Summary
Background
Lymphatic malformations (LMs), slow‐flow vascular anomalies resulting from abnormal development of lymphatic channels, often progress rapidly after trauma or infection.
Objectives
...To explore the possible mechanism by which local infection promotes the progression of LMs.
Methods
Immunohistochemistry in serial sections and immunofluorescence were performed to label polarized macrophages. Tertiary lymphoid organs (TLOs) in LMs were identified using antibodies against CD3 (a T‐cell marker), CD20 (a B‐cell marker) and PNAd (a high endothelial venule marker). Pearson's correlation and cluster analysis were carried out to delineate the relationship between macrophage infiltration and TLO formation. Rat models of LM were established to examine the role of lipopolysaccharide in LM development.
Results
Compared with normal skin tissues, both M1‐ and M2‐polarized macrophages were prevalent in LMs. Moreover, M2‐polarized macrophages were significantly increased in infected LMs with an elevated density of TLOs. M2‐polarized macrophages were observed in the centre of TLOs accompanied by intensive staining of macrophage colony‐stimulating factor, a strong chemotactic factor for monocytes/macrophages, suggesting that macrophages might be recruited through TLOs. Cluster analysis and Pearson's correlation suggested a close relationship between macrophage infiltration and TLO formation. Furthermore, the expression of CD68 was also correlated with that of vascular endothelial growth factor (VEGF)‐C and Ki67. Importantly, in an established LM rat model, lipopolysaccharide promoted the progression of the malformations with increased macrophage infiltration and TLO formation.
Conclusions
M2‐polarized macrophages that may be recruited through TLOs in infected LMs may contribute to the progression of the disease by secreting VEGF‐C, and therefore accelerating the proliferation of lymphatic endothelial cells.
What's already known about this topic?
Infection in lymphatic malformations (LMs) promotes the development of the disease.
Tertiary lymphoid organs (TLOs) are found in most LMs.
Macrophages intensively promote lymphangiogenesis in pathological conditions.
What does this study add?
M2‐polarized macrophages are increased in LMs compared with skin tissues.
A close relationship between M2‐polarized macrophages and TLOs was uncovered in LMs.
M2‐polarized macrophages and TLOs might contribute to the progression of LMs after infection.
What is the translational message?
Infection or inflammation in LMs indicated poor prognosis of the disease.
Targeting M2‐polarized macrophages might be a promising therapy for LMs.
Targeting TLO formation might alleviate the progression of LMs by reducing macrophage recruitment and lymphatic vessel formation.
High-energy cosmic-ray electrons and positrons (CREs), which lose energy quickly during their propagation, provide a probe of Galactic high-energy processes and may enable the observation of ...phenomena such as dark-matter particle annihilation or decay. The CRE spectrum has been measured directly up to approximately 2 teraelectronvolts in previous balloon- or space-borne experiments, and indirectly up to approximately 5 teraelectronvolts using ground-based Cherenkov γ-ray telescope arrays. Evidence for a spectral break in the teraelectronvolt energy range has been provided by indirect measurements, although the results were qualified by sizeable systematic uncertainties. Here we report a direct measurement of CREs in the energy range 25 gigaelectronvolts to 4.6 teraelectronvolts by the Dark Matter Particle Explorer (DAMPE) with unprecedentedly high energy resolution and low background. The largest part of the spectrum can be well fitted by a 'smoothly broken power-law' model rather than a single power-law model. The direct detection of a spectral break at about 0.9 teraelectronvolts confirms the evidence found by previous indirect measurements, clarifies the behaviour of the CRE spectrum at energies above 1 teraelectronvolt and sheds light on the physical origin of the sub-teraelectronvolt CREs.
Summary
Background
Previous studies have implicated vascular destabilization and changes in extracellular matrix (ECM) composition in venous malformations (VMs).
Objectives
To evaluate the expression ...levels of the connective tissue growth factor (CCN) family of matricellular proteins in VMs and explore their association with vascular destabilization.
Methods
The expression levels of CCNs 1–6, transforming growth factor (TGF)‐β, phosphorylated Tie2 and phosphorylated platelet‐derived growth factor receptor β in normal human skin tissues and VMs were detected by immunohistochemistry. Correlation between tested proteins was explored using the Spearman rank correlation test, followed by clustering analysis. In vitro studies using human umbilical vein endothelial cells (HUVECs) were performed for mechanism investigation.
Results
Expression of CCN2 was found to be strongly positive in fibroblast‐like cells, endothelial cells and around blood vessels in normal human skin tissues, but it was significantly downregulated in VMs. Correlation analyses showed that expression levels of CCN2 and TGF‐β in VMs were positively correlated. The immunoreactivity of CCN2 was also closely correlated with perivascular α‐smooth muscle cell actin+ cell coverage in VMs. Moreover, in vitro studies in HUVECs indicated that CCN2 might act as a downstream target of TGF‐β, as demonstrated by the findings that treatment with exogenous TGF‐β or exogenous CCN2 could significantly upregulate the expression level of CCN2, and increase the expression levels of ECM components. Upregulation of the TGF‐β/CCN2 pathway was also detected in bleomycin‐treated VM specimens.
Conclusions
This study unmasks the downregulation of the TGF‐β/CCN2 pathway in VMs, and indicates its target potential for sclerotherapy.
What's already known about this topic?
Venous malformations (VMs) are made manifest by enlarged venous channels covered with few perivascular cells, indicating vascular destabilization.
The extracellular matrix (ECM) is closely associated with cell adhesion, smooth muscle cell proliferation, migration and differentiation, and thereby plays a pivotal role in vascular stability.
Changes in ECM composition in VMs have been demonstrated.
What does this study add?
The transforming growth factor (TGF)‐β/connective tissue growth factor (CCN)2 pathway is downregulated in VMs when compared with normal human skin tissues, and is closely correlated with vascular destabilization.
The sclerosant bleomycin A5 upregulates the TGF‐β/CCN2 pathway, and increases ECM production in human umbilical vein endothelial cells.
Upregulation of TGF‐β and CCN2 expression was found in bleomycin‐treated VMs, which was accompanied by increased perivascular α‐smooth muscle actin+ cell coverage.
Migmatite gneisses are widespread in the Dabie orogen, but their formation ages are poorly constrained. Eight samples of migmatite, including leucosome, melanosome, and banded gneiss, were selected ...for U–Pb dating and Hf isotope analysis. Most metamorphic zircon occurs as overgrowths around inherited igneous cores or as newly grown grains. Morphological and internal structure features suggest that their growth is associated with partial melting. According to the Hf isotope ratio relationships between metamorphic zircon and inherited cores, three formation mechanisms for metamorphic zircon can be determined, which are dissolution–reprecipitation of pre‐existing zircon, breakdown of Zr‐bearing phase other than zircon in a closed system and crystallization from externally derived Zr‐bearing melt. Four samples contain magmatic zircon cores, yielding upper intercept U–Pb ages of 807 ± 35–768 ± 12 Ma suggesting that the protoliths of the migmatites are Neoproterozoic in age. The migmatite zircon yields weighted mean two‐stage Hf model ages of 2513 ± 97–894 ± 54 Ma, indicating reworking of both juvenile and ancient crustal materials at the time of their protolith formation. The metamorphic zircons give U–Pb ages of 145 ± 2–120 ± 2 Ma. The oldest age indicates that partial melting commenced prior to 145 Ma, which also constrains the onset of extensional tectonism in this region to pre‐145 Ma. The youngest age of 120 Ma was obtained from an undeformed granitic vein, indicating that deformation in this area was complete at this time. Two major episodes of partial melting were dated at 139 ± 1 and 123 ± 1Ma. The first episode of partial melting is obviously older than the timing of post‐collision magmatism, corresponding to regional extension. The second episode of partial melting is coeval with the widespread post‐collision magmatism, indicating the gravitational collapse and delamination of the orogenic lithospheric keel of the Dabie orogen, which were possibly triggered by the uprising of the Cretaceous mid‐Pacific superplume.
This Letter reports a measurement of the flux and energy spectrum of electron antineutrinos from six 2.9 GWth nuclear reactors with six detectors deployed in two near (effective baselines 512 and 561 ...m) and one far (1579 m) underground experimental halls in the Daya Bay experiment. Using 217 days of data, 296 721 and 41 589 inverse β decay (IBD) candidates were detected in the near and far halls, respectively. The measured IBD yield is (1.55±0.04) ×10(-18) cm(2) GW(-1) day(-1) or (5.92±0.14) ×10(-43) cm(2) fission(-1). This flux measurement is consistent with previous short-baseline reactor antineutrino experiments and is 0.946±0.022 (0.991±0.023) relative to the flux predicted with the Huber-Mueller (ILL-Vogel) fissile antineutrino model. The measured IBD positron energy spectrum deviates from both spectral predictions by more than 2σ over the full energy range with a local significance of up to ∼4σ between 4-6 MeV. A reactor antineutrino spectrum of IBD reactions is extracted from the measured positron energy spectrum for model-independent predictions.
Understanding how flowering phenology responds to warming and cooling (i.e., symmetric or asymmetric response) is needed to predict the response of flowering phenology to future climate change that ...will happen with the occurrence of warm and cold years superimposed upon a long-term trend. A three-year reciprocal translocation experiment was performed along an elevation gradient from 3200 m to 3800 m in the Tibetan Plateau for six alpine plants. Transplanting to lower elevation (warming) advanced the first flowering date (FFD) and transplanting to higher elevation (cooling) had the opposite effect. The FFD of early spring flowering plants (ESF) was four times less sensitive to warming than to cooling (by −2.1 d/°C and 8.4 d/°C, respectively), while midsummer flowering plants (MSF) were about twice as sensitive to warming than to cooling (−8.0 d/°C and 4.9 d/°C, respectively). Compared with pooled warming and cooling data, warming alone significantly underpredicted 3.1 d/°C for ESF and overestimated 1.7 d/°C for MSF. These results suggest that future empirical and experimental studies should consider nonlinear temperature responses that can cause such warming-cooling asymmetries as well as differing life strategies (ESF vs. MSF) among plant species.
MicroRNAs are a class of small, non‐coding RNAs that can negatively regulate protein‐coding genes, and are associated with almost all known physiological and pathological processes, especially ...cancer. The number of studies documenting miRNA expression patterns in malignancy continues to expand rapidly, with continuously gained critical information regarding how aberrantly expressed miRNAs may contribute to carcinogenesis. miRNAs can influence cancer pathogenesis, playing a potential role as either oncogenes or tumour suppressors. Recently, several miRNAs have been reported to exert different regulatory functions in oesophageal cancer – the carcinoma typically arising from the epithelial lining of the oesophagus. These miRNAs also have potential clinical applications towards developing biomarkers or targets for possible use in diagnosis or therapy in oesophageal cancer. In this review, we have summarized the two (oncogenic or tumour suppressive) roles of miRNAs here, and their applications as potential biomarkers or therapeutic targets, which may illuminate future treatment for oesophageal cancer.
Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin ...of cosmological FRBs is still not settled. Here we report the detection of1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref.9). These observations show irregular short-time variation ofthe Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (au; Earth-Sun distance) ofthe source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.
Accurate determination of stellar atmospheric parameters and elemental abundances is crucial for Galactic archaeology via large-scale spectroscopic surveys. In this paper, we estimate stellar ...atmospheric parameters -- effective temperature T sub( eff), surface gravity log g and metallicity Fe/H, absolute magnitudes M sub( V) and M sub( Ks), ...-element to metal (and iron) abundance ratio .../M (and .../Fe), as well as carbon and nitrogen abundances C/H and N/H from the Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST) spectra with a multivariate regression method based on kernel-based principal component analysis, using stars in common with other surveys (Hipparcos, Kepler, Apache Point Observatory Galactic Evolution Experiment) as training data sets. Both internal and external examinations indicate that given a spectral signal-to-noise ratio (SNR) better than 50, our method is capable of delivering stellar parameters with a precision of ~100 K for T sub( eff), ~0.1 dex for log g, 0.3-0.4 mag for M sub( V) and M sub( Ks), 0.1 dex for Fe/H, C/H and N/H, and better than 0.05 dex for .../M (.../Fe). The results are satisfactory even for a spectral SNR of 20. The work presents first determinations of C/H and N/H abundances from a vast data set of LAMOST, and, to our knowledge, the first reported implementation of absolute magnitude estimation directly based on a vast data set of observed spectra. The derived stellar parameters for millions of stars from the LAMOST surveys will be publicly available in the form of value-added catalogues. (ProQuest: ... denotes formulae/symbols omitted.)
Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. Long noncoding RNAs (lncRNAs) are emerging as new ...players in gene regulation. However, it is not yet clear whether lncRNAs can regulate necrosis in cardiomyocytes. Here, we report that a long noncoding RNA, named necrosis-related factor (NRF), regulates cardiomyocytes necrosis by targeting miR-873 and RIPK1 (receptor-interacting serine/threonine-protein kinase 1)/RIPK3 (receptor-interacting serine/threonine-protein kinase 3). Our results show that RIPK1 and RIPK3 participate in H2O2-induced cardiomyocytes necrosis. miR-873 suppresses the translation of RIPK1/RIPK3 and inhibits RIPK1/RIPK3-mediated necrotic cell death in cardiomyocytes. miR-873 reduces myocardial infarct size upon ischemia/reperfusion (I/R) injury in the animal model. In exploring the molecular mechanism by which miR-873 expression is regulated, we identify NRF as an endogenous sponge RNA and repress miR-873 expression. NRF directly binds to miR-873 and regulates RIPK1/RIPK3 expression and necrosis. Knockdown of NRF antagonizes necrosis in cardiomyocytes and reduces necrosis and myocardial infarction upon I/R injury. Further, we identify that p53 transcriptionally activates NRF expression. P53 regulates cardiomyocytes necrosis and myocardial I/R injury through NRF and miR-873.Our results identify a novel mechanism involving NRF and miR-873 in regulating programmed necrosis in the heart and suggest a potential therapeutic avenue for cardiovascular diseases.
PDF
