnormal chromosomes between the two groups were analyzed. RESULTS: The percentage of CD8+T cells in AA group was significantly higher than that in hypo-MDS group (P=0.001), while the percentage of CD4+ T cells and the CD4+/CD8+ ratio in AA group were obviously lower than those in hypo-MDS group (P=0.015 and 0.001, respectively). Furthermore, the proportion of CD4+ and CD8+ activated T (TA) cells, and memory Tregs in AA group was distinctly lower than those in hypo-MDS group (P=0.043, 0.015 and 0.024, respectively). Nevertheless, the percentage of CD8+ naive T (TN) cells in AA patients was remarkably higher (P=0.044). And hypo-MDS patients had declined lymphocyte counts (P=0.025), increased levels of total bilirubin (TBil), lactate dehydrogenase (LDH), vitamin B12 and proportion of BM blasts than AA patients (P=0.019, 0.023, 0.027 and 0.045, respectively). CONCLUSION: In this study it was confirmed that the percentages of CD4+ and CD8+ TA cells, memory Tregs and CD8+ TN cells were significantly different between AA and hypo-MDS patients, which provide an essential basis for the identification of these two diseases.

Ultrafast Switching from the Charge Density Wave Phase to a Metastable Metallic State in 1T-TiSe_{2}.

The ultrafast electronic structures of the charge density wave material 1T-TiSe_{2} were investigated by high-resolution time- and angle-resolved photoemission spectroscopy. We found that the quasiparticle populations drove ultrafast electronic phase transitions in 1T-TiSe_{2} within 100 fs after photoexcitation, and a metastable metallic state, which was significantly different from the equilibrium normal phase, was evidenced far below the charge density wave transition temperature. Detailed time- and pump-fluence-dependent experiments revealed that the photoinduced metastable metallic state was a result of the halted motion of the atoms through the coherent electron-phonon coupling process, and the lifetime of this state was prolonged to picoseconds with the highest pump fluence used in this study. Ultrafast electronic dynamics were well captured by the time-dependent Ginzburg-Landau model. Our work demonstrates a mechanism for realizing novel electronic states by photoinducing coherent motion of atoms in the lattice.

Interleukin-10 promoter variability is associated with the susceptibility, severity, and clinical outcomes of aplasitc anemia in Han-Chinese population.

INTRODUCTION: Acquired aplastic anemia (AA), a heterogeneous bone marrow (BM) failure disease, is mainly mediated by the immune destruction of hematopoietic stem cells (HSCs). Given the predominant role of immunosuppressive therapy (IST) in AA, it is sensible to theorize that variants of cytokine genes might affect the outcome of IST. METHODS: In this study, we analyzed three single nucleotide polymorphisms (SNPs) of interleukin (IL)-10 gene in promoter region to clarify their relationship with susceptibility, clinical efficacy and prognosis of AA. RESULTS: We observed that CT genotype of IL-10 rs1800896 was associated with a decreased risk of AA (adjusted OR = 0.541 [95% CI 0.295-0.993], p = .047). Besides, the disease severity differed considerably by IL-10 gene promoter genotypes and alleles. Furthermore, IL-10 SNPs influenced efficacy of IST, with unfavorable response exhibited by rs1800871 and rs1800872 in dominant models (GG + AG vs. AA, adjusted OR = 0.409 [95% CI 0.178-0.943, p = .036] for rs1800871 and GG + GT vs. TT, adjusted OR = 0.396 [95% CI 0.173-0.909, p = .028] for rs1800872, respectively). CONCLUSION: The polymorphisms of IL-10 promoter region were informatively genetic risk factors which might be conducive to the insights into the mechanisms of AA and the design of individual regimens.

A sample-position-autocorrection system with precision better than 1 µm in angle-resolved photoemission experiments.

We present the development of a high-precision sample-position-autocorrection system for photoemission experiments. A binocular vision method based on image pattern matching calculations was realized to track the sample position with an accuracy better than 1 µm, which was much smaller than the spot size of the incident laser. We illustrate the performance of the sample-position-autocorrection system with representative photoemission data on the topological insulator Bi2Se3 and an optimally doped cuprate superconductor Bi2Sr2CaCu2O8+δ. Our method provides new possibilities for studying the temperature-dependent electronic structures in quantum materials using laser-based or spatially resolved photoemission systems with high precision and efficiency.

Visible Light-Promoted Radical-Mediated Ring-Opening/Cyclization of Vinyl Benzotriazoles: An Alternative Approach to Phenanthridines.

A visible light-promoted radical-mediated ring-opening/cyclization of vinyl benzotriazoles has been developed. The method provides an efficient and practical approach to synthesize functionalized phenanthridines from vinyl benzotriazoles with alkyl bromides under mild conditions. Significantly, the readily available and bench-stable vinyl benzotriazoles can serve as valuable alternative radical acceptors during the synthesis of phenanthridines.

Palladium-Catalyzed Carbonylative [5+1] Cycloaddition of N-Tosyl Vinylaziridines: Solvent-Controlled Divergent Synthesis of α,ß- and ß,γ-Unsaturated δ-Lactams.

A palladium-catalyzed carbonylative [5+1] cycloaddition of N-tosyl vinylaziridines with CO has been developed. This protocol affords an efficient and practical approach for solvent-controlled divergent synthesis of α,ß-unsaturated δ-lactams in dimethylformamide and ß,γ-unsaturated δ-lactams in tetrahydrofuran in good to excellent yields. Significantly, the step- and atom-economical reactions are more regioselective toward [5+1] cycloaddition than toward [3+1] cycloaddition.

Anomalous Contribution to the Nematic Electronic States from the Structural Transition in FeSe Revealed by Time- and Angle-Resolved Photoemission Spectroscopy.

High-resolution time- and angle-resolved photoemission measurements were made on FeSe superconductors. With ultrafast photoexcitation, two critical excitation fluences that correspond to two ultrafast electronic phase transitions were found only in the d_{yz}-orbit-derived band near the Brillouin-zone center within our time and energy resolution. Upon comparison to the detailed temperature dependent measurements, we conclude that there are two equilibrium electronic phase transitions (at approximately 90 and 120 K) above the superconducting transition temperature, and an anomalous contribution on the scale of 10 meV to the nematic states from the structural transition is experimentally determined. Our observations strongly suggest that the electronic phase transition at 120 K must be taken into account in the energy band development of FeSe, and, furthermore, the contribution of the structural transition plays an important role in the nematic phase of iron-based high-temperature superconductors.

Visible-Light-Induced 1,6-Enynes Triggered C-Br Bond Homolysis of Bromomalonates: Solvent-Controlled Divergent Synthesis of Carbonylated and Hydroxylated Benzofurans.

Visible-light-induced 1,6-enyne-triggered C-Br bond homolysis of bromomalonates has been developed. This transition-metal-free, photocatalyst-free, and oxidant- and additive-free protocol affords an efficient approach for divergent synthesis of carbonylated and hydroxylated benzofurans from 1,6-enynes and bromomalonates under mild conditions. Significantly, mechanistic studies reveal that the homolysis of C-Br bonds appears to experience an energy-transfer pathway, and the atom-transfer radical addition products are the key intermediates to generate carbonylated and hydroxylated benzofurans.

The novel SLC40A1 (T419I) variant results in a loss-of-function phenotype and may provide insights into the mechanism of large granular lymphocytic leukemia and pure red cell aplasia.

Variants in the solute carrier family 40 member 1 (SLC40A1) gene are the molecular basis of ferroportin disease, which is an autosomal dominant hereditary hemochromatosis. Here, we present a patient with pure red cell aplasia (PRCA) and large granular lymphocytic leukemia (LGLL) associated with an extremely high levels of serum ferritin and iron overload syndrome. Whole exon sequencing revealed a novel heterozygous variant in SLC40A1 (p.T419I), which was found in his daughter as well. A series of functional studies in vitro of the T419I variant in ferroportin were conducted and the results revealed a reduced capacity of iron export from cells without changes in protein localization and its sensitivity to hepcidin. Intracellular iron storage in mutated cells was significantly higher than that of wild-type. These findings suggest that the novel variant p.T419I can cause the classical form of ferroportin disease and an elevated intracellular iron level indicates a potential novel pathogenic mechanism underlying PRCA and LGLL.

Observation and measurement of applied anatomical features for thoracic intervertebral foramen puncture on computed tomography images.

BACKGROUND: Thoracic intervertebral foramen puncture is the key step for interventional therapy on the thoracic nerve roots or dorsal root ganglia. The anatomical features of the thoracic spine are complex, and puncture injury to the pleura, blood vessels, spinal cord, and other tissues may cause serious complications. The spatial anatomical characteristics and related parameters for thoracic intervertebral foramen puncture remain poorly understood. AIM: To observe and summarize the spatially applied anatomical characteristics for intervertebral foramen puncture on different vertebral segments. METHODS: A total of 88 patients (41 males and 47 females) who underwent thoracic minimally invasive interventional treatment at Nanjing Drum Tower Hospital from January 2019 to June 2020 were included. Computed tomography images of 167 thoracic vertebral segments scanned in the prone position were collected. The width of the intertransverse space (DP), the height of the rib neck/head above the lower transverse process (DR), the width of the lateral border of the articular process/lamina (WP), and the width of the posterior border of the vertebral body (WV) were measured. At the upper 1/3 of the intervertebral foramina, the horizontal inclination angle (α) from the lateral border of the articular process/lamina to the posterolateral border of the vertebral body was measured. The ratios DR/DP and WP/WV were calculated. The intervertebral foramen parameters were compared between segments. RESULTS: No rib head/neck occlusion (DR/DP > 0) was found in the intertransverse spaces of T1-2 and T12-L1. The incidence of occlusion for the upper thoracic segments (T1-5, n = 138), middle thoracic segments (T5-9, n = 116), and lower thoracic segments (T9-L1, n = 80) were 76.81%, 100%, and 82.50%, respectively. The incidence of occlusion for the middle thoracic segments was significantly higher than that for the upper and lower thoracic segments (P < 0.05). The incidence of > 1/2 occlusion (DR/DP > 1/2) for the upper, middle, and lower thoracic segments was 7.97%, 74.14%, and 32.50%, respectively. The incidence of > 1/2 occlusion for the middle thoracic segments was significantly higher than that for the upper and lower thoracic segments (P < 0.05). WP was longer than WV on T1-2 to T9-10 and shorter than WV on T10-11 to T12-L1. The horizontal puncture angle (α) into the external opening of the intervertebral foramina was positively correlated with the segments of the thoracic vertebrae from the cephalic to caudal portion (left: r = 0.772, P < 0.01; right: r = 0.771, P < 0.01), and the horizontal inclination angle for T11-12 and T12-L1 was 90°. CONCLUSION: It is necessary to identify the spatial impact of the rib head/neck on the puncture path of the intervertebral foramina and design appropriate puncture angles for different segments.

Myeloid neoplasm with eosinophilia and rearrangement of platelet-derived growth factor receptor beta gene in children: Two case reports.

BACKGROUND: Myeloid neoplasm (MN) with eosinophilia and rearrangement of platelet-derived growth factor receptor beta (PDGFRB) shows a good therapeutic response to imatinib in adults. MN is rarely found in children, and the efficacy of imatinib on pediatric patients remain unclear. CASE SUMMARY: We report 2 pediatric cases diagnosed with MN with eosinophilia and PDGFRB rearrangement who were treated with imatinib. Case 1 was a 1-year-old girl admitted to the hospital because of "abdominal distension with hyperleukocytosis for 3 mo". She had leukocytosis, anemia, and eosinophilia (the absolute eosinophil count (AEC) was 8960/µL), and her fluorescence in situ hybridization (FISH) test revealed that PDGFRB rearrangement was detected in 70% of 500 interphase cells. Case 2 was a 2-year-old girl admitted to the hospital because of "recurrent fever and rashes for 1 mo". Her blood cell count showed an AEC of 3540/µL. The FISH test revealed that PDGFRB rearrangement was detected in 71% of 500 interphase cells. Both patients were diagnosed as MN with eosinophilia and PDGFRB rearrangement. Imatinib was added into their treatment regimen. As expected, complete hematologic remission was achieved after 1 mo of treatment, and symptoms disappeared. CONCLUSION: Although MN with eosinophilia and PDGFRB rearrangement usually occurs in adults, it can be found in children. The therapeutic benefits of imatinib in these 2 pediatric patients were consistent with its reported effects in adult patients.

Meta-Dehydrogenative Alkylation of Arenes with Ethers, Ketones, and Esters Catalyzed by Ruthenium.

A meta-dehydrogenative alkylation of arenes with cyclic ethers, ketones, and esters catalyzed by ruthenium is achieved in the presence of a di-tert-butyl peroxide (DTBP) oxidant. Interestingly, when quinoline and isoquinoline are employed as the directing group, or a chain ether as alkylation reagent, the system produces Minisci reaction products. Mechanistic study indicates that meta-dehydrogenative alkylation is a radical process initiated by DTBP with the assistance of a CAr-Ru bond ortho/para-directing effect.

Accuracy study of a binocular-stereo-vision-based navigation robot for minimally invasive interventional procedures.

BACKGROUND: Medical robot is a promising surgical tool, but no specific one has been designed for interventional treatment of chronic pain. We developed a computed tomography-image based navigation robot using a new registration method with binocular vision. This kind of robot is appropriate for minimal invasive interventional procedures and easy to operate. The feasibility, accuracy and stability of this new robot need to be tested. AIM: To assess quantitatively the feasibility, accuracy and stability of the binocular-stereo-vision-based navigation robot for minimally invasive interventional procedures. METHODS: A box model was designed for assessing the accuracy for targets at different distances. Nine (three sets) lead spheres were embedded in the model as puncture goals. The entry-to-target distances were set 50 mm (short-distance), 100 mm (medium-distance) and 150 mm (long-distance). Puncture procedure was repeated three times for each goal. The Euclidian error of each puncture was calculated and statistically analyzed. Three head phantoms were used to explore the clinical feasibility and stability. Three independent operators conducted foramen ovale placement on head phantoms (both sides) by freehand or under the guidance of robot (18 punctures with each method). The operation time, adjustment time and one-time success rate were recorded, and the two guidance methods were compared. RESULTS: On the box model, the mean puncture errors of navigation robot were 1.7 ± 0.9 mm for the short-distance target, 2.4 ± 1.0 mm for the moderate target and 4.4 ± 1.4 mm for the long-distance target. On the head phantom, no obvious differences in operation time and adjustment time were found among the three performers (P > 0.05). The median adjustment time was significantly less under the guidance of the robot than under free hand. The one-time success rate was significantly higher with the robot (P < 0.05). There was no obvious difference in operation time between the two methods (P > 0.05). CONCLUSION: In the laboratory environment, accuracy of binocular-stereo-vision-based navigation robot is acceptable for target at 100 mm depth or less. Compared with freehand, foramen ovale placement accuracy can be improved with robot guidance.

Efficacy of Platelet-Rich Plasma Containing Xenogenic Adipose Tissue-Derived Stromal Cells on Restoring Intervertebral Disc Degeneration: A Preclinical Study in a Rabbit Model.

Objective: Platelet-rich plasma (PRP) containing multiple growth factors is a promising strategy for disc degeneration. Thus, this study hypothesizes that the combination of PRP and adipose tissue-derived stromal cells (ADSCs) may repair degenerative disc more effectively than using each one of them alone. Methods: The model of early intervertebral disc degeneration was induced by annular puncture in the New Zealand rabbit. Autologous PRP was extracted from fresh arterial blood by using two centrifugation techniques. ADSC was offered by the Center for Clinic Stem Cell Research. Four weeks after the first experiment, PRP or ADSCs or a combination of PRP and ADSCs was injected into the punctured intervertebral disc. Four weeks later, disc height and signal intensity on T2-weighted magnetic resonance imaging (MRI) were assessed. Results: One month after puncture, we detected relatively narrow discs and lower signal intensity in MRI T2-weighted images. At four weeks after injection, the PRP-ADSC group statistically significantly restored discs, compared with PRP, ADSCs, or negative control group. Conclusions: The combination of PRP and ADSCs shows an effective potential to restore degenerated intervertebral discs in the rabbit.