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The formation of germinal centers (GCs) is crucial for humoral immunity and vaccine efficacy. Constant stimulation through microbiota drives the formation of constitutive GCs in Peyer’s patches (PPs), which generate B cells that produce antibodies against gut antigens derived from commensal bacteria and infectious pathogens. However, the molecular mechanism that regulates this persistent process is poorly understood. We report that Ewing Sarcoma Breakpoint Region 1 (EWSR1) is a brake to constitutive GC generation and immunoglobulin G (IgG) production in PPs, vaccination-induced GC formation, and IgG responses. Mechanistically, EWSR1 suppresses Bcl6 upregulation after antigen encounter, thereby negatively regulating induced GC B cell generation and IgG production. We further showed that tumor necrosis factor receptor-associated factor (TRAF) 3 serves as a negative regulator of EWSR1. These results established that the TRAF3–EWSR1 signaling axis acts as a checkpoint for Bcl6 expression and GC responses, indicating that this axis is a therapeutic target to tune GC responses and humoral immunity in infectious diseases.

The fluid intake and hydration status during pregnancy may influence the health outcomes of both the mother and the fetus. However, there are few studies related to this. The aim of the present study was to investigate fluid intake behaviors among pregnant women in their second trimester, to evaluate their hydration status and pregnancy complications, and to further explore the association of fluid intake and the amniotic fluid index (AFI). Participants’ total fluid intake (TFI) levels were determined using a 7-day 24 h fluid intake questionnaire. The levels of water intake from food were not recorded or measured. Morning urine samples were collected, and both urine osmolality levels and urine specific gravity (USG) were tested to evaluate their hydration status. Fasting blood samples were also collected and measured for osmolality and complete blood count (CBC). A total of 324 participants completed the study. They were divided into four groups based on quartiles of TFI, including participants with lower (LFI1 and LFI2) and higher (HFI1 and HFI2) fluid intake levels. The median TFI was 1485 mL, and the median values of the four groups with different TFI levels were 1348, 1449, 1530, and 1609 mL, respectively. Only 3.4% of the participants attained the recommended value following an adequate water intake (1.7 L) level for pregnant women in China. Plain water was the main TFI resource (78.8~100.00%), and differences in the plain water intake levels among the four groups were evident (χ2 = 222.027, p < 0.05). The urine osmolality decreased sequentially with increasing TFI values from the LFI1 to HFI2 group, and significant differences in the urine osmolality levels among the four groups were evident (p < 0.05). Meanwhile, the percentage of dehydrated participants decreased from 26.8% in the LFI1 group to 0.0% in the HFI2 group (χ2 = 131.241, p < 0.05). Participants with higher TFI values had higher AFI values (χ2 = 58.386, all p < 0.05), and moderate-intensity correlations were found between TFI and urine osmolality, hydration status, and AFI (all p < 0.05). A large proportion of the participants had insufficient TFIs during the second trimester of pregnancy, and a proportion of the participants were dehydrated. The preliminary analysis showed that the AFI was correlated with the TFI during the second trimester of pregnancy. A sufficient TFI is necessary for pregnant women to improve their hydration status and may have effects on their health. The results can provide appropriate scientific references for the development of beneficial recommendations concerning adequate water intake levels for pregnant women in China.

On 21 May 2021, an Mw 7.4 earthquake occurred in Maduo County, Qinghai Province, China. A dense network of high-rate (1 Hz) Global Navigation Satellite System (GNSS) stations around the epicenter provided one of the most complete recordings of GNSS kinematic displacements in Tibet to date. We used these data retrospectively to test a prototype earthquake early warning (EEW) system. Here, we present the results of that test, in which the EEW system archived high-rate GNSS displacement streams, and then used them to track evolving magnitude and slip. The geodetic module in the EEW system issued the first alert 34 s after the earthquake onset. The first alert had a moment magnitude (Mw) of 6.65, which then increased until reaching a stable value (Mw 7.4) 61 s after the earthquake onset. Testing results show good agreement with rapid GNSS displacements and postprocessed GNSS displacements; moreover, the rapid finite-fault inversion is consistent with postinversion magnitude and rupture dimensions. Our findings confirm the viability and usefulness of this EEW system in quasi-real-time magnitude estimation and finite-fault slip inversion.

Identifying the location of fault creep, quantifying its rate and spatiotemporal variation are critical for seismic hazard assessment. Interferometric Synthetic Aperture Radar (InSAR) observations have identified substantial shallow aseismic slip along the Kangding segment of the Xianshuihe fault, with rates reaching up to ~20 mm/yr. Due to the Kangding earthquake in 2014, whether the aseismic slip along the segment reflects the secular creep, afterslip effects, or their joint contribution remains unresolved. In this study, we characterize the temporal evolution of shallow creep rates on the fault plane, using both ascending and descending Sentinel-1A/B data spanning 2014-2021. The results indicate most of afterslip ends within two years following the 2014 Kangding earthquake. With the afterslip disappearing, the number of earthquakes distributed in the afterslip zone gradually decreases. We then identify a ~15 km-long creeping segment with a steady slip rate ~13 mm/yr between Huiyuan temple and Jinlong temple. In addition, a series of seismic clusters located within the creeping segment potentially bear the signature of repeating earthquakes, although we must confirm this hypothesis. Considering that the ruptures of historical strong earthquakes do not fully penetrate the creeping segment, it might act as a barrier to arrest the next earthquake rupture.

Aim: To study the clinical effect and safety of iron supplementation in the treatment of mild thalassemia complicated by iron deficiency in late pregnancy. Methods: 376 patients with mild thalassemia complicated by iron deficiency in late pregnancy treated in our hospital from July 2019 to June 2021 were selected and recruited in the research group, and 200 normal pregnant women treated in the same period were selected and recruited in the control group. Hemoglobin (Hb), reticulocyte blood, red blood protein (RET he) level, ferritin (SF) level, soluble transferrin receptor (sTfR) level, adverse maternal and infant outcomes, etc. were analyzed. Results: There was no significant difference in the levels of SF, Hb, RET he and sTfR between the two groups before treatment. After treatment, the levels of SF, Hb, RET he and sTfR in the research group were significantly improved, which was statistically significant compared with the control group. The frequencies of intrapartum hemorrhage, premature delivery, stillbirth, hemorrhagic shock, and neonatal asphyxia in the research group were 289±47.88, 36 (9.57%), 0 (0.00%), 25 (6.65%), and 6 (1.26%), respectively. The frequencies of intrapartum hemorrhage, premature delivery, stillbirth, hemorrhagic shock, and neonatal asphyxia in the control group were 284 ± 46.99, 7 (3.50%), 0 (0.00%), 6 (3.00%), and 0 (0.00%), respectively. There were significant differences in preterm delivery and hemorrhagic shock, and there was no significant difference in other delivery outcomes. Conclusions: Under the premise of strictly controlling the iron reserve in pregnant women, continuous medication until the end of delivery may be conducive to the control of maternal thalassemia complicated by iron deficiency and the improvement of pregnancy outcome.

The generated stochastic slip ruptures.

Objective. This study aimed to investigate the efficacy and safety of anti-PD-1 immunotherapy combined with gemcitabine chemotherapy in multiline treatment of advanced pancreatic cancer. Methods. A retrospective analysis was performed on the clinical data of 32 patients with advanced pancreatic cancer treated with sintilimab regimen from January 2019 to December 2021 in our hospital. All patients were followed up until death or April 2022, in the form of outpatient, in-hospital review, or telephone follow-up. Follow-up content included routine blood, liver and kidney functions, tumor markers, plain or enhanced abdominal CT, and abdominal MRI examinations. Clinical efficacy was evaluated according to mRECIST criteria, and the severity of adverse effects was evaluated according to American Institute for Cancer Research (AICR) Standard Term for Adverse Events, Version 5.0. Results. During treatment, the dosage of sintilimab was halved in 2 patients due to adverse reactions. All patients were treated with sintilimab for 1~10 times, with an average of 6 ± 4 times. The total response rate (ORR) and disease control rate (DCR) were 6.25% and 12.50% and 25.00% and 37.50%, respectively, after 1 and 3 months of treatment. The mean follow-up time of 32 patients was 1-12 months, and the median follow-up time was 4 ± 3 months. By the end point of follow-up, a total of 25 patients died, and the median progression-free survival (PFS) was 3.8 (95% CI (1.85-5.63)) months. The median overall survival (OS) was 5.1 months (95% CI (3.63~7.68). After treatment, the levels of tumor markers CA125, CEA and CA199 were partly decreased compared with those before treatment (all P < 0.001 ). After treatment, the blood routine indexes d-dimer, CRP (C-reactive protein), NLR (neutral granulocyte to lymphocyte ratio), and MLR (monocyte to lymphocyte ratio) decreased compared with those before treatment. In 32 patients with advanced pancreatic cancer, the adverse reactions with an incidence more than 10% included fatigue, rash, hypothyroidism, hyperuricemia, and renal insufficiency. Only 2 patients showed grade 3 fatigue symptom, and all the others showed no adverse reactions of grades 3~5. In this study, all patients’ adverse reactions were relieved after symptomatic treatment. Conclusion. Gemcitabine chemotherapy in multiline treatment of advanced pancreatic cancer with sintilimab can achieve certain clinical benefits without serious adverse reactions.

Active crustal deformation of the Tibetan plateau results in destructive continental earthquakes and is therefore the focus of intense research interest. Increases in the numbers of Global Navigation Satellite System (GNSS) networks and stations deployed in Tibet are allowing for the characterization of crustal deformation during different phases of the earthquake cycle. Here, we present the status of a “seismic + high-rate GNSS” network deployed in eastern Tibet, including its data streams and data processing system, with the goal of supporting quasi-real-time earthquake source determination. Furthermore, we use this network to test a prototype earthquake early warning (EEW) system using data from the 2008 Mw 7.9 Wenchuan earthquake, the 2011 Mw 9.0 Tohoku earthquake, and 2200 synthetic earthquakes with moment magnitudes ranging from 6.5 to 7.5 on the southern Longmen Shan fault and Anninghe fault. The results show that our current methodology could respond to moderate-to-large earthquakes (magnitude 7+) within tens of seconds after the origin time, with implications for EEW applications in China.

Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections. We show that TNF receptor-associated factor 2 (TRAF2) maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections. This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase (NIK) and degradation of the proapoptotic factor Bim. NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105. Interestingly, while NIK is required for Tpl2-ERK signaling under normal conditions, uncontrolled NIK activation due to loss of its negative regulator, TRAF2, causes constitutive degradation of p105 and Tpl2, leading to severe defects in ERK activation and effector/memory CD8 T cell survival. Thus, TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.

This article focuses on the atomization characteristics of fan air-assisted nozzles, which is important in the emerging process of dust removal via air-assisted nozzles in underground coal mines. A...

Investigating the interaction between slow-slip events (SSEs) and large earthquakes provides insights into earthquake-triggering mechanisms and is crucial for earthquake hazard assessment. In this study, we used Sentinel-1 Interferometric Synthetic Aperture Radar and Global Positioning System (GPS) data to estimate the source parameters of the 2018 Mw 7.2 Pinotepa, Mexico, earthquake. The results show that the earthquake ruptured both the seismogenic zone and a long-term SSE area, with two asperities ruptured during the event. GPS time-series data indicate that an SSE was initiated approximately during March 2017 below Oaxaca; the SSE ruptured an area below the source region of the Pinotepa earthquake and intruded into the seismogenic zone. The spatiotemporal proximity may suggest that the SSE triggered the Pinotepa earthquake. We propose that the triggering mechanism may either have been Coulomb stress loading or weakening of the source area by fluid migration. Furthermore, we calculated the seismic moment deficit and Coulomb failure stress changes and conclude that the Oaxaca area still has the potential for large earthquakes.

Swine pneumonia is a great threat for pig industry around the world, which is usually accompanied with neutrophils infiltration in the airway. Although interleukin-8 (CXCL8) and its receptors, CXC chemokine receptor 1 and 2 (CXCR1/2) in human have been well documented, the expression and function of CXCR1/2 is still unknown in swine. To explore the feasibility to develop new veterinary anti-inflammatory drugs targeting porcine CXCR1/2, we detected CXCR1/2 expression in swine pneumonia through Real-Time PCR and immunohistochemistry for the first time. Two porcine CXCR1/2 antagonists, CXCL8(3–72)N11R/G31P (pN11R) and CXCL8(3–72)G31P (pG31P) were prepared and their anti-inflammatory effects were evaluated using cell chemotaxis assays and animal experiments. Our data showed that CXCR1/2 expression, which was closely related to neutrophil infiltration in the lung, was significantly up-regulated in swine pneumonia. The pN11R and pG31P could effectively inhibit the directional migration of neutrophils in vitro. In vivo data also indicated that both pN11R and pG31P significantly relieved LPS-induced pneumonia in mice through decreasing the expression of TNF-α, CXCL8, and IL-1β, and inhibiting neutrophil influx into the lung. pG31P was more efficient. Our study suggested that it is possible to develop new veterinary anti-inflammatory drugs targeting porcine CXCR1/2, and pG31P is a promising candidate.

SUMMARY We combine Global Positioning System (GPS) velocity field with Interferometric Synthetic Aperture Radar (InSAR) results to study the interseismic deformation across the western Altyn Tagh fault (ATF) at longitude 86° E. GPS and InSAR data are consistent after correcting for the contribution from vertical deformation in the InSAR line-of-sight map. InSAR and GPS data identify an area of ∼2 mm a−1 sinistral shear and ∼6 mm a−1 of NS shortening located ∼150 km south of the ATF near the Manyi fault system. Excluding the data located in that area, Bayesian inversion of a 2-D profile across the ATF indicate a locking depth of 14.8 ± 3.5 km and a slip rate of 8.0 ± 0.4 mm a−1, lying at the lower range of previously published estimates. In addition, we find no significant offset between the fault at depth and the surface fault trace and no asymmetry of the interseismic profile that implicitly reveal lateral variations of the elastic strength across the ATF. Detailed analysis of InSAR profile across the fault show no distinguishable surface creep along the western ATF. Our study highlights how different data sets, data selection and model assumption might impact results on the ATF slip rate, locking depth and rheological contrast across the fault.

TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor—TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1–TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1–TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ–TBKBP1–TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression. Zhu et al. show that, in response to growth factors, TBKBP1 recruits TBK1 to promote its activation by PKCθ, thereby facilitating mTORC1 activation, tumour-mediated immunosuppression and tumourigenesis.

Coseismic slip of the 1973 Ms 7.6 Luhuo earthquake--related files

Decadal postseismic deformation of the 1973 Ms 7.6 Luhuo earthquake and frictional properties on the Xianshuihe fault--related files

Significance Macrophages play a crucial role in chronic inflammatory diseases, such as nonalcoholic steatohepatitis (NASH) and inflammatory bowel disease, but how the proinflammatory function of macrophages is controlled is not well understood. In this work, we identified TBK1 as a pivotal anti-inflammatory factor in macrophages that restricts inflammation in different disease models. Myeloid cell–specific TBK1 deficiency causes spontaneous development of metabolic disorders in aged mice and exacerbates high-fat diet–induced fatty liver disease with NASH-like symptoms. The Tbk1-MKO mice are also hypersensitive to experimental colitis. We obtained genetic evidence that TBK1 is crucial for controlling proinflammatory signaling pathway in macrophages. These findings establish TBK1 as a pivotal anti-inflammatory factor and a potential therapeutic target for the treatment of inflammatory diseases., Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell–conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the Tbk1-MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell–specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1β. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of Tbk1-MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.

International audience; We use Global Positioning System (GPS) and Interferometric Synthetic Aperture Radar (InSAR) data to quantify the interseismic coupling along the Xianshuihe-Xiaojiang fault system (XXFS). Our results confirm 7–11 mm/a of left-lateral strike-slip motion along the XXFS. South of the Shimian County, high interseismic coupling is found down to 20 km-depth along the Anninghe-Zemuhe fault. A second 130 km-long section, highly coupled down to 10–15 km-depth, is identified along the northern Xiaojiang fault. North of the Kangding County, the Xianshuihe fault appears to be predominantly creeping at depth. Previously identified long-lasting surface creep following the 1973 M 7.6 Luhuo earthquake has now ended, possibly marking the initiation of a new period of stress accumulation and progressive relocking of the fault. Farther south along the fault, we identify a ∼30 km-long section (∼30.2°–30.4°N) creeping at ∼7 mm/yr. Furthermore, creep accelerated by ∼2 mm/yr during the 2008–2014 period, possibly as a result of the static Coulomb failure stress increment induced by the 2008 Mw 7.9 Wenchuan earthquake, that occurred ∼200 km northeast of it. The 2014 Mw 5.9 Kangding earthquake occurred along the creeping section at the end of the period of accelerated creep. Finally, taking advantage of the long historical records of past large earthquakes available since 1327, we quantitatively compare the moment budget along the XXFS. Results highlight that along the Anninghe, Zemuhe, and Xiaojiang faults, moment deficit for Mw > 7 earthquakes has now accumulated.

Peak ground displacement (PGD) and peak ground velocity (PGV) are critical parameters during earthquake early warning, as they can provide rapid magnitude estimation before rupture end. In this study, we used the high-rate Global Navigation Satellite System (GNSS) data from 55 continuous stations to estimate the magnitude of the 2021 Maduo earthquake in western China. We used the relative positioning method and variometric approach to acquire real-time GNSS displacement and velocity waveforms, respectively. The results showed the amplitude of displacement and velocity waveforms gradually decreased with increasing hypocentral distance. Our results showed that the fluctuation of PGD magnitudes over time is smaller than that of PGV magnitudes. Nonetheless, the earthquake magnitudes estimated from both methods were consistent with their counterparts (Mw 7.3) reported by the United States Geological Survey (USGS). The final magnitude estimated from the PGD and PGV methods were Mw 7.25 and Mw 7.31, respectively. In addition, our results highlighted how the number of high-rate GNSS stations could influence the stability and convergence time of magnitude estimation.

Microglia have been implicated in neuroinflammatory diseases, including multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). We demonstrate that microglia mediate EAE disease progression via a mechanism relying on the noncanonical nuclear factor kB (NF-κB) pathway. Microglia-specific deletion of the noncanonical NF-κB-inducing kinase (NIK) impairs EAE disease progression. Although microglial NIK is dispensable for the initial phase of T cell infiltration into the central nervous system (CNS) and EAE disease onset, it is critical for the subsequent CNS recruitment of inflammatory T cells and monocytes. Our data suggest that following their initial CNS infiltration, T cells activate the microglial noncanonical NF-κB pathway, which synergizes with the T cell-derived cytokine granulocyte-macrophage colony-stimulating factor to induce expression of chemokines involved in the second-wave of T cell recruitment and disease progression. These findings highlight a mechanism of microglial function that is dependent on NIK signaling and required for EAE disease progression.

GPS and InSAR data used in the Bayesian inversion.

To compare current nonalcoholic fatty liver disease (NAFLD)-related algorithms to find suitable algorithms for NAFLD, especially lean NAFLD in middle-aged and elderly Chinese population.NAFLD is the most common cause of chronic liver disease in the world today. Various algorithms based on obesity indicators, blood lipids, and liver enzymes, etc. have been developed to screen NAFLD.General, anthropometric and biochemical characteristics were collected. One-way analysis of variance and the χ test were applied to test the differences in continuous and categorical variables, respectively. Multivariable logistic regression analyses, adjusted by age, gender, body mass index, tobacco use, alcohol consumption, and physical activities, were used to investigate the associations between NAFLD-related algorithms and NAFLD. The accuracy and cut-off point of NAFLD-related algorithms to detect NAFLD were evaluated by area under the receiver operator characteristic curve and the maximum Youden index analysis, respectively.In 8 NAFLD-related algorithms, the receiver operator characteristic of fatty liver index (FLI) and waist circumstance-to-height ratio (WHR) for NAFLD were in the whole (0.83 and 0.84), lean (0.74 and 0.74), and overweight/obese (0.71 and 0.72) population, respectively, which were higher than those of other algorithms. The cut-off points of WHR and FLI for NAFLD were different in the overall (0.50 and 20), lean (0.47 and 10), and overweight/obese (0.53 and 45) population.WHR and FLI could be the most accurate of 8 algorithms for the noninvasive diagnosis of NAFLD in both lean and overweight/obese population.

NF-κB, a family of transcription factors regulating diverse biological processes including immune responses, is activated by canonical and noncanonical pathways based on degradation of IκBα and processing of the IκB-like protein p100, respectively. Although p100 responds to noncanonical NF-κB stimuli for processing, it does not undergo degradation, but rather becomes accumulated, along with canonical NF-κB activation. We show here that the stability of p100 is tightly controlled by a deubiquitinase, Otub1. Otub1 deficiency not only promotes signal-induced p100 processing and noncanonical NF-κB activation but also causes steady-state p100 degradation, leading to aberrant NF-κB activation in the canonical pathway. B-cell-conditional deletion of Otub1 results in B-cell hyperplasia, antibody hyper-production, and lupus-like autoimmunity. Otub1-deficient B cells display aberrantly activated phenotypes and overproduce the cytokine IL-6, contributing to autoimmunity induction. Thus, maintenance of p100 stability by Otub1 serves as an unusual mechanism of NF-κB regulation that prevents autoimmunity.