Purpose. To study the relationship between surface membrane-bound APRIL and ITP. Methods. The peripheral blood of all subjects, 50 patients diagnosed with ITP and 25 healthy controls, was collected. ...Flow cytometry was used to detect the expression of membrane-bound APRIL on immune cells and platelets. ELISA was used to detect the content of soluble APRIL in plasma. Results. Membrane-bound APRIL was only expressed on the surface of platelets in both ITP patients and controls. APRIL expression on the platelet surface was significantly lower in newly diagnosed (P<0.001) and chronic (P<0.001) ITP patients than in controls. Platelet surface APRIL level was significantly enhanced in patients with complete remission after treatment (P=0.02) but not in those with no response after treatment. Platelet surface APRIL level in ITP patients was negatively correlated with serum APRIL level (r=−0.09765, P=0.0424). Conclusions. Platelet surface APRIL may play a key immunoregulative role. Platelet surface APRIL is likely to be one source of the excessive serum APRIL in ITP patients. The effectiveness of treatment may be measured by determining the platelet surface APRIL levels in ITP patients.
Abstract Recently, we have demonstrated a method to record the longitudinal phase-space distribution of a pulsed cryogenic buffer gas cooled beam of barium fluoride molecules with high resolution. In ...this paper, we use this method to determine the influence of various source parameters. Besides the expected dependence on temperature and pressure, the forward velocity of the molecules is strongly correlated with the time they exit the cell, revealing the dynamics of the gas inside the cell. Three observations are particularly noteworthy: (1) The velocity of the barium fluoride molecules increases rapidly as a function of time, reaches a maximum 50–200 µ s after the ablation pulse and then decreases exponentially. We attribute this to the buffer gas being heated up by the plume of hot atoms released from the target by the ablation pulse and subsequently being cooled down via conduction to the cell walls. (2) The time constant associated with the exponentially decreasing temperature increases when the source is used for a longer period of time, which we attribute to the formation of a layer of isolating dust on the walls of the cell. By thoroughly cleaning the cell, the time constant is reset to its initial value. (3) The velocity of the molecules at the trailing end of the molecular pulse depends on the length of the cell. For short cells, the velocity is significantly higher than expected from the sudden freeze model. We attribute this to the target remaining warm over the duration of the molecular pulse giving rise to a temperature gradient within the cell. Our observations will help to optimize the source parameters for producing the most intense molecular beam at the target velocity.
Based on the assumption of constant-stress (Dugdale) interface bonding, a theoretical model is established in order to characterize the entire peeling response of an elastic film from a rigid ...substrate. The relationship between the peeling force and the peeling displacement and the relationship between the cohesive zone length and the peeling displacement at different peeling stages are analyzed. Closed-form solutions of the maximum peeling force and the maximum length of cohesive zone are further derived theoretically. It is found that both the maximum peeling force and the maximum length of cohesive zone depend on the interface strength, interface toughness and bending stiffness of the film. Combined with the classical Kendall's model, the cohesive zone length in the steady-state peeling stage is further given. A new method to simultaneously determine the interface strength and interface toughness is proposed, as long as the maximum peeling force, steady-state peeling force and film's bending stiffness are obtained from peeling tests. The results of this paper should be very helpful for interface performance prediction and interface design of film/substrate systems.
Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, ...using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease.
Essentials
Positive family histories suggest the existence of hereditary immune thrombocytopenia (ITP).
The predisposing gene for familial ITP was screened in two familial ITP patients.
The G76S ...mutation on TNFRSF13B led to immune dysfunction and induced megakaryocyte apoptosis.
The G76S mutation on TNFRSF13B is a gain‐of‐function mutation and a predisposing variant for ITP.
Summary
Background
Most immune thrombocytopenia (ITP) is sporadic but a positive family history of ITP in some patients suggests that hereditary forms exist. Because of the rarity of familial ITP families available for study and the heterogeneity of sporadic ITP, family linkage analysis or genome‐wide association studies are limited.
Objectives
Based on one ITP pedigree, we try to identify the predisposing gene in familial or sporadic ITP and reveal the way in which it causes thrombocytopenia.
Methods
Gene expression profiling analysis and whole‐exome sequencing were performed on samples from family members with ITP, sporadic ITP cases and healthy individuals. We also evaluated the influence of potential pathogenic mutation on immune function and megakaryocyte apoptosis.
Results
Whole‐exome sequencing identified a potential pathologic p.G76S heterozygous mutation on the TNFRSF13B gene in familial ITP patients. ITP patients harboring the G76S mutation displayed an upregulated ‘cytokine–cytokine receptor interaction’ signal, increased serum TNFα, IL‐17α, IFNγ and BAFF levels, and enhanced binding capacity of APRIL ligand to B cells. Additionally, Epstein‐Barr virus (EBV)‐transformed B cells with the G76S mutation could induce human megakaryocyte line (Meg‐01) apoptosis significantly.
Conclusion
p.G76S mutation on the TNFRSF13B gene is responsible for ITP, and is a genetic predisposing factor for familial or sporadic ITP.
Drawing upon the social amplification of risk (SARF) and the issue-attention cycle framework, we examined the amplification of COVID-19 risk-related tweets through (a) topics: key interests of ...discussion; (b) temperament: emotions of tweets; (c) topography (i.e., location); and (d) temporality (i.e., over time). We computationally analyzed 1,641,273 tweets, and conducted manual content analysis on a subset of 6,000 tweets to identify how topics, temperament, and topography of COVID-19 tweets were associated with risk amplification - retweet and favorite count - using negative binomial regression. We found 11 dominant COVID-19 topics-health impact, economic impact, reports of lockdowns, report of new cases, the need to stay home, coping with COVID-19, news about President Trump, government support, fight with COVID-19 by non-government entities, origins, and preventive measure in our corpus of tweets across the issue-attention cycle. The negative binomial regression results showed that at the pre-problem stage, topics on President Trump, speculation of origins, and initiatives to fight COVID-19 by non-government entities were most likely to be amplified, underscoring the inherent politicization of COVID-19 and erosion of trust in governments from the start of the pandemic. We also found that while tweets with negative emotions were consistently amplified throughout the issue-attention cycle, surprisingly tweets with positive emotions were amplified during the height of the pandemic - this counter-intuitive finding indicated signs of premature and misplaced optimism. Finally, our results showed that the locations of COVID-19 tweet amplification corresponded to the shifting COVID-19 hotspots across different continents across the issue-attention cycle. Theoretical and practical implications of risk amplification on social media are discussed.
The tripartite motif protein TRIM24 (tripartite motif-containing 24) has been found to play distinct roles in tumor development and progression, according to different tumor contexts. However, it ...remains elusive whether TRIM24 plays a role in malignant gliomas that are the most common and deadly primary brain tumors in adults. We report here that TRIM24 expression is positively correlated with glioma malignancy and is negatively associated with prognosis of patients with newly diagnosed glioblastoma, which is the most malignant form of gliomas but displays highly heterogeneous clinical outcome. The multivariate Cox regression analysis demonstrates the independent predictive value of TRIM24 expression level for overall and progression-free survival. Knockdown of TRIM24 suppresses cell proliferation, cell cycle progression, clone formation and in vivo tumor development, whereas overexpression of TRIM24 promotes cell growth. Chromatin immunoprecipitation, real-time reverse transcription-PCR and mutation analyses demonstrate that TRIM24 binds to the PIK3CA promoter via its PHD-Bromo domain to activate the transcription of PIK3CA gene, thus enhancing phosphatidylinositide 3-kinase (PI3K)/Akt signaling. The pan-PI3K inhibitor LY294002 and small interfering RNA targeting PIK3CA both abrogate the growth-promoting effect of TRIM24. Moreover, TRIM24 regulates the expression of DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) through PI3K/Akt/nuclear factor-κB signaling transduction and enhances resistance to temozolomide, the standard chemotherapeutic agent for glioblastoma. Finally, glioblastoma patients with low TRIM24 expression benefit from chemotherapy, whereas those with high TRIM24 expression do not have such benefit. Our results suggest that TRIM24 might serve as a potential prognostic marker and therapeutic target for the management of malignant gliomas.
Context.
No robust detection of prompt electromagnetic counterparts to fast radio bursts (FRBs) has yet been obtained, in spite of several multi-wavelength searches having been carried out so far. ...Specifically, X/
γ
-rays counterparts are predicted by some models.
Aims.
We aim to search for prompt
γ
-ray counterparts in the Insight-Hard X-ray Modulation Telescope (Insight-HXMT) data, taking advantage of the unique combination of the large effective area in the keV–MeV energy range, and of sub-ms time resolution.
Methods.
We selected 39 FRBs that were promptly visible from the High-Energy (HE) instrument aboard Insight-HXMT. After calculating the expected arrival times at the location of the spacecraft, we searched for a significant excess in both individual and cumulative time profiles over a wide range of time resolutions, from several seconds down to sub-ms scales. Using the dispersion measures in excess of the Galactic terms, we estimated the upper limits on the redshifts.
Results.
No convincing signal was found, and for each FRB we constrained the
γ
-ray isotropic-equivalent luminosity and the released energy as a function of emission timescale. For the nearest FRB source, the periodic repeater FRB 180916.J0158+65, we find
L
γ
, iso
< 5.5 × 10
47
erg s
−1
over 1 s, whereas
L
γ
, iso
< 10
49
− 10
51
erg s
−1
for the bulk of FRBs. The same values scale up by a factor of ∼100 for a ms-long emission.
Conclusions.
Even on a timescale comparable with that of the radio pulse itself, no keV–MeV emission is observed. A systematic association with either long or short GRBs is ruled out with high confidence, except for sub-luminous events, as is the case for the core-collapse of massive stars (long) or binary neutron star mergers (short) viewed off axis. Only giant flares from extragalactic magnetars at least ten times more energetic than Galactic siblings are ruled out for the nearest FRB.
Background and Aims
Hypoxia is one of the central players in shaping the immune context of the tumor microenvironment (TME). However, the complex interplay between immune cell infiltrates within the ...hypoxic TME of HCC remains to be elucidated.
Approach and Results
We analyzed the immune landscapes of hypoxia‐low and hypoxia‐high tumor regions using cytometry by time of light, immunohistochemistry, and transcriptomic analyses. The mechanisms of immunosuppression in immune subsets of interest were further explored using in vitro hypoxia assays. Regulatory T cells (Tregs) and a number of immunosuppressive myeloid subsets, including M2 macrophages and human leukocyte antigen–DR isotype (HLA‐DRlo) type 2 conventional dendritic cell (cDC2), were found to be significantly enriched in hypoxia‐high tumor regions. On the other hand, the abundance of active granzyme Bhi PD‐1lo CD8+ T cells in hypoxia‐low tumor regions implied a relatively active immune landscape compared with hypoxia‐high regions. The up‐regulation of cancer‐associated genes in the tumor tissues and immunosuppressive genes in the tumor‐infiltrating leukocytes supported a highly pro‐tumorigenic network in hypoxic HCC. Chemokine genes such as CCL20 (C‐C motif chemokine ligand 20) and CXCL5 (C‐X‐C motif chemokine ligand 5) were associated with recruitment of both Tregs and HLA‐DRlo cDC2 to hypoxia‐high microenvironments. The interaction between Tregs and cDC2 under a hypoxic TME resulted in a loss of antigen‐presenting HLA‐DR on cDC2.
Conclusions
We uncovered the unique immunosuppressive landscapes and identified key immune subsets enriched in hypoxic HCC. In particular, we identified a potential Treg‐mediated immunosuppression through interaction with a cDC2 subset in HCC that could be exploited for immunotherapies.
We performed the broadband (1-100 keV) spectral analysis of the first Galactic Be ultraluminous X-ray pulsar (BeULX) Swift J0243.6+6124 observed by Insight-HXMT during the 2017−2018 outburst. The ...results show spectral transitions at two typical luminosities, roughly consistently with those reported previously via pure timing analysis. We find that the spectrum evolves and becomes softer and has higher cutoff energies until the luminosity reaches L1 (∼1.5 × 1038 erg s−1). Afterwards the spectrum becomes harder with lower cutoff energies until the luminosity increases to L2 (∼4.4 × 1038 erg s−1), around which the second spectral transition occurs. Beyond L2, the spectrum softens again and has larger cutoff energies. Similar behaviors were observed previously in other high-mass X-ray binary systems (HMXBs), especially for the second transition at higher luminosities, which is believed to have a correlation with the magnetic field of the harbored neutron star. Accordingly, we speculate that Swift J0243.6+6124 owns a neutron star with magnetic field strength >1013 G. The spectral transition at around L1 of Swift J0243.6+6124 is first observed thoroughly for any HMXB outburst characterized by strong evolution of the thermal component: the temperature of the blackbody drops sharply accompanied by a sudden increase of the blackbody radius. These spectral transitions can in principle be understood in a general scenario of balancing the emission patterns between the pencil and the fan beams at the magnetic pole, for which the extreme brightness of Swift J0243.6+6124 may provide an almost unique lab to probe the details.
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