The H3K4 demethylase JMJ1 is required for proper timing of flowering in Brachypodium distachyon.

Flowering is a key developmental transition in the plant life cycle. In temperate climates, flowering often occurs in response to the perception of seasonal cues such as changes in day-length and temperature. However, the mechanisms that have evolved to control the timing of flowering in temperate grasses are not fully understood. We identified a Brachypodium distachyon mutant whose flowering is delayed under inductive long-day conditions due to a mutation in the JMJ1 gene, which encodes a Jumonji domain-containing protein. JMJ1 is a histone demethylase that mainly demethylates H3K4me2 and H3K4me3 in vitro and in vivo. Analysis of the genome-wide distribution of H3K4me1, H3K4me2, and H3K4me3 in wild-type plants by chromatin immunoprecipitation and sequencing combined with RNA sequencing revealed that H3K4m1 and H3K4me3 are positively associated with gene transcript levels, whereas H3K4me2 is negatively correlated with transcript levels. Furthermore, JMJ1 directly binds to the chromatin of the flowering regulator genes VRN1 and ID1 and affects their transcription by modifying their H3K4me2 and H3K4me3 levels. Genetic analyses indicated that JMJ1 promotes flowering by activating VRN1 expression. Our study reveals a role for JMJ1-mediated chromatin modification in the proper timing of flowering in B. distachyon.

Proteomic Characterization Identifies Clinically Relevant Subgroups of Gastrointestinal Stromal Tumors.

BACKGROUND & AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities. METHODS: Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models. RESULTS: Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis. CONCLUSIONS: Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.

14-Electron Redox Chemistry Enabled by Salen-Based π-Conjugated Framework Polymer Boosting High-Performance Lithium-Ion Storage.

A paucity of redox centers, poor charge transport properties, and low structural stability of organic materials obstruct their use in practical applications. Herein, these issues have been addressed through the use of a redox-active salen-based framework polymer (RSFP) containing multiple redox-active centers in π-conjugated configuration for applications in lithium-ion batteries (LIBs). Based on its unique architecture, RSFP exhibits a superior reversible capacity of 671.8 mAh g-1 at 0.05 A g-1 after 168 charge-discharge cycles. Importantly, the lithiation/de-lithiation performance is enhanced during operation, leading to an unprecedented reversible capacity of 946.2 mAh g-1 after 3500 cycles at 2 A g-1. The structural evolution of RSFP is studied ex situ using X-ray photoelectron spectroscopy, revealing multiple active C═N, C─O, and C═O sites and aromatic sites such as benzene rings. Remarkably, the emergence of C═O originated from C─O is triggered by an electrochemical process, which is beneficial for improving reversible lithiation/delithiation behavior. Furthermore, the respective strong and weak binding interactions between redox centers and lithium ions, corresponding to theoretical capacities of 670.1 and 938.2 mAh g-1, have been identified by density functional theory calculations manifesting 14-electron redox reactions. This work sheds new light on routes for the development of redox-active organic materials for energy storage applications.

Associations between immune cells signatures and osteoarthritis: An integrated analysis of bidirectional Mendelian randomization and Bayesian colocalization.

BACKGROUND: Previous investigations have explored the associations between immune cell signatures and osteoarthritis (OA); however, causality remains unclear. This study employs an integrated analysis, combining bidirectional Mendelian randomization (MR) and Bayesian colocalization (Coloc), to investigate causal relationships between 731 immune cells signatures and OA, identifying shared causal variants. METHODS: Utilizing publicly available summary data, this study primarily employs inverse variance weighting (IVW). Supplementary methods include MR-Egger regression, weighted median, weight mode, and simple mode. Various sensitivity tests, including Cochran's Q test, MR pleiotropy Residual Sum and Outlier, and leave-one-out tests, were conducted to assess the robustness of the analysis results. Coloc was employed to identify shared causal genetic variants among potential associations. RESULTS: IVW analysis revealed 196 immune cell signatures potentially linked to OA across diverse subtypes. Reverse MR analyses indicated the causal impact of OA on the levels of 140 immune cell signatures, with subtype-specific variations. Notably, several specific associations, including CD64 on CD14-CD16 + monocyte for Hip OA (OR = 1.0593, 95 % CI: 1.0260-1.0938, P = 0.0004), HLA-DR on CD14 + CD16- monocyte (OR = 0.9664, 95 % CI: 0.9497-0.9834, P = 0.0001), HLA-DR on CD14 + monocyte (OR = 0.9680, 95 % CI: 0.9509-0.9853, P = 0.0003) in the Knee or Hip OA, PDL-1 on CD14-CD16 + monocyte by All OA (OR = 1.7091, 95 %CI:1.2494-2.3378, P = 0.0008), and herpesvirus entry mediator on effector memory CD4 + T cell by Spine OA (OR = 0.5200, 95 %CI:0.3577-0.7561, P = 0.0006) remained significant post-Bonferroni correction. Sensitivity tests validated the credibility of the IVW analysis. Additionally, Coloc revealed several potential associations among shared genetic variants, including rs115328872, rs1800973, and rs317667. CONCLUSIONS: Our findings provide evidence for the potential involvement of immune cell signatures in OA development, revealing avenues for early prevention and innovative therapeutic strategies.

Circulating cytokines levels and osteoarthritis: A Mendelian randomization study.

BACKGROUND: Previous traditional observational studies have suggested the contribution of several cytokines and growth factors to the development of osteoarthritis (OA). This study aimed to determine the association of circulating cytokine and growth factor levels with OA. METHODS: We used two-sample Mendelian randomization (MR) to explore the causality between circulating cytokine and growth factor levels and OA [including knee or hip OA (K/HOA), knee OA (KOA), and hip OA (HOA)]. Summary level data for circulating cytokine and growth factor levels were sourced from a genome-wide association study (GWAS) involving 8,293 participants of Finnish ancestry. Single-nucleotide polymorphisms related to K/HOA (39,427 cases and 378,169 controls), KOA (24,955 cases and 378,169 controls), and HOA (15,704 cases and 378,169 controls) were obtained from a previous GWAS. The inverse variance weighted (IVW) method was primarily used for our MR analysis. For exposures to only one relevant SNP as IV, we used the Wald ratio as the major method to assess causal effects. We also conducted a series of sensitivity analyses to improve the robustness of the results. RESULTS: Circulating vascular endothelial growth factor levels were suggestively associated with an increased risk of K/HOA (odds ratio (OR) = 1.034; 95 % confidence interval (CI) = 1.013-1.055; P = 0.001), KOA (OR = 1.034; 95 % CI = 1.014-1.065; P = 0.002), and HOA (OR = 1.039; 95 % CI = 1.003-1.067; P = 0.034). Circulating interleukin (IL)-12p70 levels was suggestively associated with K/HOA (OR = 1.047; 95 % CI = 1.018-1.077; P = 0.001), KOA (OR = 1.058; 95 % CI = 1.022-1.095; P = 0.001), and HOA (OR = 1.044; 95 % CI = 1.000-1.091; P = 0.048). Circulating IL-18 levels were suggestively associated with HOA (OR = 1.068; 95 % CI = 1.014-1.125; P = 0.012). However, limited evidence exists to support causal genetic relationships between other circulating cytokines, growth factor levels and K/HOA, KOA, and HOA. CONCLUSIONS: Our MR analysis provides suggestive evidence of causal relationships between circulating cytokines and growth factors levels and OA, providing new insights into the etiology of OA.

miR-30e-5p regulates leukemia stem cell self-renewal through the Cyb561/ROS signaling pathway.

Leukemia stem cells (LSC) represent a crucial and rare subset of cells present in acute myeloid leukemia (AML); they play a pivotal role in the initiation, maintenance, and relapse of this disease. Targeting LSC holds great promise for preventing AML relapse and improving long-term outcomes. However the precise molecular mechanisms governing LSC self-renewal are still poorly understood. Here, we present compelling evidence that the expression of miR-30e-5p, a potential tumor-suppressive microRNA, is significantly lower in AML samples than in healthy bone marrow samples. Forced expression of miR- 30e effectively inhibits leukemogenesis, impairs LSC self-renewal, and delays leukemia progression. Mechanistically, Cyb561 acts as a direct target of miR-30e-5p in LSC, and its deficiency restricts the self-renewal of LSC by activating reactive oxygen series signaling and markedly prolongs recipients' survival. Moreover, genetic or pharmacological overexpression of miR-30e-5p or knockdown of Cyb561 suppresses the growth of human AML cells. In conclusion, our findings establish the crucial role of the miR-30e-5p/Cyb561/ROS axis in finely regulating LSC self-renewal, highlighting Cyb561 as a potential therapeutic target for LSC-directed therapies.

Wavelength-tunable spatiotemporal mode-locking in a large-mode-area Er:ZBLAN fiber laser at 2.8†µm.

We report a tunable spatiotemporally mode-locked large-mode-area Er:ZBLAN fiber laser based on the nonlinear polarization rotation technique. A diffraction grating is introduced to select the operating wavelength. Under the spectral and spatial filtering effects provided by the grating and spatial coupling respectively, stable ps-level spatiotemporally mode-locked pulses around 2.8 µm with a repetition rate of 43.4 MHz are generated. Through a careful adjustment of the grating, a broad wavelength tuning range from 2747 to 2797 nm is realized. To the best of our knowledge, this is the first wavelength-tunable spatiotemporally mode-locked fiber laser in the mid-infrared region.

Differential expression and prognostic value of TLR4 in kidney renal clear cell carcinoma.

Human Toll-like receptor (TLR) family plays a crucial role in immunity and cancer progression. However, the specific role of human Toll-like receptor 4 (TLR4) in kidney renal clear cell carcinoma (KIRC) remains obscure. Thus, we used single-cell RNA sequencing (RNA-seq) and bulk RNA-seq data combined with in vitro studies to evaluate the expression and prognostic value of TLR4 in KIRC. In our study, we observed that TLR4 was over expressed in KIRC tissues compared to normal renal tissues. And the expression of TLR4 was higher in macrophages/monocytes than other cell types. Besides, there is a close association between TLR4 expression and immune cell infiltration (Neutrophils, Macrophages, T cells and B cells) in KIRC. Immunohistochemical staining also showed that TLR4 was overexpressed in inflammatory infiltration renal tissue compared with normal tissue. Meanwhile, high expression of TLR4 exhibited correlations with improved survival, lower tumor grade and stage. Interestingly, the protective significance of TLR4 only showed in female patients (HR = 0.37, P < 0.01), other than male patients (HR = 0.71, P = 0.08) with KIRC. Consistently, KIRC samples with lymph node metastasis showed lower expression of TLR4. Knockdown of TLR4 in 786-O cell line increased cell proliferation and clonogenic capacity. In summary, this study found TLR4 could inhibit the progression of kidney cancer and was associated with improved survival in KIRC. The overexpression of TLR4 in macrophages and the close association between TLR4 and immune cell infiltration also underline the critical role of TLR4 in building the immune microenvironment for kidney cancer. These results may offer insights into the mechanism and immune microenvironment of kidney cancer.

Fat-Poor Hepatic Angiomyolipoma in Noncirrhotic Livers: Imaging Features, Pathology, and Differential Diagnosis.

OBJECTIVE: To investigate imaging features of fat-poor hepatic angiomyolipomas in noncirrhotic livers in order to enhance the diagnostic accuracy for this condition. METHODS: The clinical and imaging data of 19 patients with fat-poor hepatic angiomyolipoma (fpHAML) was retrospectively analyzed. RESULTS: Of the 19 patients without hepatitis, cirrhosis, or sarcoidosis, 16 had no clinical symptoms. There were 20 lesions in 19 patients. Macroscopic fat, calcification, hemorrhage, necrosis, and pseudocapsule were not observed in the 20 lesions. All lesions showed marked enhancement on the arterial phase, and the degree of enhancement was significantly higher than that in the adjacent hepatic parenchyma. In 8 cases, the enhancement of the portal phase was higher than that in the arterial phase. Multiple intratumor vessels were observed in the tumor, and lesions with diameters larger than 3.0 cm were more frequently observed. The degree of enhancement of 18 lesions on portal phase or delayed phase was slightly higher than or equal to that in the surrounding hepatic parenchyma. The lesions were hyperintense on diffusion-weighted imaging and showed homogeneous hypointensity on the hepatobiliary phase. Only 6 cases showed the presence of an early draining vein. CONCLUSIONS: These imaging features have some implications for the diagnosis of fpHAML. Therefore, an increased awareness of fpHAML is needed among radiologists.

China's energy-water-land system co-evolution under carbon neutrality goal and climate impacts.

China's 2060 carbon neutrality goal has significant implications for energy, water, and land systems. However, the multi-sector dynamics among China's energy-water-land system have rarely been examined explicitly. This study adopts an integrated assessment framework to simulate China's energy-water-land system co-evolution under alternative carbon neutrality scenarios and climate impacts. Results show that although the net zero emission target provides the incentive for the energy system to move away from fossil fuels, total water withdrawal will increase due to the deployment of nuclear, bioenergy, and coal power plants with carbon capture and storage. Diversifying the negative emission technologies, by leveraging direct air capture technology, can alleviate the potential water stress and land use conflicts, which would otherwise be exacerbated by large-scale deployment of afforestation and bioenergy with carbon capture and storage. Northwest and northeast regions of China are the hotspots experiencing water withdrawal increases, while Bohai Rim and coastal regions are identified to experience fierce land competition. This study demonstrates the potential for general applicability to carry out resource planning and policy evaluation from the multi-sector coordination perspective.

The Development of Aptamer-Based Gold Nanoparticle Lateral Flow Test Strips for the Detection of SARS-CoV-2 S Proteins on the Surface of Cold-Chain Food Packaging.

The COVID-19 pandemic over recent years has shown a great need for the rapid, low-cost, and on-site detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this study, an aptamer-based colloidal gold nanoparticle lateral flow test strip was well developed to realize the visual detection of wild-type SARS-CoV-2 spike proteins (SPs) and multiple variants. Under the optimal reaction conditions, a low detection limit of SARS-CoV-2 S proteins of 0.68 nM was acquired, and the actual detection recovery was 83.3% to 108.8% for real-world samples. This suggests a potential tool for the prompt detection of SARS-CoV-2 with good sensitivity and accuracy, and a new method for the development of alternative antibody test strips for the detection of other viral targets.

Hydrogenation of CO2 to Light Olefins over ZnZrOx /SSZ-13.

Converting CO2 to olefins is an ideal route to achieve carbon neutrality. However, selective hydrogenation to light olefins, especially single-component olefin, while reducing CH4 formation remains a great challenge. Herein, we developed ZnZrOx /SSZ-13 tandem catalyst for the highly selective hydrogenation of CO2 to light olefins. This catalyst shows C2 = -C4 = and propylene selectivity up to 89.4 % and 52 %, respectively, while CH4 is suppressed down to 2 %, and there is no obvious deactivation. It is demonstrated that the isolated moderate Brønsted acid sites (BAS) of SSZ-13 promotes the rapid conversion of intermediate species derived from ZnZrOx , thereby enhancing the kinetic coupling of the reactions and inhibit the formation of alkanes and improve the light olefins selectivity. Besides, the weaker BAS of SSZ-13 promote the conversion of intermediates into aromatics with 4-6 methyl groups, which is conducive to the aromatics cycle. Accordingly, more propene can be obtained by elevating the Si/Al ratio of SSZ-13. This provides an efficient strategy for CO2 hydrogenation to light olefins with high selectivity.

Construction of pH-Sensitive Nanovaccines Encapsulating Tumor Cell Lysates and Immune Adjuvants for Breast Cancer Therapy.

The current immunotherapy strategies for triple negative breast cancer (TNBC) are greatly limited due to the immunosuppressive tumor microenvironment (TME). Immunization with cancer vaccines composed of tumor cell lysates (TCL) can induce an effective antitumor immune response. However, this approach also has the disadvantages of inefficient antigen delivery to the tumor tissues and the limited immune response elicited by single-antigen vaccines. To overcome these limitations, a pH-sensitive nanocalcium carbonate (CaCO3 ) carrier loaded with TCL and immune adjuvant CpG (CpG oligodeoxynucleotide 1826) is herein constructed for TNBC immunotherapy. This tailor-made nanovaccine, termed CaCO3 @TCL/CpG, not only neutralizes the acidic TME through the consumption of lactate by CaCO3 , which increases the proportion of the M1/M2 macrophages and promotes infiltration of effector immune cells but also activates the dendritic cells in the tumor tissues and recruits cytotoxic T cells to further kill the tumor cells. In vivo fluorescence imaging study shows that the pegylated nanovaccine could stay longer in the blood circulation and extravasate preferentially into tumor site. Besides, the nanovaccine exhibits high cytotoxicity in 4T1 cells and significantly inhibits tumor growth of tumor-bearing mice. Overall, this pH-sensitive nanovaccine is a promising nanoplatform for enhanced immunotherapy of TNBC.

Histone chaperones AtChz1A and AtChz1B are required for H2A.Z deposition and interact with the SWR1 chromatin-remodeling complex in Arabidopsis thaliana.

The histone variant H2A.Z plays key functions in transcription and genome stability in all eukaryotes ranging from yeast to human, but the molecular mechanisms by which H2A.Z is incorporated into chromatin remain largely obscure. Here, we characterized the two homologs of yeast Chaperone for H2A.Z-H2B (Chz1) in Arabidopsis thaliana, AtChz1A and AtChz1B. AtChz1A/AtChz1B were verified to bind to H2A.Z-H2B and facilitate nucleosome assembly in vitro. Simultaneous knockdown of AtChz1A and AtChz1B, which exhibit redundant functions, led to a genome-wide reduction in H2A.Z and phenotypes similar to those of the H2A.Z-deficient mutant hta9-1hta11-2, including early flowering and abnormal flower morphologies. Interestingly, AtChz1A was found to physically interact with ACTIN-RELATED PROTEIN 6 (ARP6), an evolutionarily conserved subunit of the SWR1 chromatin-remodeling complex. Genetic interaction analyses showed that atchz1a-1atchz1b-1 was hypostatic to arp6-1. Consistently, genome-wide profiling analyses revealed partially overlapping genes and fewer misregulated genes and H2A.Z-reduced chromatin regions in atchz1a-1atchz1b-1 compared with arp6-1. Together, our results demonstrate that AtChz1A and AtChz1B act as histone chaperones to assist the deposition of H2A.Z into chromatin via interacting with SWR1, thereby playing critical roles in the transcription of genes involved in flowering and many other processes.

Soliton rain in all-polarization-maintaining mode locked fiber laser.

For the first time the phenomenon of soliton rain is observed in a mode-locked fiber laser with all-polarization-maintaining (all-PM) architecture. The laser is mode-locked using a semiconductor saturable absorber mirror (SESAM) and operates in the all-normal dispersion (ANDi) regime. The operation state of the laser can be switched from dissipative soliton to soliton rain by simply raising the pump power, without any manipulation of the intracavity polarization state given that all components of the resonator are made of PM fibers. The soliton rain generated in the laser is self-starting and replicable, since it occurs in every individual operation of the laser as the pump power is increased to an approximately invariant value.

Frequency-domain-resolved investigation of unitary h-shaped pulses.

We experimentally investigate the generation of h-shaped pulse in an all-polarization-maintaining (PM) and all-normal-dispersion (ANDi) mode-locked fiber laser. The generated pulse is demonstrated to be a unitary pulse, instead of a noise-like pulse (NLP). Furthermore, by employing an external filtering system, the obtained h-shaped pulse can be resolved into rectangular-shaped pulses, chair-like pulses, and Gaussian pulses. The authentic AC traces with a double-scale structure of unitary h-shaped pulses and chair-like pulses are observed on the autocorrelator. The chirp of h-shaped pulses is also proved similar to that of DSR pulses. To the best of our knowledge, this is the first time that the existence of unitary h-shaped pulse generation has been confirmed. Moreover, our experimental results reveal the close relationship of formation mechanisms of dissipative soliton resonance (DSR) pulses, h-shaped pulses, and chair-like pulses, which helps to unify the essences of such "DSR-like" pulses.

Mid-infrared ultrashort pulses generated from a hybrid mode-locked Er:ZBLAN fiber laser.

By combining nonlinear polarization rotation (NPR) and semiconductor saturable absorber, we report a hybrid mode-locked Er:ZBLAN fiber oscillator at 2.8 µm. Stable 325-fs mode-locked pulses with an average power of 131 mW and a record signal-to-noise ratio of 79 dB at the fundamental frequency of 55.4 MHz are generated. Numerical simulations are carried out based on the modified coupled nonlinear Schrödinger equations, and offer new insights into the underlying dynamics of pulse generation. The simulations indicate that compared with Er:ZBLAN fiber lasers mode-locked by NPR alone, the hybrid mode-locked Er:ZBLAN fiber oscillator allows a wider range and a lower threshold of the pump power while maintaining the ultrashort pulse width. Moreover, we numerically demonstrate that the hybrid mode-locked oscillator is less sensitive to the variation of polarization states, which will increase its robustness against environmental disturbance. This is the first time that the hybrid mode-locking technique is applied in the mid-infrared, opening up new opportunities for the development of stable ultrafast mid-infrared laser sources and practical applications outside the laboratory.

976†nm all-polarization-maintaining mode-locked fiber laser based on nonlinear polarization evolution.

An all-polarization-maintaining (PM) mode-locked fiber laser based upon nonlinear polarization evolution (NPE) that operates around 976 nm is presented. The NPE-based mode-locking is realized using a special section of the laser which comprises three pieces of PM fibers with specific deviation angles between the polarization axes and a polarization-dependent isolator. By optimizing the NPE section and adjusting the pump power, dissipative soliton (DS) pulses with a pulse duration of ∼6 ps, a spectral bandwidth of >10 nm and a maximum pulse energy of 0.54 nJ are generated. Self-starting, steady mode-locking operation is achievable within a pump power range of ∼2 W. Moreover, by incorporating a segment of passive fiber into the appropriate location in the laser resonator, an intermediate regime between stable single-pulse mode-locking and noise-like pulse (NLP) is realized in the laser. Our work expands the dimension of the research on the mode-locked Yb-doped fiber laser operating around 976 nm.

All-fiber 3.4-W 2.8-µm ultra-short pulse MOPA system seeded by the soliton self-frequency shift of 2-µm pulses.

We report an all-fiber 2.8-µm ultra-short pulse master oscillator power amplifier (MOPA) system seeded by a soliton self-frequency shift from a mode-locked thulium-doped fiber laser. This all-fiber laser source delivers 2.8-µm pulses with an average power of 3.42 W, a pulse width of 115 fs, and a pulse energy of 45.4 nJ. We demonstrate, to the best of our knowledge, the first femtosecond watt-level all-fiber 2.8-µm laser system. A 2.8-µm pulse seed was obtained via the soliton self-frequency shift of 2-µm ultra-short pulses in a cascaded silica and passive fluoride fiber. A novel, to the best of our knowledge, high-efficiency and compact home-made end-pump silica-fluoride fiber combiner was fabricated and used in this MOPA system. Nonlinear amplification of the 2.8-µm pulse was realized, and soliton self-compression was observed accompanied by spectral broadening.

High-energy femtosecond pulse generation from a hybrid mode-locked large-mode-area Er:ZBLAN fiber laser.

We report a hybrid mode-locked fiber laser at 2.8 µm based on a large-mode-area Er:ZBLAN fiber. Reliable self-starting mode-locking is achieved via the combination of nonlinear polarization rotation and a semiconductor saturable absorber. Stable mode-locked pulses with a pulse energy of 9.4 nJ and a pulse duration of 325 fs are generated. To the best of our knowledge, this is the highest pulse energy directly generated from a femtosecond mode-locked fluoride fiber laser (MLFFL) to date. The measured M2 factors are below 1.13, indicating a nearly diffraction-limited beam quality. Demonstration of this laser provides a feasible scheme for the pulse energy scaling of mid-infrared MLFFLs. Moreover, a peculiar multi-soliton mode-locking state is also observed, in which the time interval between the solitons varies irregularly from tens of picoseconds to several nanoseconds.