ABSTRACT
The use of particle accelerators as photon sources has enabled advances in science and technology1. Currently the workhorses of such sources are storage-ring-based synchrotron radiation facilities2-4 and linear-accelerator-based free-electron lasers5-14. Synchrotron radiation facilities deliver photons with high repetition rates but relatively low power, owing to their temporally incoherent nature. Free-electron lasers produce radiation with high peak brightness, but their repetition rate is limited by the driving sources. The steady-state microbunching15-22 (SSMB) mechanism has been proposed to generate high-repetition, high-power radiation at wavelengths ranging from the terahertz scale to the extreme ultraviolet. This is accomplished by using microbunching-enabled multiparticle coherent enhancement of the radiation in an electron storage ring on a steady-state turn-by-turn basis. A crucial step in unveiling the potential of SSMB as a future photon source is the demonstration of its mechanism in a real machine. Here we report an experimental demonstration of the SSMB mechanism. We show that electron bunches stored in a quasi-isochronous ring can yield sub-micrometre microbunching and coherent radiation, one complete revolution after energy modulation induced by a 1,064-nanometre-wavelength laser. Our results verify that the optical phases of electrons can be correlated turn by turn at a precision of sub-laser wavelengths. On the basis of this phase correlation, we expect that SSMB will be realized by applying a phase-locked laser that interacts with the electrons turn by turn. This demonstration represents a milestone towards the implementation of an SSMB-based high-repetition, high-power photon source.
ABSTRACT
Piezo1 functions as a special transducer of mechanostress into electrochemical signals and is implicated in the pathogenesis of various diseases across different disciplines. However, whether Piezo1 contributes to the pathogenesis of lupus nephritis (LN) remains elusive. To study this, we applied an agonist and antagonist of Piezo1 to treat lupus-prone MRL/lpr mice. Additionally, a podocyte-specific Piezo1 knockout mouse model was also generated to substantiate the role of Piezo1 in podocyte injury induced by pristane, a murine model of LN. A marked upregulation of Piezo1 was found in podocytes in both human and murine LN. The Piezo1 antagonist, GsMTx4, significantly alleviated glomerulonephritis and tubulointerstitial damage, improved kidney function, decreased proteinuria, and mitigated podocyte foot process effacement in MRL/lpr mice. Moreover, podocyte-specific Piezo1 deletion showed protective effects on the progression of proteinuria and podocyte foot process effacement in the murine LN model. Mechanistically, Piezo1 expression was upregulated by inflammatory cytokines (IL-6, TNF-α and IFN-γ), soluble urokinase Plasminogen Activator Receptor and its own activation. Activation of Piezo1 elicited calcium influx, which subsequently enhanced Rac1 activity and increased active paxillin, thereby promoting cytoskeleton remodeling and decreasing podocyte motility. Thus, our work demonstrated that Piezo1 contributed to podocyte injury and proteinuria progression in LN. Hence, targeted therapy aimed at decreasing or inhibiting Piezo1 could represent a novel strategy to treat LN.
ABSTRACT
Acute lung injury (ALI) is one of the life-threatening complications of sepsis, and macrophage polarization plays a crucial role in the sepsis-associated ALI. However, the regulatory mechanisms of macrophage polarization in ALI and in the development of inflammation are largely unknown. In this study, we demonstrated that macrophage polarization occurs in sepsis-associated ALI and is accompanied by mitochondrial dysfunction and inflammation, and a decrease of PRDX3 promotes the initiation of macrophage polarization and mitochondrial dysfunction. Mechanistically, PRDX3 overexpression promotes M1 macrophages to differentiate into M2 macrophages, and enhances mitochondrial functional recovery after injury by reducing the level of glycolysis and increasing TCA cycle activity. In conclusion, we identified PRDX3 as a critical hub integrating oxidative stress, inflammation, and metabolic reprogramming in macrophage polarization. The findings illustrate an adaptive mechanism underlying the link between macrophage polarization and sepsis-associated ALI.
Subject(s)
Acute Lung Injury , Macrophages , Peroxiredoxin III , Humans , Acute Lung Injury/metabolism , Inflammation/metabolism , Lipopolysaccharides , Macrophages/metabolism , Mitochondrial Diseases/complications , Mitochondrial Diseases/metabolism , Peroxiredoxin III/metabolism , Sepsis/metabolism , Animals , MiceABSTRACT
Anyons, exotic quasiparticles in two-dimensional space exhibiting nontrivial exchange statistics, play a crucial role in universal topological quantum computing. One notable proposal to manifest the fractional statistics of anyons is the toric code model; however, scaling up its size through quantum simulation poses a serious challenge because of its highly entangled ground state. In this Letter, we demonstrate that a modular superconducting quantum processor enables hardware-pragmatic implementation of the toric code model. Through in-parallel control across separate modules, we generate a 10-qubit toric code ground state in four steps and realize six distinct braiding paths to benchmark the performance of anyonic statistics. The path independence of the anyonic braiding statistics is verified by correlation measurements in an efficient and scalable fashion. Our modular approach, serving as a hardware embodiment of the toric code model, offers a promising avenue toward scalable simulation of topological phases, paving the way for quantum simulation in a distributed fashion.
ABSTRACT
BACKGROUND: Optimal medical therapy (OMT) for uncomplicated type B aortic dissection (uTBAD) provides excellent short-term outcomes during follow up; however, its long-term therapeutic effectiveness is unsatisfactory. This study evaluated the predictive value of systemic immune-inflammation index (SII) for adverse events among patients with acute uTBAD undergoing OMT. METHODS: We performed a retrospective analysis of a prospectively maintained database between 2013 and 2020. The primary end point in this study was composite outcomes including aortic intervention, all-cause mortality, retrograde type A aortic dissection (rTAAD) and aortic diameter growth > 5 mm. The patients were divided into high and low SII groups according to the optimal cut-off value of SII as determined using the receiver operating characteristic curve. Cox proportional hazards models were constructed to estimate the hazards ratios and identify the predictors of composite outcomes. RESULTS: A total of 124 patients with acute uTBAD who underwent OMT were enrolled. One patient died during hospitalisation. At the end of a mean follow-up duration of 51 ± 23 months, 53 (43.1%) patients experienced composite outcomes, 15 patients (12.2%) died, 31 (25.2%) underwent aortic intervention, 21 (17.1%) exhibited diameter growth of > 5 mm, and 2 developed rTAAD. The patients were divided into low SII group (n = 78, 62.9%) and high SII group (n = 46, 37.1%) as per the optimal cut-off SII value of 1449. The incidence of composite outcomes in high SII group was significantly higher than that in low SII (28 [60.9%] vs. 26[33.3%], p < 0.01). Patients with high SII demonstrated significantly higher mortality rate than those with a low SII (11 [23.9%] vs. 5 [6.4%], respectively; p < 0.01). In addition, the high SII group had significantly higher rate of aortic-related reinterventions than the low SII group (16 [34.8%] vs. 15 [19.2%], p = 0.03). Multivariable Cox analyses showed that a high SII score was independently associated with composite outcomes rate (hazard ratio, 2.15; 95% confidence interval, 1.22-3.78; p < 0.01). CONCLUSIONS: The long-term therapeutic effectiveness of OMT alone in patients with acute uTBAD is unsatisfactory. An SII > 1449 at the time of diagnosis is an independent predictor of OMT failure.
Subject(s)
Aortic Aneurysm, Thoracic , Aortic Dissection , Humans , Retrospective Studies , Aortography , Aortic Dissection/diagnostic imaging , Aortic Dissection/therapy , Inflammation , PrognosisABSTRACT
PURPOSE: To evaluate microvasculature alterations of the peripapillary retina and macula and to assess whether the changes can detect preclinical retinopathy in systemic lupus erythematosus patients. METHODS: Cross-sectional study of 32 systemic lupus erythematosus patients without retinopathy and 22 normal controls. Optical coherence tomography angiography was used to measure the microvasculature of the peripapillary retina and macula. Vessel densities (VD, %) and fractal dimensions of superficial capillary plexus (SCP) and deep capillary plexus were calculated. RESULTS: Compared with controls, macular vessel densities of the whole image SCP (macular vessel density of SCP-wi) and macular vessel density of inferior SCP (macular vessel density of SCP-i) were significantly reduced in systemic lupus erythematosus patients ( P < 0.05). The peripapillary vessel densities (peripapillary vessel density [pVD]) of a 2.5-mm circle of SCP (pVD of SCP Φ2.5 ), pVD of SCP Φ3.5 , and pVD of inferior region of the inner circle of SCP (pVD of SCP-ii) were significantly reduced in patients treated with hydroxychloroquine >5 years. Macular vessel density of SCP-wi declined with age (ß = -0.12; P < 0.01) and pVD of SCP-ii declined with hydroxychloroquine cumulative dose (ß = -0.01; P < 0.01). Macular vessel density of SCP-i had the best discrimination power of 0.77 ( P < 0.01). CONCLUSION: Systemic lupus erythematosus patients without ocular involvement had microvasculature alterations that were particularly evident in the SCP. Peripapillary retina microvasculature may be reduced in patients with longer hydroxychloroquine treatment.
Subject(s)
Lupus Erythematosus, Systemic , Retinal Diseases , Humans , Tomography, Optical Coherence/methods , Fluorescein Angiography/methods , Retinal Vessels/diagnostic imaging , Cross-Sectional Studies , Hydroxychloroquine , Retina , Microvessels , Retinal Diseases/diagnosis , Retinal Diseases/etiology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/drug therapyABSTRACT
The aryl hydrocarbon receptor (AHR) has been identified as a significant driver of tumorigenesis. However, its clinical significance in acute myeloid leukemia (AML) remains largely unclear. In this study, RNA-Seq data from AML patients (bone marrow samples from 173 newly diagnosed AML patients) obtained from the TCGA database, and normal human RNA-Seq data (bone marrow samples from 70 healthy individuals) obtained from the GTEX database are downloaded for external validation and complementarity. The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes. In vitro experiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance. These findings deepen our understanding of the AHR signaling pathway's involvement in AML.
Subject(s)
Cytarabine , Leukemia, Myeloid, Acute , Humans , Cytarabine/pharmacology , Oxidative Phosphorylation , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolismABSTRACT
Humic acid (HA) is a typical refractory organic matter, so it is of great significance to investigate its effect on the performance of Anammox granular sludge. When the dosage of HA ≤ 50 mg/L, HA promotes the total nitrogen removal rate (NRR) to 1.45 kg/(m3·day). When HA was between 50 and 100 mg/L, the NRR of Anammox was stable. At this time, the adsorption of HA causes the sludge to gradually turn from red to brown, but the activities of heme and enzymes showed that its capacity was not affected. When HA levels reached 250 mg/L, the NRR dropped to 0.11 kg/(m3·day). Moderate HA levels promoted the release of extracellular polymeric substance (EPS), but excessive HA levels lead to a decrease in EPS concentrations. HA inhibited Anammox activity, which indirectly hindered the transmission of substrate and accumulated substrate toxicity. Although HA promoted the increase of heterotrophic microbial abundance in Anammox system, the microbial diversity decreased gradually. With the increase of HA concentration, the abundance of Candidatus_Brocadia, the main functional microorganism of Anammox system, decreased gradually, while the abundance of Candidatus_Kuenenia increased gradually.
Subject(s)
Humic Substances , Nitrogen , Sewage , Waste Disposal, Fluid , Sewage/microbiology , Waste Disposal, Fluid/methods , Bioreactors/microbiology , Microbiota , AnaerobiosisABSTRACT
Oligodendrocyte precursor cells (OPCs) are uniformly distributed in the mammalian brain; however, their function is rather heterogeneous in respect to their origin, location, receptor/channel expression and age. The basic helix-loop-helix transcription factor Olig2 is expressed in all OPCs as a pivotal determinant of their differentiation. Here, we identified a subset (2%-26%) of OPCs lacking Olig2 in various brain regions including cortex, corpus callosum, CA1 and dentate gyrus. These Olig2 negative (Olig2neg ) OPCs were enriched in the juvenile brain and decreased subsequently with age, being rarely detectable in the adult brain. However, the loss of this population was not due to apoptosis or microglia-dependent phagocytosis. Unlike Olig2pos OPCs, these subset cells were rarely labeled for the mitotic marker Ki67. And, accordingly, BrdU was incorporated only by a three-day long-term labeling but not by a 2-hour short pulse, suggesting these cells do not proliferate any more but were derived from proliferating OPCs. The Olig2neg OPCs exhibited a less complex morphology than Olig2pos ones. Olig2neg OPCs preferentially remain in a precursor stage rather than differentiating into highly branched oligodendrocytes. Changing the adjacent brain environment, for example, by acute injuries or by complex motor learning tasks, stimulated the transition of Olig2pos OPCs to Olig2neg cells in the adult. Taken together, our results demonstrate that OPCs transiently suppress Olig2 upon changes of the brain activity.
Subject(s)
Brain Injuries , Oligodendrocyte Precursor Cells , Animals , Oligodendrocyte Precursor Cells/metabolism , Nerve Tissue Proteins/metabolism , Oligodendrocyte Transcription Factor 2/metabolism , Oligodendroglia/metabolism , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Brain Injuries/metabolism , Mammals/metabolismABSTRACT
The high-mobility-group domain-containing transcription factor Sox9 confers glial competence to neuroepithelial precursors in the developing central nervous system and is an important determinant of astroglial and oligodendroglial specification. In oligodendroglial cells, it remains expressed in oligodendrocyte progenitor cells (OPCs) of the developing nervous system, but is shut off in differentiating oligodendrocytes as well as in OPCs that persist in the adult nervous system. To better understand the role of Sox9 in OPCs, we generated mouse models that allowed oligodendroglial expression of a Sox9 transgene during development or in the adult. With transgene expression beginning in the last trimester of pregnancy, the number of OPCs increased dramatically, followed by comparable gains in the number of pre-myelinating and myelinating oligodendrocytes as assessed by marker gene expression. This argues that Sox9 boosts oligodendrogenesis during ontogenetic development at all stages, including terminal oligodendrocyte differentiation. When Sox9 transgene expression started in the adult, many transgene-expressing OPCs failed to maintain their progenitor cell identity and instead converted into myelinating oligodendrocytes. As infrequent and inefficient differentiation of adult OPCs is one of the main obstacles to effective remyelination in demyelinating diseases such as Multiple Sclerosis, increased Sox9 levels in adult OPCs may substantially increase their remyelination capacity.
Subject(s)
Multiple Sclerosis , Oligodendroglia , Mice , Animals , Oligodendroglia/metabolism , Cell Differentiation/physiology , Neuroglia/metabolism , Multiple Sclerosis/metabolism , Stem Cells/metabolism , Myelin Sheath/metabolismABSTRACT
NG2 glia represents a distinct type of macroglial cells in the CNS and is unique among glia because they receive synaptic input from neurons. They are abundantly present in white and gray matter. While the majority of white matter NG2 glia differentiates into oligodendrocytes, the physiological impact of gray matter NG2 glia and their synaptic input are still ill defined. Here, we asked whether dysfunctional NG2 glia affect neuronal signaling and behavior. We generated mice with inducible deletion of the K+ channel Kir4.1 in NG2 glia and performed comparative electrophysiological, immunohistochemical, molecular and behavioral analyses. Kir4.1 was deleted at postnatal day 23-26 (recombination efficiency about 75%) and mice were investigated 3-8 weeks later. Notably, these mice with dysfunctional NG2 glia demonstrated improved spatial memory as revealed by testing new object location recognition while working and social memory remained unaffected. Focussing on the hippocampus, we found that loss of Kir4.1 potentiated synaptic depolarizations of NG2 glia and stimulated the expression of myelin basic protein while proliferation and differentiation of hippocampal NG2 glia remained largely unaffected. Mice with targeted deletion of the K+ channel in NG2 glia showed impaired long-term potentiation at CA3-CA1 synapses, which could be fully rescued by extracellular application of a TrkB receptor agonist. Our data demonstrate that proper NG2 glia function is important for normal brain function and behavior.
Subject(s)
Neuroglia , Proteoglycans , Mice , Animals , Proteoglycans/metabolism , Neuroglia/metabolism , Neurons/metabolism , Oligodendroglia/metabolism , Neuronal Plasticity , Antigens/metabolismABSTRACT
The chaperon protein sigma-1 receptor (S1R) has been discovered over 40 years ago. Recent pharmacological studies using S1R exogenous ligands demonstrated a promising therapeutical potential of targeting the S1R in several neurological disorders. Although intensive in vitro studies have revealed S1Rs are mainly residing at the membrane of the endoplasmic reticulum (ER), the cell-specific in vivo expression pattern of S1Rs is still unclear, mainly because of the lack of a reliable detection method which also prevented a comprehensive functional analysis. Here, first, we identified a highly specific antibody using S1R knockout (KO) mice and established an immunohistochemical protocol involving a 1% sodium dodecyl sulphate (SDS) antigen retrieval step. Second, we characterized the S1R expression in the mouse brain and can demonstrate that the S1R is widely expressed: in principal neurons, interneurons and all glial cell types. In addition, unlike reported in previous studies, we showed that the S1R expression in astrocytes is not colocalized with the astrocytic cytoskeleton protein GFAP. Thus, our results raise concerns over previously reported S1R properties. Finally, we generated a Cre-dependent S1R conditional KO mouse (S1R flox) to study cell-type-specific functions of the S1R. As a proof of concept, we successfully ablated S1R expressions in neurons or microglia employing neuronal and microglial Cre-expressing mice, respectively. In summary, we provide powerful tools to cell-specifically detect, delete and functionally characterize S1R in vivo.
Subject(s)
Neurons , Receptors, sigma , Mice , Animals , Neurons/metabolism , Neuroglia/metabolism , Receptors, sigma/genetics , Astrocytes/metabolism , Mice, Knockout , Sigma-1 ReceptorABSTRACT
Acute myeloid leukemia (AML) is a heterogeneous blood cancer. Effective immunotherapies for AML are hindered by a lack of understanding of the tumor microenvironment (TME). Here, we retrieved published single-cell RNA sequencing data for 128,688 cells derived from 29 bone marrow aspirates, including 21 AML patients and eight healthy donors. We established a global tumor ecosystem including nine main cell types. Myeloid, T, and NK cells were further re-clustered and annotated. Developmental trajectory analysis indicated that exhausted CD8+ T cells might develop via tissue residual memory T cells (TRM) in the AML TME. Significantly higher expression levels of exhaustion molecules in AML TRM cells suggested that these cells were influenced by the TME and entered an exhausted state. Meanwhile, the upregulation of checkpoint molecules and downregulation of granzyme were also observed in AML NK cells, suggesting an exhaustion state. In conclusion, our comprehensive profiling of T/NK subpopulations provides deeper insights into the AML immunosuppressive ecosystem, which is critical for immunotherapies.
ABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive, lethal disease in which ectopic lung fibroblast (LF) activation plays a vital part. We have previously shown that alamandine (ALA) exerts anti-fibrosis effects via the MAS-related G-protein coupled receptor D (MrgD). Here, we further investigate how it moderates transforming growth factor ß1 (TGF-ß1)-induced LF activation by regulating glucose metabolism and mitochondria autophagy (mitophagy). METHODS: In vitro, we examined glycolysis-related protein hexokinase 2 (HK2), 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and lactic acid in cells treated with TGF-ß1. The oxygen consumption rate and the extracellular acidification rate were detected using Seahorse assays. Then, mitophagy was evaluated using transmission electron microscopy, mt-Keima, and the co-localization of Parkin and COX IV with LC3 and LAMP1, respectively. The autophagic degradation of HK2 and PFKFB3 was detected by 3MA and bafilomycin A1 and assessed by their co-localization with LC3 and LAMP1, respectively. The effects of ALA on LF activation markers collagen I and α-SMA were detected. The effects of ALA on glucose metabolism, mitophagy, and the activation of LF were also investigated in vivo. RESULTS: We found that the ALA/MrgD axis improved TGF-ß1-mediated LF activation by repressing glycolysis by downregulating HK2 and PFKFB3 expression. Lactic acid sustained positive feedback between glycolysis and LF activation by maintaining the expression of HK2 and PFKFB3. We also showed that glycolysis enhancement resulted from blocking the autophagic degradation of HK2 and PFKFB3 while upregulated mRNA levels by TGF-ß1, while all of those improved by ALA adding. Importantly, we determined that moderation of Parkin/LC3-mediated mitophagy by TGF-ß1 also promotes glycolysis but is reversed by ALA. Furthermore, we proved that ALA counteracts the effects of bleomycin on HK2, PFKFB3, LC3, Parkin, and LF activation in vivo. CONCLUSION: In this study, we show that the ALA/MrgD axis prevents TGF-ß1-mediated fibroblast activation via regulation of aerobic glycolysis and mitophagy.
Subject(s)
Mitophagy , Transforming Growth Factor beta1 , Transforming Growth Factor beta1/metabolism , Fibroblasts/metabolism , Glycolysis , Ubiquitin-Protein Ligases/metabolism , Glucose/metabolismABSTRACT
OBJECTIVE: To report the results of optimal medical treatment (OMT) and endovascular aortic repair (EVAR) in patients with uncomplicated isolated abdominal aortic dissection (IAAD). METHODS: A retrospective review of 96 consecutive patients with uncomplicated IAAD (uIAAD) managed at a single tertiary vascular unit between January 2011 and July 2021 was conducted. Standard methods for univariate and survival analyses were used. The primary outcomes were all-cause mortality. Secondary end points included uIAAD progression, interventional complications, and follow-up aortic intervention. RESULTS: Initially, 53.1% of patients (51/96) were managed with OMT. No in-hospital deaths occurred. During follow-up, three patients died, and three and two patients who were initially managed with OMT subsequently required endovascular treatment and surgical management, respectively. Initially, 46.9% of patients (45/96) underwent EVAR. One patient died during hospital admission; nine patients had an endoleak after operation and one needed reintervention. Furthermore, during follow-up, five patients died; four patients needed reoperation, one surgery and three endovascular treatments. The overall long-term mortality was 8.4%, and follow-up aortic intervention rate was 9.5% (median follow-up, 54 months; interquartile range, 33-81 months) with no significant difference between groups. Of note, 12 patients (12.6%) suffered uIAAD progression, which was higher in the OMT group than EVAR group (10 [19.6%] vs 2 [4.5%]; P = .03). CONCLUSIONS: uIAAD may be managed safely by OMT with regular surveillance, despite the risk of disease progression. Compared with OMT, EVAR could significantly prevent uIAAD progression. For anatomically suitable patients with uIAAD progression and who are unresponsive to OMT, pre-emptive EVAR is a safe and feasible option.
Subject(s)
Aortic Aneurysm, Abdominal , Aortic Dissection , Blood Vessel Prosthesis Implantation , Dissection, Abdominal Aorta , Endovascular Procedures , Humans , Endovascular Aneurysm Repair , Aortic Aneurysm, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/surgery , Treatment Outcome , Blood Vessel Prosthesis Implantation/adverse effects , Time Factors , Aortic Dissection/diagnostic imaging , Aortic Dissection/surgery , Retrospective Studies , Risk Factors , Postoperative ComplicationsABSTRACT
Gate-based quantum computation has been extensively investigated using quantum circuits based on qubits. In many cases, such qubits are actually made out of multilevel systems but with only two states being used for computational purpose. While such a strategy has the advantage of being in line with the common binary logic, it in some sense wastes the ready-for-use resources in the large Hilbert space of these intrinsic multidimensional systems. Quantum computation beyond qubits (e.g., using qutrits or qudits) has thus been discussed and argued to be more efficient than its qubit counterpart in certain scenarios. However, one of the essential elements for qutrit-based quantum computation, two-qutrit quantum gate, remains a major challenge. In this Letter, we propose and demonstrate a highly efficient and scalable two-qutrit quantum gate in superconducting quantum circuits. Using a tunable coupler to control the cross-Kerr coupling between two qutrits, our scheme realizes a two-qutrit conditional phase gate with fidelity 89.3% by combining simple pulses applied to the coupler with single-qutrit operations. We further use such a two-qutrit gate to prepare an EPR state of two qutrits with a fidelity of 95.5%. Our scheme takes advantage of a tunable qutrit-qutrit coupling with a large on:off ratio. It therefore offers both high efficiency and low crosstalk between qutrits, thus being friendly for scaling up. Our Letter constitutes an important step toward scalable qutrit-based quantum computation.
ABSTRACT
OBJECTIVE: To investigate the efficacy and safety of telitacicept treatment in a Chinese SLE cohort, with real-life settings. METHODS: All patients with SLE who were receiving telitacicept treatment at least 4 weeks were included, and were followed up. Patients received subcutaneous injection of telitacicept weekly based on the standard treatment. SLE responder index-4 (SRI-4) was assessed before the first administration and at least 4 weeks after the first administration. Disease flares during the follow-up period were defined as an increase in disease activity and the number or dose of immunosuppressive drugs. RESULTS: After 4-45 weeks' administration of telitacicept, 80% (n = 16) reached SRI-4 response. The prednisolone dosage declined from a mean of 30.25 mg/d (95% CI 21.99-38.51) before treatment to 13.25 mg/d (95% CI 9.92-16.58) after treatment. The proportion of patients without receiving an immunosuppressive drug increased from 15% to 43% at the endpoint. 19 cases showed various reduction of IgM after treatment (p < 0.05) and C3 and C4 showed either stable or an upward trend. The 24 h urinary protein median value of the 14 cases (baseline 24 h urinary protein >0.5 g/d) showed significant reduction, and 7 of them turned negative. Adverse events were mild to moderate and controllable. CONCLUSION: Telitacicept is a potential treatment option for patients with SLE, especially in lupus nephritis, with significantly increased SRI-4 response rate and reduced the glucocorticoid and immunosuppressive drugs.
Subject(s)
Lupus Erythematosus, Systemic , Humans , Lupus Erythematosus, Systemic/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Treatment Outcome , Immunosuppressive Agents/adverse effects , Severity of Illness IndexABSTRACT
BACKGROUND: Patients with omphalocele, a midline abdominal wall defect at the umbilical cord base, have a low survival rate. However, the long-term outcomes of fetuses with prenatally diagnosed omphalocele have scarcely been studied. Therefore, we investigated the ultrasonographic features, genetic characteristics, and maternal and fetal outcomes of fetuses with omphalocele and provided a reference for the perinatal management of such cases. METHODS: A total of 120 pregnant females with fetal omphalocele were diagnosed using prenatal ultrasonography at the Fujian Provincial Maternity and Child Health Hospital from January 2015 to March 2022. Amniotic fluid or cord blood samples were drawn at different gestational weeks for routine karyotype analysis, chromosomal microarray analysis (CMA) detection, and whole exome sequencing (WES). The maternal and fetal outcomes were followed up. RESULTS: Among the 120 fetuses, 27 were diagnosed with isolated omphalocele and 93 with nonisolated omphalocele using prenatal ultrasonography. Cardiac anomalies were the most observed cause in 17 fetuses. Routine karyotyping and CMA were performed on 35 patients, and chromosomal abnormalities were observed in five patients, trisomy 18 in three, trisomy 13 in one, and chromosome 8-11 translocation in one patient; all were non-isolated omphalocele cases. Six nonisolated cases had normal CMA results and conventional karyotype tests, and further WES examination revealed one pathogenic variant and two suspected pathogenic variants. Of the 120 fetuses, 112 were successfully followed up. Eighty of the 112 patients requested pregnancy termination. Seven of the cases died in utero. A 72% 1-year survival rate was observed from the successful 25 live births. CONCLUSION: The prognosis of fetuses with nonisolated omphalocele varies greatly, and individualized analysis should be performed to determine fetal retention carefully. Routine karyotyping with CMA testing should be provided for fetuses with omphalocele. WES is an option if karyotype and CMA tests are normal. If the fetal karyotype is normal and no associated abnormalities are observed, fetuses with omphalocele could have a high survival rate, and most will have a good prognosis.
Subject(s)
Hernia, Umbilical , Pregnancy , Child , Humans , Female , Hernia, Umbilical/diagnostic imaging , Hernia, Umbilical/genetics , Prenatal Care , China , Family , Amniotic FluidABSTRACT
BACKGROUND: Abdominal aortic aneurysms (AAAs) can result in high mortality upon rupture but are usually undiagnosed because of the absence of symptoms in the early stage. Ultrasound screening is regarded as an impactful way to prevent the AAA-related death but cannot be performed efficiently; therefore, a target population, especially in Asia, for this procedure is lacking. Additionally, although dyslipidaemia and atherosclerosis are associated with AAA. However, it remains undetermined whether the non-high-density lipoprotein-cholesterol to high-density lipoprotein-cholesterol ratio (NHHR) is associated with AAA. Therefore, this study was aimed at examining whether NHHR is associated with AAA. METHOD: A total of 9559 participants who underwent AAA screening at Guangdong Provincial People's Hospital and through screening in two communities in Dongguan, from June 2019 to June 2021 joined in this screening program. The diagnosis of AAA was confirmed by the ultrasound examination of the abdominal aorta rather than any known or suspected AAA. Clinical and laboratory data of participants were collected. The participants were separated into a normal group and an AAA group according to the abdominal aortic status. To eliminate confounding factors, a propensity score matching (PSM) approach was utilized. The independent relationship between NHHR and AAA was assessed through the utilization of multivariable logistic regression analysis. In addition, internal consistency was evaluated through subgroup analysis, which controlled for significant risk factors. RESULTS: Of all the participants, 219 (2.29%) participants were diagnosed with AAA. A significant elevation in NHHR was identified in the AAA group when contrasted with that in the normal group (P < 0.001). As demonstrated by the results of the multivariable logistic regression analysis, AAA was independently associated with NHHR before (odds ratio [OR], 1.440, P < 0.001) and after PSM (OR, 1.515, P < 0.001). Significant extension was observed in the areas under the receiver operating characteristic curves (AUROCs) of NHHR compared to those of single lipid parameters before and after PSM. An accordant association between NHHR and AAA in different subgroups was demonstrated by subgroup analysis. CONCLUSION: In the Chinese population, there is an independent association between NHHR and AAA. NHHR might be propitious to distinguish individuals with high risk of AAA.
Subject(s)
Aortic Aneurysm, Abdominal , East Asian People , Humans , Cholesterol , Risk Factors , Cholesterol, HDL , Aortic Aneurysm, Abdominal/epidemiology , Aortic Aneurysm, Abdominal/etiologyABSTRACT
Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling.SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.