Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder. Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain regions, particularly the VTA. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. Attenuation of H3Q5dop during abstinence induced persistent changes in gene expression programs associated with neuronal signaling and dopaminergic function in heroin abstinence and led to reduced heroin-seeking behavior. Interestingly, the observed changes in molecular pathways after heroin SA showed significant yet reversed overlap with the same genes altered in cocaine SA. These findings establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in heroin-induced functional plasticity in VTA. Opioid Use Disorder (OUD) has dramatically increased to epidemic proportions in recent years, with heroin dependence growing more than 50% over the last decade and accounting for more drug-related deaths  than anyRecently, our laboratory demonstrated that in addition to modulating downstream synaptic activity as a neurotransmitter, dopamine itself plays a direct role in epigenetically coordinating gene expression within these dopaminergic cells in the VTA . We prevAll drugs of abuse are thought to elicit changes in dopaminergic neurotransmission from VTA, although different classes of substances act on this system through distinct cellular mechanisms. In addition, the magnitude and temporal dynamics of dopamine transmission vary widely between drugs, even within class, highlighting the importance of delineating substance-specific mechanisms in order to develop targeted therapeutic strategies to address the molecular changes associated with each drug . In the ad libitum. All procedures were done in accordance with NIH guidelines and the Institutional Animal Care and Use Committees of the Icahn School of Medicine at Mount Sinai and the State University of New York at Buffalo.Male Sprague-Dawley rats  were singly housed during self-administration experimental procedures, and maintained on a 12 h reverse light/dark cycle with food and water available For both heroin SA and saline SA, rats were implanted with chronic indwelling jugular catheters, as previously reported , 16. RatRats were allowed to recover from jugular catheterization surgery for 5 d, and then were trained to SA heroin (0.02 mg/kg/inf) or saline (as a non-reinforcement control) in operant chambers for 3 h each day for a period of 10 d. A response in the active hole nose poke resulted in an intravenous injection of heroin (0.02 mg/kg/inf) or saline using a fixed ratio 1 (FR1) schedule of reinforcement on day 1 that was increased to FR3 on day 3 and maintained for the remainder of the experiment . ResponsFor the cue-induced seeking behavior, on AD30, rats were returned to operant chambers for a testing duration of 1 h. During the test duration, rats were subjected to extinction-like conditions whereby responses in an active hole delivered only the cue light previously associated with drug availability. The total number of active responses in the active hole was an operational measure of heroin-seeking behavior , 18.2, 0.34 M sucrose, 10% glycerol, 1 mM EDTA, 1X protease inhibitor cocktail and 1X phosphostop inhibitor. After homogenization, 0.1% TritonX-100 was added, samples were incubated on ice for 30 min and then centrifuged for 5 min at 1300 × g at 4 °C. Supernatants  were discarded, and nuclear pellets were resuspended in Buffer A to remove any remaining cytosolic contamination, followed by centrifugation for 5 min at 1300 × g at 4 °C. Supernatants were then discarded and pellets resuspended and sonicated in sample buffer containing 0.3 M sucrose, 5 mM HEPES, 1% SDS and 1X protease inhibitor cocktail. Protein concentrations were measured with the DC protein assay kit (BioRad), and 10–15 ug of protein was loaded onto 4–12% NuPage BisTris gels (Invitrogen) for electrophoresis. Proteins were next transferred to nitrocellulose membranes and blocked for 1 h in 5% milk in PBS + 0.1% Tween 20 (PBST), followed by primary antibody incubation for two days at 4 °C. The following antibodies were used in this manuscript: rabbit anti-H3Q5dop , rabbit anti-H3K4me3Q5dop , rabbit anti-H3K4me3 , mouse anti-Tgm2  and rabbit anti-H3 . Membranes were then washed 3X in PBST (10 min) and incubated for 1 h with horseradish peroxidase conjugated anti-rabbit  or anti-mouse  secondary antibodies  in 5% milk/PBST at RT. After three more washes with PBST, bands were detected using enhanced chemiluminescence . Densitometry was used to quantify protein bands using Image J Software (NIH), and proteins were normalized to total H3. H3 measurements were obtained from the same membrane as the protein of interest after stripping the primary antibody for 10 min in Restore Stripping Buffer (Thermo #21059).VTA tissues were collected from heroin SA rats (2 mm punches) on AD1, AD14 or AD30 and frozen. Nuclear fractions were purified via homogenization in Buffer A containing 10 mM HEPES (pH 7.9), 10 mM KCl, 1.5 mM MgClAdeno-associated virus H3.3 constructs [empty vs. wildtype (WT) vs. (Q5A)-Flag-HA] were generated and validated, as previously described , 12, 19.Rat brains were removed and immediately snap frozen. Brains were then sectioned to 100 uM thick coronal slices on a cryostat at −20 °C, and 2 mm punches were dissected from virally infected VTA using GFP-fluorescence illuminated via a NIGHTSEA Dual Fluorescent Protein flashlight (#DFP-1). Total RNA was then extracted from punches using Trizol (Thermo Fisher #15596026)-chloroform, followed by cleanup and elution into RNAase-free water using Qiagen minelute (#74204) columns, as per manufacturer instructions. Following elution, RNA samples were enriched for mRNA via polyA tail selection beads, and mRNA libraries were prepared using the Illumina Truseq RNA Library Prep Kit V2 (#RS-122-2001). Libraries were pooled and sequenced on the Illumina Novaseq platform. RNA-seq data were pre-processed and analyzed, as previously described . BrieflyGeneOverlap R package version 1.26.0 [Differentially expressed (DEx) genes were defined at FDR cutoff <0.05, Log2FC ± 0.2. Threshold free Rank-Rank Hypergeometric Overlap (RRHO) maps were generated to visualize transcriptome-wide gene expression concordance patterns as previously described , using Rn 1.26.0 . Processn 1.26.0 , depositp value [p value) on the X-axis, and the combined score of the enrichment (bubble size). The combined score is derived from both the p value and the z-score (deviation from expected rank based on gene set size) calculated by the following formula: c = ln(p) * z. Fill color represents the database source of terms. For Fig. p value [p value) on the X-axis to indicate directionality of expression of genes analyzed, and the number of DEx genes overlapping with the gene set (bubble size), and the comparison source of DEx genes (fill color).In order to determine if differential gene expression comparisons showed significant overlaps with annotated gene sets, we performed GO Enrichment Analyses using the EnrichR package (Version 3.0) against EnrichR’s gene set databases Panther Pathway, GO Biological Process 2021, and GO Molecular Function 2021. Enrichments were ranked by adj. p value , compute p value . Multivat tests were performed to compare saline vs. heroin conditions at different time points. For all behavioral testing involving more than two treatments and time points, Two-way ANOVAs were performed with subsequent Dunnett’s  or Tukey’s post hoc analyses for multiple comparisons (MC) (as indicated throughout the text). In molecular analyses, all animals used were included as separate ns (samples were not pooled). Significance was determined at p < 0.05. All data are represented as mean ± SEM.For western blot comparisons, Student’s P = 0.0089, followed by Dunnett’s MC test for d1 vs. d5-d10; p = 0.03-p = 0.0008) [via Student’s t test . This increase persisted to extended abstinence periods (AD14), via Student’s t test . Neither H3K4me3Q5dop nor total H3K4me3 . The writer enzyme for H3Q5dop was unaffected in its expression during periods of abstinence from heroin  , but not combinatorial H3 lysine 4 (K4) trimethyl (me3) Q5dop, was previously found to accumulate in VTA during prolonged, but not acute, abstinence from cocaine SA , we hypo 0.0008) . Followi 0.0008) . On abstme3 Fig.  showed i05) Fig. . TogetheTo explore the functional consequences of H3Q5dop accumulation during heroin abstinence, we used an AAV2 vector that expresses the H3 variant, H3.3, with a glutamine-to-alanine substitution at position 5 (H3.3Q5A), which cannot be dopaminylated. This H3.3Q5A construct has been shown to strongly express the mutant H3.3Q5A protein in a nuclear-specific manner in adult neurons, resulting in downregulation of H3Q5dop . Importavs. both heroin empty and heroin H3.3 WT vectors . For both comparisons, we identified a robust pattern of anti-correlation, demonstrating that the H3.3Q5A mutant induced reversed gene expression patterns compared to heroin empty vector and heroin H3.3 WT groups.We first utilized a threshold free Rank-Rank Hypergeometric Overlap (RRHO) analysis  to charaA-B).To profile specific heroin-induced gene expression changes, we employed pairwise comparisons to identify differentially expressed (DEx) genes between heroin groups (empty vector and H3.3 WT) vs. saline groups (empty vector and H3.3 WT), defined at a false discovery rate (FDR) of <0.05, log2FC ± 0.2. We identified 736 upregulated and 1005 downregulated DEx genes between the heroin empty vs. saline empty conditions, and 303 upregulated and 823 downregulated DEx genes between heroin H3.3 WT and saline H3.3 WT comparisons, respectively  that were reversed between heroin H3.3Q5A vs. heroin empty and heroin H3.3 WT conditions  on the set of overlapping DEx genes , virus , and interaction  observed. Tukey’s MC tests revealed significant differences between heroin H3.3 Q5A vs. heroin empty (p = 0.0007) and heroin H3.3Q5A vs. heroin H3.3 WT (p = 0.0288), and no significant effects between saline viral groups (p > 0.05). Importantly, we have previously shown that this H3.3Q5A mutant histone does not affect operant behavior for natural rewards [Finally, to investigate the consequences of reducing H3Q5dop levels on heroin relapse-relevant behaviors, we put an independent cohort of animals through chronic heroin self-administration, followed by intra-VTA viral infusions on AD1, using the same three viral vectors discussed above Fig. . On AD30 rewards . TogetheAs part of its mechanism of action, heroin exposures increase neurotransmission from dopaminergic neurons in VTA to reward-processing projection regions in striatum, among other neuronal regions. These fluctuations in dopamine signaling are thought to contribute to maladaptive plasticity and impaired decision-making observed during substance dependence. However, the mechanisms that mediate these processes at the epigenetic level are not fully characterized. Here, we showed that H3Q5dop rapidly accumulates in rodent VTA at 24 h post-heroin SA, and that this increase persisted during protracted periods of heroin abstinence . We next profiled gene expression changes that occurred after attenuating levels of H3Q5dop during heroin abstinence and identified highly significant overlap with regulation of opioid and dopaminergic signaling, cytokine pathways, and synaptic transmission/regulation of neuronal action potential related processes. Finally, these transcriptomic changes coincided with a significant decrease in drug-seeking behavior after 30 d of heroin abstinence. Together, these data indicate that H3Q5dop plays a critical role in promoting persistent functional alterations that drive maladaptive behaviors related to heroin relapse vulnerability.Our findings also highlight the critical role of H3Q5dop in regulating epigenetic changes after chronic exposures to, and abstinence from, different drugs of abuse . However, we also observed key differences between the substances with respect to both the dynamics and gene targets of H3Q5dop. First, we found that H3Q5dop is significantly increased in rodent VTA as soon as AD1 post-heroin SA, an increase that persists throughout more extended periods of abstinence. In contrast, levels of H3Q5dop during cocaine abstinence remained unchanged 24 h after the last day of cocaine SA, and then slowly accumulated during long-term withdrawal . This temporal difference in H3Q5dop dynamics may reflect differences in dopaminergic activity in response to either substance, particularly during more acute periods of abstinence—for example, electrophysiology and fiber photometry studies have demonstrated that while cocaine exposures lead to immediate inhibition of dopaminergic VTA neurons, heroin exposures strongly activate these projections . FurtherAnother major finding revealed in our current study relates to VTA gene expression changes mediated by H3Q5dop in response to heroin vs. cocaine SA. Our RNA-seq analyses found that heroin abstinence induced robust changes in genes involved with interneuron transmission activity, oligodendrocyte myelination, and ECM remodeling. These transcriptomic changes correlate to current hypotheses regarding opiate disinhibition of GABAergic regulation of dopaminergic activity through local interneuron networks in the VTA, thereby leading to increased DA output from the VTA , 33. TheImportantly, reducing accumulation of H3Q5dop with a dominant negative H3.3 mutant virus led to specific gene expression changes in molecular processes mediating action potential generation, membrane conductance, and synaptic regulation, as well as signaling cascades directly related to opioid and dopaminergic pathways. The renormalization of these gene expression alterations led to significantly reduced drug-seeking behavior following extended abstinence from heroin SA, suggesting that these pathways contribute to relapse vulnerability in drug dependence. Together, our data show that H3Qdop accumulation may regulate a state of increased neuronal plasticity, derived from aberrant signals that disrupt the balance of excitatory/inhibitory modulation of VTA activity. Given that chronic heroin use followed by withdrawal induces adaptations in dopaminergic neurotransmission and changes in membrane ion conductance and ion channels , it is nFinally, our previous work established that the H3Q5dop modification may be an upstream epigenetic regulator of dopaminergic neurotransmission in drug dependence. Our current findings suggest that manipulation of H3Q5dop during different stages of drug dependence may represent a useful tool to reveal important gene expression profiles that are unique to specific classes of substances. Moving forward, delineating specific transcriptional signatures that effectively promote reward-circuit remodeling for different drugs of abuse may provide insights to guide clinicians in tailoring therapeutic strategies towards the unique mechanisms of action for a given drug class. For example, substances like nicotine and alcohol, which also converge on promoting dopamine outflow, have distinct molecular interactions with cellular substrates in the VTA. Further study of H3Q5dop dynamics in the context of these different substances may reveal distinct epigenetic mechanisms that translate their respective receptor-binding signals into increased plasticity. Importantly, recent reports of sex-specific dopamine activity after heroin exposure and increased heroin-seeking behaviors in females highlight the need to expand investigations of H3Q5dop mechanisms in female subjects . OverallSupplemental MaterialExtended Data Table 1


Patients with plasma cell type idiopathic multicentric Castleman disease (PC‐iMCD) often show elevated serum IgG4 levels and IgG4‐positive cell infiltration in tissues due to overproduction of interleukin‐6, and may meet the diagnostic criteria for IgG4‐related disease (IgG4‐RD). Although PC‐iMCD has been listed as a major exclusion disease for IgG4‐RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4‐RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC‐iMCD, from IgG4‐RD. Validation was performed on 57 PC‐iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4‐RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC‐iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4‐RD. All these patients with PC‐iMCD were excluded from a diagnosis of IgG4‐RD by the proposed criteria. Additionally, 6.9% of IgG4‐RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings. CRPC‐reactive proteinIgG4‐RDimmunoglobulin G4‐related diseaseIL‐6interleukin‐6PC‐iMCDplasma cell type idiopathic multicentric Castleman diseaseCastleman disease is a rare lymphoproliferative disorder that shares several basic pathological features. Castleman disease is classified into multicentric and unicentric types based on its clinical manifestations.IgG4‐related disease (IgG4‐RD) is a systemic disorder characterized by high serum IgG4 levels and mass‐forming lesions with fibrosis and infiltration of abundant IgG4‐positive cells.A major problem in the diagnosis of IgG4‐RD is the difficulty in differentiating it from its mimickers. Hyper IL‐6 syndrome, including PC‐iMCD, is one of the most important mimickers. Hyper IL‐6 syndrome is associated with polyclonal hypergammaglobulinemia, accompanied by elevated serum IgG4 levels and tissue infiltration of IgG4‐positive cells. PC‐iMCD is mentioned as an exclusion disease in the diagnostic criteria for IgG4‐RD, but in practice, it is difficult to differentiate between the two because of overlapping features. However, the treatment strategy is different; IgG4‐RD is typically responsive to steroid monotherapy, whereas PC‐iMCD is less responsive to steroids as first‐line therapy, and thus IL‐6 receptor blockade therapy is required.In this study, we assessed whether the proposed exclusion criteria of IgG4‐RDn = 57) and IgG4‐RD (n = 29) between 1996 and 2021 at the Department of Pathology  were pathologically examined. In PC‐iMCD, 39 cases presented lymph node lesions and 19 cases exhibited lung lesions. One patient had both lymph node and lung lesions. In IgG4‐RD, 22 cases presented lymph node lesions and seven cases presented lung lesions. The lung lesions in both PC‐iMCD and IgG4‐RD are the same as those included in our previous report.In total, 86 Japanese patients with PC‐iMCD .Immunohistochemical staining was performed on an automated Bond Max instrument  using the following primary antibodies: HHV‐8 ; IgG4 ; IgG , CD20 , and CD3 . In situ hybridization was also performed for the κ and λ light chains .The number of IgG‐ and IgG4‐positive cells was estimated in the area with the highest density of IgG4‐positive cells. The numbers of cells in three different HPFs  were counted, and the average was calculated to obtain the number of IgG4‐positive cells and the IgG4‐/IgG‐positive cell ratio.We applied the pathological and comprehensive criteriaClinical information, including age, gender, and laboratory data  was obtained from medical records. The correlation between the number of IgG4‐positive cells in tissues and the serum immunoglobulin levels was examined and compared between PC‐iMCD and IgG4‐RD.p < 0.05 was considered statistically significant.Statistical analyses were conducted using SPSS for Windows version 23.0 . A The demographics and laboratory findings of the patients are summarized in Table p < 0.001).Among the patients with lymph node lesions, 25 males and 14 females were diagnosed with PC‐iMCD, whereas seven males and 15 females were diagnosed with IgG4‐RD. The mean ages of the PC‐iMCD and IgG4‐RD patients were 53.9 (range 34–89 years) and 68.1 years (range 47–81 years), respectively. PC‐iMCD patients were younger than IgG4‐RD patients . The serum IgG4/IgG ratio of IgG4‐RD patients was higher than that of PC‐iMCD patients (p < 0.001). There was no significant difference in serum IgG4 and serum IgE levels between the two groups .The laboratory findings revealed that the levels of serum IgG, IgA, IgM, and CRP in the PC‐iMCD patients were significantly higher than those in the IgG4‐RD patients  patients with PC‐iMCD had serum IgG4 levels >135 mg/dL. Elevation of IgA and IgM above the reference level was observed in 15/19 (78.9%) and 11/19 (57.9%) of PC‐iMCD patients, respectively, while none of them was observed in IgG4‐RD patients. Elevation of CRP ≥ 1.0 mg/dL was observed in all patients with PC‐iMCD (31/31) but not in patients with IgG4‐RD (0/18).p = 0.008).Among patients with lung lesions, 8 males and 11 females were diagnosed with PC‐iMCD, whereas seven males were diagnosed with IgG4‐RD. The mean ages of the PC‐iMCD and IgG4‐RD patients were 49 (range 26–73 years) and 65.9 years (range 39–77 years), respectively. PC‐iMCD patients were younger than IgG4‐RD patients . The serum IgG4 levels and IgG4/IgG ratio of the IgG4‐RD group were significantly higher than those in the PC‐iMCD group . There was no significant difference between the serum IgE levels of the two groups (p = 1.000).The laboratory data indicated that the levels of serum IgG, IgA, and CRP were significantly higher in the PC‐iMCD group than in the IgG4‐RD group (All cases (17/17) with PC‐iMCD had serum IgG4 levels >135 mg/dL. Elevation of IgA and IgM above the reference level was observed in 12/16 (75.0%) and 2/2 (100%) of PC‐iMCD patients, respectively, while none of them was observed in IgG4‐RD patients. Elevation of CRP ≥ 1.0 mg/dL was observed in 17/19 of PC‐iMCD patients and one IgG4‐RD patient (1/7).Pathologically, the lymph node and lung lesions of PC‐iMCD patients exhibited normal to hyperplastic germinal centers with expanded interfollicular area. Sheet‐like proliferation of mature PCs and hemosiderin deposition were observed in the lymph node from PC‐iMCD patients Figure . In contA large number of IgG4‐positive cells were found in both the lungs and lymph nodes of PC‐iMCD patients. The number of IgG4‐positive cells and IgG4/IgG‐positive cell ratio in PC‐iMCD patients are shown in Table Eight cases of lymph node lesions (20.5%) and eight cases of lung lesions (42.1%) met the pathological criteria for IgG4‐RD (IgG4‐positive cell with >50/HPF and IgG4/IgG ratio >40%).The clinical and pathological findings of 16 PC‐iMCD patients who met the pathological criteria for IgG4‐RDPathological findings revealed sheet‐like proliferation of mature PCs in all cases, except one case with lung lesion. A high degree of hemosiderin deposition was observed in 4/8 (50%) cases with lymph node lesion and 1/8 (12.5%) case with lung lesion. Neutrophilic infiltration was observed in one lung lesion.In lung lesions of PC‐iMCD patients, obliterative vasculitis was sometimes observed . In one PC‐iMCD case with lung lesion, storiform‐like fibrosis and obliterative vasculitis were observed, which were difficult to differentiate from those in IgG4‐RD. However, in this case, marked hemosiderin deposition was observed, and the criterion of IgG4/IgG‐positive cell ratio >40% was not met . Positive correlations were also noted between serum IgG levels and the number of IgG4‐positive cells in lymph node cases in the IgG4‐RD group and lung lesion cases in the PC‐iMCD group, but these correlations were not statistically significant . A weak and insignificant inverse correlation was observed in the lung lesion cases of IgG4‐RD . Serum IgA and the number of IgG4‐positive cells showed no relationship in lymph node cases in both the PC‐iMCD and IgG4‐RD groups. In contrast, there was a weak positive correlation in lung lesion cases of PC‐iMCD . Serum IgM and the number of IgG4‐positive cells were not correlated in the lymph node cases of PC‐iMCD. The IgM levels in lung lesion cases were not evaluated because they were rarely measured.In the lymph node cases, there was a significant positive correlation between the serum IgG levels and the number of IgG4‐positive cells in PC‐iMCD group  and regulatory T cells (Treg) is thought to play an important role. Upregulation of Th2 cytokines, such as IL‐4, IL‐5, and IL‐13, promotes the production of IgE and eosinophils.Overproduction of IL‐6 is deeply related to PC‐iMCD pathogenesis.Using the differences in pathogenesis,In PC‐iMCD, a higher number of IgG4‐positive cells in the tissue is more likely cause it to be misdiagnosed as IgG4‐RD. Since the exclusion criteria include serum IgA and IgM levels, we were interested in the relationship between the number of IgG4‐positive cells in the tissues and serum gamma globulin levels and investigated the correlation.In the current analysis, a positive correlation was noted between the number of IgG4‐positive cells and serum IgG levels in both lymph nodes and lungs of PC‐iMCD, but a significant difference was only seen in lymph nodes. This result may be related to the number of affected lesions. Most of our cases in which lymph node lesions of PC‐iMCD showed multiple lymphadenopathy, whereas in the group of cases in which lung lesions were sampled, lesions other than lung were localized to a few sites. This may mean that the serum IgG level is related to the overall amount of lesions. If this hypothesis is correct, serum IgG level and number of IgG4‐positive cells may reflect the disease activity of PC‐iMCD, but further study is needed.In this study, all PC‐iMCD cases that met the pathological criteria for IgG4‐RDIn IgG4‐RD, there were two cases that met the exclusion criteria. In one of the cases, dense proliferation of mature PCs was observed, but there was also a prominent eosinophilic and lymphocytic infiltration Figure S, which wIn conclusion, we validated the accuracy of the proposed exclusion criteria for IgG4‐RDThe authors declare no competing interests.Conception and design of the study: Asami Nishikori, Midori Filiz Nishimura, and Yasuharu Sato. Acquisition and analysis of data: Asami Nishikori and Midori Filiz Nishimura. Drafting the manuscript; Asami Nishikori and Midori Filiz Nishimura. Review and editing the manuscript: Yoshito Nishimura, Kenji Notohara, Akira Satou, and Seiji Nakamura. Resources; Yasuharu Sato. Supervision; Midori Filiz Nishimura and Yasuharu Sato.Supplementary figure 1.Click here for additional data file.


The order of influence of the pore structure parameters on the peak strain is: T  > T  > T  > T  > APR > PSSA > total porosity.Existing concrete random aggregate modeling methods (CRAMMs) have deficiencies in in the parameterization of the mesoscale pore structure. A novel CRAMM is proposed, whose pore structure is determined by the pore gradation, total porosity, sub-porosity, and pore size of each pore gradation segment. To study the influence of pore structure on the mechanical properties of concrete, 25 mesoscopic concrete specimens with the same aggregate structure but different meso-scale pore structures are constructed and subjected to uniaxial compression tests. For the first time, the influence of sub-porosity of each pore gradation segment, average pore radius (APR), pore specific surface area (PSSA), and total porosity on concrete failure process, compressive strength, peak strain, and elastic modulus were quantitatively and qualitatively analyzed. Results indicate that the pore structure makes the germination and propagation of the damage in cement mortar show obvious locality and affects the formation and expansion of macroscopic cracks. However, it does not accelerate the propagation of the damage in cement mortar from the periphery to the center of the specimen, nor does it change the phenomenon that the ITZ is more damaged than other meso-components of concrete before peak stress. Macroscopic cracks occur in the descending section of the stress–strain curve, and the sudden drops in the descending section of the stress–strain curve are often accompanied by the generation and expansion of macroscopic cracks. The quadratic polynomial, exponential, and power functions can well fit the relationship between total porosity and compressive strength and the relationship between PSSA and compressive strength. The linear, exponential, and power functions can well reflect the relationship between total porosity and compressive modulus and the relationship between compressive modulus and PSSA. For concrete specimens with the same total porosity, the elastic modulus and strength show randomness with the increase in the sub-porosity of macropores and are basically not affected by the APR. Based on the grey relational analysis, the effects of pore structure parameters on the elastic modulus and compressive strength are in the same order: total porosity > T [k It is assumed that the smaller pores are mixed with the mortar to form a homogeneous mortar. To study the effect of sub-porosity, the Lar-type specimens with relatively high macropore content, the Sma-type specimens with relatively high content of small pores, and the Mid-type specimen with relatively medium content of large and small pores were established for each total porosity, as shown in Scholars have adopted various methods to test the pore structure of concrete. Qin et al.  used CT A new aggregate and pore generation algorithm is proposed, which introduces pore gradation, total porosity, pore size, and sub-porosity of each pore-gradated segments to characterize the pore structure. The flow chart is shown in (1)1 between sample boundary and pore boundary.The minimum distance δ(2)2.Minimum thickness of cement mortar layer δ(3)Aagg has n rows and m columns; where n is the number of aggregates, m is equal to the number of random numbers of aggregate information. For two-dimensional circular aggregates, the random numbers for determining aggregate information include the x coordinate of the aggregate center, the y coordinate of the aggregate center, and the radius of the aggregate, so m = 3.The array (4)porK has (n + k) rows and m columns, where k is equal to the number of pores. The first n rows of the array porK are equal to the array Aagg.The array Structural parameters include:The Boolean operations—“overlapping” and “subtraction”—are applied to generate mortar. Keeping the aggregate structure parameters unchanged and changing the pore structure parameters, concrete specimens with different pore structures and the same aggregate structure can be generated.1 = δ2 = 0.5 mm, 25 CRAMs with different pore structures are constructed based on the CVM. The size of all specimens established is 50 mm × 50 mm, and Aggregates are typically modeled as circles, ovals, or polygons. The mechanical properties of concrete are affected by aggregate shape, but not significantly . Zhu LiaITZ, which has an important influence on the development of micro-cracks in concrete ,61, has nt and tt are the normal traction and tangential traction on adjacent virtual surfaces, respectively. The bilinear traction–separation law is adopted for zero-thickness CIEs:D is defined to describe the damage evolution process, which monotonically varies from 0 to 1: The CIEs can be damaged and destroyed by excessive tension, shearing, or a combination. The quadratic nominal stress law is used to judge damage initiation in this paper. As the damaged state of the CIEs progresses, the material begins to soften. The scalar damage variable The traction for the damage state is a function of the traction without damage and the damage variable:The pre-processing functionality in ANSYS is used to mesh the aggregate and cement mortar and the triangular elements are applied to make the cracking path more real. For the ordinary concrete as the research object of this paper, the aggregates are generally not destroyed when the concrete is damaged. Therefore, the four-node zero-thickness cohesive interface elements (CIEs) are only inserted in the cement mortar  and the ITZ  by the CIEs insertion scheme, as shown in To verify the effectiveness of the CRAMs established in this paper in characterizing the mechanical behaviors of concrete, based on the real specimens prepared by Sucor-zewski , a 50 mmAs shown in Quasi-state uniaxial compression experiments are performed on 25 mesoscopic specimens with different pore structures, as shown in Concrete cracking is a process in which microscopic cracks are initiated, expanded, connected, and finally form macroscopic cracks . Based omax < 0.3~0.5);The initiation stage of micro-cracks ;The stable development stage of micro-cracks ;The unstable crack propagation stage (σ/σmax ≈ 0.999 (ε < peak strain εc) are shown in max ≈ 0.999 (ε < εc) are shown in max ≈ 0.999 (ε < εc) are shown in The CIEs with D = 0.9 when σ/σAfter reaching the ultimate stress, macroscopic cracks form first in the most severely damaged area of the ITZ, and quickly penetrate with the surrounding cracks in the ITZ and cement mortar, as shown in Taking specimen L-2-1 as an example, the failure process analysis of the concrete specimen with pores is illustrated.max < 0.3~0.5);The initiation stage of micro-cracks (σ/σmax ≈ 0.36 are shown in The CIEs with D = 0.27 and D = 0.86 when σ/σ2.max < 0.75~0.9)The stable development stage of micro-cracks .max ≈ 0.989(ε < εc) are shown in max ≈ 0.989(ε < εc) are shown in Damage in ITZ and mortar develops rapidly under high stress. The CIEs for D = 0.83 when σ/σIn recent years, more and more attention has been paid to the experimental research of concrete meso-structure. Using CT technology to observe and study internal cracks in concrete has gradually become a research hotspot. Dang Fanning et al.  used CT The stress–strain curves of the 25 specimens established in this paper are shown in The compressive strength, elastic modulus, and peak strain of the 25 specimens are shown in In existing studies, the relationship between the pore structure and mechanical behaviors of concrete is usually described by polynomial relationships ,57, expoAs can be seen from The experimental study  and numeAs can be seen from The moduli of the three types of specimens are shown in The relationship between peak strain and total porosity are shown in −3, which is close to the maximum value of the peak strain of all specimens. This is why the peak strain of the Lar-type specimen with total porosity = 1% is comparable to that of the Sma-type specimen. The peak strain of the specimen L-2-1 is 0.901 × 10−3, which is the minimum value of the peak strain of all specimens. This is why the Lar-type specimen with total porosity = 2% drops sharply. By studying the visual cracking process of the specimen L-1-1 and the specimen L-2-1, it is found that the peak strain is closely related to the morphology of the first macroscopic crack of the specimen. After the specimen reaches peak strain, the first macroscopic crack germinates in the most damaged areas in the cement mortar. Therefore, the morphology of the first macroscopic crack can reflect the damage of the specimen when it is under peak stress to a certain extent. If the first macroscopic crack passes through the middle of the specimen and has a long length, the specimen often exhibits strong ductility and has a large peak strain, such as the L-1-1 specimen. We call this morphology of the first macroscopic crack Mode 1. −3. Specimen S-3-2 belongs to Mode 2 with a small peak strain of 0.958 × 10−3, which is 0.181 × 10−3 less than that of the S-3-1 specimen. The peak strain and the morphology of the first macroscopic crack are affected by many factors, such as porosity, pore spatial distribution, and aggregate structure. As can been seen from the large difference between the peak strains of specimen L-3-1 and specimen L-3-2, the influence of pore spatial distribution on the peak strain cannot be ignored.The relationship between peak strain and PSSA are shown in When the number of the sub-sample is too small to fully present the maternal information, the method of mathematical–statistical analysis lacks accuracy, and it is prone to inconsistency between the quantitative results and the qualitative analysis. In this case, the grey system analysis method should be used. GRA is a method to compare the degree of correlation among factors according to the degree of similarity or degree of dissimilarity in the development trend of factors, which is proposed by Deng Julong . It is u1,k2] > T  > T  > T  > APR > PSSA. For pores with a diameter of 0.3~1.6 mm, the larger the pore size, the smaller the effect of its content on the compressive strength. Compressive strength is most affected by total porosity. The pore structure parameters studied in this paper have the same sequential effect on the elastic modulus and compressive strength of concrete. The descending order of influence of pore structure parameters on peak strain is: T  > T  > T  > T  > APR > PSSA > total porosity. Among the pore structure parameters studied, total porosity is the least important factor affecting peak strain, but the most important factor affecting compressive strength and modulus. Peak strain is most affected by sub-porosity of pores with radii in the range of 0.25~0.4 mm. Among the pore structure parameters considered in this paper, PSSA has the least influence on the compressive strength and modulus. However, from the analysis in It can be found from A novel CRAMM is proposed to model the pore structure by parameters such as pore gradation, total porosity, pore size, and sub-porosity of each pore gradation. To study the effect of pore structure on the mechanical behavior of concrete, 25 mesoscopic concrete specimens with different pore structures but the same aggregate structure are established and subjected to uniaxial compression tests. The effects of total porosity, sub-porosity of each pore gradation, PSSA, and APR on the concrete cracking process, modulus, peak strain, and compressive strength are investigated. (1)Under uniaxial compressive loading, the cracking process of specimens with pores and specimens without pores is very similar. The damage first germinates at the periphery of the sample and then expands toward the center. The damage of the ITZ spreads to the center of the specimen in the relatively stable stage of the micro-cracks, which is faster than that of cement mortar. The damage of cement mortar spreads toward the center of the sample in the stable development stage of the micro-cracks.(2)The presence of the pore structure does not accelerate this expansion process, nor does it change the phenomenon that the most damaged area in the concrete before peak stress is the ITZ. However, the pore structure makes the germination and propagation of the damage in cement mortar show obvious locality. The initiation and propagation of macroscopic cracks are greatly affected by the pore structure.(3)The sudden drops in the descending section of the stress–strain curve are often accompanied by the generation and expansion of macroscopic cracks.(4)The quadratic polynomial, exponential, and power functions can well fit the relationship between total porosity and compressive strength and the relationship between PSSA and compressive strength.(5)The linear, exponential, and power functions can well characterize the relationship between compressive modulus and total porosity and the relationship between PSSA and compressive modulus.(6)For the concrete specimens with the same aggregate structure and total porosity, the modulus and compressive strength show randomness with the increase in the sub-porosity of macropores, and the APR has little effect on compressive strength and modulus.(7)The influence of pore space distribution and sub-porosity on peak strain is greater than that of total porosity on peak strain. The effects of PSSA and APR on peak strain do not show obvious regularity.(8)According to the GRA, the pore structure parameters considered in this paper have the same order of influence on the modulus and compressive strength of concrete, which is different from the order of influence on the peak strain. Total porosity has the least effect on peak strain but the largest effect on compressive strength and modulus. For pores with a diameter of 0.3~1.6 mm, the larger the pore size, the smaller the effect of its content on the modulus and compressive strength. The peak strain is most affected by the sub-porosity of pores with radii in the range of 0.25~0.4 mm.


Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway.This study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC.I2>50%). Safety analysis was performed based on adverse events reported in all studies.We searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (Eleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% , while the pooled DCR was 69.1% . ORRs were higher for tepotinib  and savolitinib  than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs ) and DCRs ) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1%  and 95.4% , respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema , alanine aminotransferase (ALT) elevation , and lipase elevation .MET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation. Lung cancer is the leading cause of cancer-related death worldwide, resulting in an estimated 1.6 million deaths each year . Non-smavia various mechanisms, including protein overexpression, gene mutation, amplification, and rearrangement  to crizotinib in patients with NSCLC harboring MET alterations . DurableThis study was registered at PROSPERO under registration number CRD42022341285 and aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines during all stages of design, implementation, and reporting  conducted a systematic literature search of PubMed, Embase and the Cochrane library using the key words “c-Met inhibitor” and “non-small-cell lung cancer”. The last date of the search was June 02, 2022. The detailed search strategy is presented in Studies with relevant information on patient characteristics, treatment interventions, and outcomes were included. Eligibility was limited to articles reporting the result of clinical trials and published in English. The inclusion criteria were as follows: 1) histologically confirmed diagnosis of locally advanced or metastatic NSCLC with dysregulation of the MET pathway; 2) single-agent treatment with a MET inhibitor; 3) assessments of objective response rate  and/or disease control rate  based on the guidelines provided by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 ; and 4) via discussion. Two reviewers independently screened titles and abstracts from the data sources based on the eligibility criteria mentioned above. The full texts of the potentially relevant articles were then reviewed thoroughly to guarantee eligibility criteria. We recorded the following information from the original literature: (1) first author; (2) year of publication; (3) study design; (4) baseline patient data, including the number of patients who met the inclusion criteria, type of MET dysregulation, sex, and age; (5) type, dose, and schedule of MET inhibitor treatment; (6) Eastern Cooperative Oncology Group performance status (ECOG PS); (7) response/outcome; and (8) AEs.Two reviewers independently performed the search, study selection, and data extraction steps. In case of discrepancies, consensus was reached We used the Methodological Index for Non-randomized Studies (MINORS)  to assesQ statistic) and I  statistics were used to assess heterogeneity .Baseline patient characteristics, treatment responses, and AEs were analyzed for all enrolled studies. The ORR and DCR of NSCLC with MET-dysregulation were expressed as mean rates with 95% confidence intervals (95% CI). A subgroup analysis was performed based on different types of MET inhibitors, different types of MET dysregulation, and therapy types (monotherapy or combination therapy). The chi-square test  and I  statistogeneity . If P ≥ nd/or I  ≤ 50%, r’s test . Statistvia the database search. Among the selected studies, 1,355 duplicated articles were excluded using Endnote software. After exclusion based on titles and abstracts, 96 full-text articles were reviewed. After a full-text screening, 11 publications (882 patients) were included in this systematic review. The classifications and features of the included studies are presented in A flow chart of the screening process is shown in All non-randomized studies assessed using the MINORS index had scores ranging from 13 to 15 points, which were considered acceptable for the present meta-analysis Table 2.I  = 71%, P < 0.01). The pooled rate was 28.1%   after MET inhibitor treatment. The ORR ranged from 10.0% to 44.7%, and the random-effects model was selected given the heterogeneity among the studies .The forest plots for subgroup analyses of studies involving different types of MET dysregulation, including exon 14 skipping, MET protein overexpression, and amplification, are shown in I  = 63%, P < 0.01).All studies were included in the analysis of DCR , 70.8% , and 77.8% , respectively, with high heterogeneity among studies.The forest plots for subgroup analyses of studies involving different types of MET dysregulation, including exon 14 skipping, MET protein overexpression, and amplification, are shown in 2 =I28%) and 95.4%  without heterogeneity, respectively.All patients treated with MET inhibitors were evaluated for AEs, some of which were not included in the pooled analysis of response outcomes because the treatment response data were unavailable. There were 10 , 53–55 sSensitivity analysis was performed by removing individual studies one by one from the pooled results with high heterogeneity. The pooled analysis of ORR and DCR did not change significantly when studies were omitted, indicating that our combined results are reliable Figure 6P =0.13) (P =0.29) , indicating that MET inhibitors are tolerated by most patients. The most common adverse events above grade 3 included lower extremity edema (3.5%), ALT elevation (2.4%), and lipase elevation (2.2%).in situ hybridization (FISH) results for MET amplification are continuous variables, meaning that the selection of cut-off points is crucial. Only patients with a very high level of MET protein overexpression or amplification may benefit from these treatments, and patients with an MET status below a given threshold may exhibited diminished responses at the individual level  and the definitions/methods used to detect MET alterations in different trials. It remains highly debated whether patients with MET overexpression or amplification can benefit from MET inhibitors; however, MET exon 14 skipping is now an established biomarker, and patients with such alterations have been shown to benefit from MET-targeted therapies . MET inhal level . The resal level , which mth NSCLC . Previouth NSCLC , 49. Unlth NSCLC . The useth NSCLC , 62. OurCurrent MET-signaling-targeted therapeutic strategies include inhibiting kinase activity, preventing phosphotransferase activity, and blocking MET signaling , 63, 64.Brain metastases may occur in up to 20 to 40% of patients with stage IV NSCLC . In the The current findings indicate that MET inhibitors are well-tolerated and safe in patients with NSCLC. AEs mainly included lower-extremity edema, nausea, fatigue, diarrhea, vomiting, anorexia, ALT elevation, and creatinine elevation, most of which were mild and persisted for a short time only. Peripheral edema and nausea are the most frequent AEs in TKI trials, while anemia and fatigue are the most frequent events in trials of mAb and ADC. In our analysis, only seven deaths were reported to be associated with MET-inhibitor treatment. Although antibodies have excellent target specificity and predictable pharmacological properties, their toxicity is similar to that of molecular inhibitors.I  = 71%, P < 0.01) among ORRs and DCRs . Subgroup analyses of each drug indicated that ORRs were higher for savolitinib  and tepotinib  than for other MET inhibitors, while subgroup analyses based on MET dysregulation type indicated that both ORRs and DCRs were higher for patients with exon 14 skipping  than for those with MET protein overexpression or amplification. These findings support additional evidence regarding the heterogeneity of NSCLC.There was high heterogeneity ; Tibet Science and Technology Program (XZ202201ZY0002G); 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYJC18021) and Post-Doctor Research Project, West China Hospital (2021HXBH074).The authors thank Lichun Zhong  for advising on the data collection.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IgG4-related disease (IgG4-RD) is a recently discovered immune-mediated fibroinflammatory condition, uncommon in the pediatric population, that could involve multiple organs and induce cancer-like lesions and organ damage. Its main features are multiple injuries in different sites, a dense lymphoplasmacytic infiltrate rich in IgG4 plasma cells, storiform fibrosis, and often high serological concentrations of IgG4. Autoimmune pancreatitis is the most common manifestation, mainly in adults. Two cases of IgG4-RD in children with lymph node localization of disease are reported. Localized or systemic lymph node involvement is common, but lymph node enlargement as the first and only manifestation of IgG4-RD is unusual, and therefore, hard to differentiate from other diseases. IgG4-related lymphadenopathy (IgG4-LAD) is most likely a distinct disease, described as isolated lymphadenopathy, related to the presence of elevated numbers of IgG4-positive plasma cells. Both disorders are likely to be misdiagnosed in children because they are characterized by rare and polymorphic features. IgG4-RD and IgG4-LAD should be considered in the differential diagnosis of disorders characterized by lymphadenopathy of uncertain etiology. IgG4-related disease (IgG4-RD) is a newly recognized disorder of unknown etiology and pathogenesis. It is an immune-mediated fibroinflammatory condition that may involve multiple organs and induce cancer-like lesions and organ damage . Its maiThe histopathology includes lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis, and drastic IgG4+ plasma cell infiltrates; recently, a tru-cut biopsy has been informative enough to reach a diagnosis (6).Karim et al. described IgG4-RD features in children in a systematic review that showed 25 cases of pediatric disease involvement. Most of the pediatric patients with IgG4-RD developed orbital disease (44%) and pancreatitis (12%), with other manifestations, such as cholangitis, lymphadenopathy and lung disease, being less common .IgG4-related lymphadenopathy (IgG4-LAD) is a distinct disease, described as isolated lymphadenopathy enriched with IgG4-positive plasma cells. Most cases of IgG4-LADs are related to immune disorders . Non-specific lymphadenopathy with IgG4-positive plasma cells  should be considered in differential diagnosis .Two cases of children with lymphadenopathy associated with high levels of IgG4 plasma cells in the histological exam are reported. Both patients were admitted to the Pediatric Hemato-Oncologic Unit of the University of Catania.The first case is about a 14-year-old Caucasian male with related parents. He complained about a 5-month left submandibular lymphadenopathy. Lymph node ultrasound results showed oval morphology, hypoechoic structure, thickened capsule, and evident central stria with a 3 cm diameter. Laboratory results showed a normal blood cell count, C-reactive protein (CRP) test, and erythrosedimentation rate (ESR); the anti-cytomegalovirus, Epstein-Barr virus, Rubeola virus, Herpes simplex virus 1 and 2, toxoplasmosis, and Bartonella IgM were absent. Head and neck computed tomography (CT) scans detected multiple enlarged lymph nodes with hypervascularity and normal central hyperechoic stria. Two courses with amoxicillin-clavulanic acid and ampicillin sulbactam, respectively, were given, with no benefit. Furthermore, a tuberculosis and thyroid function test were administered and the results were negative. Immunoglobulins had normal values compared with age, but a high level of IgG4 was present: 1.85 g/L . Therefore, the patient underwent a total body CT scan, which showed bilateral lymphadenopathy in the neck with a maximum diameter of 3 cm, whereas no pathological evidence was detected in the chest or abdomen. Excisional biopsy of the neck lymph nodes revealed preserved lymph node architecture with reactive follicular hyperplasia, and immunohistochemical studies showed normal distribution of B cells (CD20-positive) and T cells (CD3-positive). No immunoreactivity for BCL-2 in germinal centers of lymphatic follicles was observed. Instead, there was marked intrafollicular but also interfollicular plasmacytosis, with an elevated number of polyclonal plasma cells. This was detected and confirmed by immunohistochemistry for kappa and lambda light chains, especially for IgG4 heavy chains  . CastlemThe second case concerns a 16-year-old boy with negative family history and a psychomotor delay. He presented in the emergency room because of two episodes of loss of consciousness and muscle tone with spontaneous resolution. His brain CT was negative. Laboratory results showed high acute-phase reactants  and anemia (Hb 8.9 g/dL). The abdominal ultrasound highlighted hepato-splenomegaly and detected some hypervascularized lymph nodes that were increased in volume (maximum diameter 5 cm) in the mesentery and mesogastric regions. Upon admission to our unit, the patient was in good general condition and reported no weight loss, sweating, or other noteworthy symptoms. Normocytic anemia was confirmed whereas hepatic and renal function blood tests, viral tests, celiac disease screening, fecal occult blood, and fecal calprotectin tests were negative, and ALPS was excluded. Electroencephalogram (EEG) showed a pathological pattern, with generalized tip/wave discharges; although the brain MRI was unremarkable, anti-epileptic therapy with Levetiracetam was administered. A neck-chest-abdomen CT scan confirmed multiple lymphadenopathies in the abdomen. A tru-cut biopsy revealed nonspecific hyperplastic lymphadenitis; subsequently, the patient underwent excisional biopsy of the biggest lymph node A,F. HistIgG4-RD is rarely detected in the pediatric population, with average age at diagnosis being over 50 years ,10,11. PDifferential diagnosis includes several disorders due to the wide histological spectrum of IgG4-related lymphadenopathy ,19,20.The main differential diagnosis is with Castleman disease , which iRosai-Dorfman disease should also be considered in the differential diagnosis between IgG4-RD with lymph node involvement and IgG4-LAD. It is an uncommon histiocytic disorder. As IgG4-RD, cervical lymphadenopathy is the main presentation, and extranodal involvement in the head and neck, intracranium, bone, heart, skin, parotid gland, periodontium, orbit, thyroid, breast, and paranasal sinuses has also been detected ,27. It iSjogren’s syndrome should also be considered in the differential diagnosis. It is a generalized autoimmune disorder, and its main feature is a lymphocytic infiltrate of the exocrine glands, causing dysfunction and organ damage. The salivary and lacrimal glands are mostly involved, leading to dry eyes and mouth, but general organ impairment is possible, manifesting in anemia, arthralgia, sensory neuropathies, respiratory disfunction, and interstitial nephritis . In the Finally, IgG4 disease should be differentiated from sarcoidosis, a multisystemic granulomatous disease. This disorder is characterized by intrathoracic involvement with symmetrical bilateral hilar adenopathy and diffuse lung micronodules; however, extrapulmonary manifestations such as skin lesions, uveitis, liver or splenic failure, and peripheral arthritis have also been reported . FurtherAll of these diseases present multi-organ and aspecific symptoms, often similar to one another; therefore, a distinct diagnosis requires a histological examination.Different types of treatment for IgG4-RD have been proposed. Patients with subclinical lymphadenopathy or mild submandibular gland enlargement can be managed with a “wait and see” approach , as in tThe presentation of IgG4-LAD could also be related to extra-nodal lesions resulting in IgG4-RD or as an isolated lesion with a clinically and biologically distinct benign and non-progressive behavior. Up to now, the association between IgG4-RD and IgG4-LAD is still not clearly described ,8,36. A 7-year retrospective analysis 2012–2018), conducted by the Italian Paediatric Haematology and Oncology Association (AIEOP), searched over 832 nodal examinations and described nine cases of LAD [, conductThe “wait and see” strategy is the most commonly used for stable cases of IgG4-LAD; however, some patients received steroid treatment resulting in early complete clinical remission .In conclusion, part of IgG4-LAD may constitute a precocious phase of IgG-RD, or IgG4-LAD may be a different entity altogether. We suggest that new IgG4-LAD patients should undergo close clinical monitoring.Furthermore, we would like to underline the relevance of including IgG4-LAD and IgG4-RD in the differential diagnosis of lymphadenopathy of uncertain etiology. Although this disease is uncommon in the pediatric population, knowledge and awareness of it could be pivotal in avoiding misdiagnosis and delaying possible care, particularly in childhood.


The development of tailings in concrete technology is not only conducive to the realization of the goal of reducing carbon emissions, but also conducive to the inhibition the occurrence of shortages of sand and gravel supplies. In this study, graphite tailings were used to replace sand in the range of 0~100%, and the mechanical mechanism of graphite tailings concrete was examined through compressive and flexural tests. The mechanical experimental results were evaluated and verified based on concrete macroscopic failure appearance, mesoscopic failure appearance, and physical characteristics of graphite tailings. The results revealed that the concrete strength increases first and then decreases with the increase of the graphite tailings content. Compared to GT00 , GT10~GT60 exhibited better mechanical properties, of which 30% was recommended as the optimal replacement rate. The mechanical properties of GT10 and GT20 had an upward trend, and GT30 had low spalling, with aggregate fragmentation found on the fracture surface. GT30 showed the best resistance to bending and deformation. The mechanical properties of GT40~GT60 had a downward trend. When the graphite tailings content was higher than 70%, the interface defects of the aggregate matrix increased, thus making it easier for cracks to propagate along the interface. Furthermore, the mechanism of graphite tailings replacing sand verified the test results from different perspectives, which provides new analysis ideas for other tailings in environment-friendly concrete. It fe cycle ,11. Morefe cycle ,12,13,142 during the treatment process [Tailings are the general term for the remaining waste after the ore is crushed and sorted, and they are one of the essential types of industrial solid waste. On one hand, the accumulation of tailings will cause environmental pollution through sand blowing or seepage . On the  process , so the  process ,18. Sinc process , the pro process , as well process . Since t process , and mol process . The com process , and whe process . Copper  process , and rep process  prepared process  used kimThe application of tailings as fine aggregates in concrete has been proven. As a kind of tailing, graphite tailings (GT) have irreversible effects on the environment, and the research on GT is in the initial stage. Currently, there are many gaps in the research on GT, and some issues are worth noting, including not knowing the optimal replacement rate of GT, whether they can completely replace sand as fine aggregates, and the application mechanism of GT in concrete. In this paper, the influence mechanism of GT in concrete is analyzed based on the basic physical properties of GT. First, GT and sand were compared to analyze the feasibility of replacing sand with GT. Subsequently, the compressive and flexural tests were performed, and the damage characteristics of GT environment-friendly concrete were analyzed in accordance with the experimental result. Lastly, GT ecological concrete was studied from four aspects, including mechanical properties, macroscopic cracks, mesoscopic appearance, and the study on the mechanism of GT substituting sand .3 and a specific surface area of 380 cm2/g. The chemical composition of the cementitious material is determined according to the Chinese standard (GB/T 176-2017) [Portland cement (P.O. 42.5 N) was the cement used in this study, with a density of 3.0 g/cm76-2017) , the che2 (92.8%). The silica fume was provided by Xinming New Building Materials Co., Ltd., Heilongjiang, China. Sand was used as fine aggregates, and the maximum particle size of the sand applied was 2.5 mm. The GT sample was obtained from a graphite mine in Jixi City, China, and the maximum particle size of GT was 1.25 mm. A polycarboxylate-based superplasticizer was provided by Tianjin Weihe Technology Development Co., Ltd., and the water reducing rate of the admixture was 30%. The basic physical properties of tailings are the prerequisites for the mechanical properties of environment-friendly concrete to meet requirements . The phy2, CaO, and Al2O3, and sand also contained a small amount of Fe2O3, MgO, K2O, and other substances . The contents of CaO, Fe2O3, and Al2O3 were 13.34%, 7.39%, and 11.52%, respectively. The material contents of sand and GT were similar, and the main chemical component was SiO2, thus laying a basis for GT to replace sand in terms of material composition.The chemical composition of the aggregate is determined according to the Chinese standard (JC/T 1084-2019) . The maibstances . The conbstances , of whicThe particle size distribution is determined according to the Chinese standard (JGJ 52-2006) . As showAggregates of different roughness will have different effects on the microstructure of concrete ,34. TablSome researchers have investigated GT to improve rubber strength, prepare ceramic tiles, and use as a cementitious material ,35,36. TVolume replacement was used as the replacement method for GT replacing sand, and there were 11 groups from 0% to 100%. The preparation process of GT environment-friendly concrete is as follows, and (a)Pour GT and sand into the mixing pot and stir at a low speed for 3 min .(b)Pour the cement and silica fume into the mixing pot and stir at a low speed for 3 min .(c)Pour the pre-mixed water–admixture mixture into the stirring pot and stir at a low speed for 2 min, then stir at a high speed for 3 min (hydration and pozzolanic reactions are carried out in the stirring pot).(d)Pour the concrete slurry into molds of 70.7 mm × 70.7 mm × 70.7 mm and 40 mm × 40 mm × 160 mm, and then put the molds on the vibrating table to vibrate for 7 min (the escape of air bubbles from the concrete increases the density of the concrete).(e)Place the vibrated concrete slurry in the environment of ambient temperature 20 ± 1 °C and relative humidity of 60% for 24 h (create a good curing environment for the concrete).(f)Demold the formed concrete and perform standard curing in a curing room at 20 ± 2 °C and a relative humidity of ≥95%, the specimens are cured for 3, 7, and 28 days (concrete hardening molding).F represents the load when the specimen is broken (N); A expresses the area of the specimen under pressure (mm2).A compressive strength test was performed in accordance with the Chinese standard . The tesF expresses the load when the specimen is broken (N); l represents the span between supports (mm); b is the side length of the square section (mm).A flexural test was performed in accordance with the Chinese standard . The tesNo obvious phenomenon was found when specimens were compressed at the beginning, whereas GT00~GT100 showed different degrees of peeling, which is to be analyzed in depth in (I)Compression stage of cracks and pores. The concrete was strengthened, and its corresponding microstructure changed. Some pores and cracks perpendicular to the force direction were compacted, and the concrete matrix was elastically compressed and more compact a.(II)Crack initiation stage. The tip of the contact between the aggregate and cement stone, the micro-cracks within the concrete, and the places with pores within the concrete were prone to stress concentration under the application of load. Moreover, a part of the original cracks within the concrete began to extend or propagate, although they were all short and small in width. As the above microscopic cracks were extended or propagated, the stress concentration was relieved, and the equilibrium was restored immediately. The stress–strain was basically close to the linear elastic relationship at this stage b.(III)Crack propagation stage. First, the existing cracks were further extended or propagated. Some cracks penetrated the mortar, some short cracks were connected to each other to form long cracks, and new cracks were generated at the same time. Subsequently, the number of continuous penetrations of the cracks increased sharply, and the crack development was accelerated. Lastly, the concrete was penetrated by cracks, and damage occurred c.The flexural phenomena of the specimens with different GT contents were nearly the same, whereas the fracture surface after concrete failure exhibited a different meso-structure, which is to be analyzed in depth in (I)Reinforcement stage. The load–displacement curve was concave at this stage, the pores and some micro-cracks within the concrete were compacted, and the stiffness of the specimen in the flexural section increased a.(II)Destruction stage. The load–displacement curve of the specimen showed linear elastic development at this stage, the force applied to the concrete led to new cracks, and the rapid propagation of the cracks caused brittle failure of the specimen b.I.Strength analysisAs depicted in The compressive strength of GT30 was 12.68% higher than that of GT00. The strength of the specimen had the minimum value when GT replacement rate was 100% (the strength was reduced by 5.37%). The extreme values of the intensity of the 3-day, 7-day, and 28-day specimens were 17.5, 17.0, and 16.3, respectively, thus suggesting that the range of the specimen decreases with the curing age. As depicted in II.Stress strain analysisStress and strain indicate the internal stress process of concrete, and the mutual coordination relationship of each component under load is also reflected ,49. As dThe elastic modulus of GT00~GT100 was obtained in accordance with the stress–strain curve . There wI.Flexural strength and load–displacement curve analysisb denotes the width of the cross-interrupt interview piece (mm); h represents the height of the cross-interrupt interview piece (mm); L expresses the span of test piece (mm); BP is the maximal load when the specimen fails; d represents the mid-span deflection when the specimen fails; BR is the bending and tensile strength when the specimen is broken (MPa); Bɛ denotes the maximal bending and tensile strain when the specimen fails (με); BS expresses the flexural modulus when the specimen is broken (MPa).The flexural modulus is capable of evaluating the ability of concrete to resist flexural deformation. According to Equations (3)–(5), the maximum flexural tensile strain  and flexII.Stress strain and energy analysisThe crack propagation direction is perpendicular to the stress direction during the period of concrete stress, and the effective bearing area of the section tends to decrease. To consume less energy, the cracks will bypass the aggregate and propagate in the interfacial transition zone and the initial micro-cracks in the matrix. As depicted in Compared to GT00, GT30 exhibits the best mechanical properties, and 60% GT can ensure that the mechanical strength of concrete meets the requirements and the ecological properties reach the maximum. However, in practical engineering applications, the ecology of concrete may be changed by dimensional effects.The propagation of concrete cracks was limited at the initial stress, and the concrete material absorbed a lot of external energy. Compared to GT00, the change range of fracture energy of GT10~GT100 was −5.09% (GT100)~7.13% (GT30). An appropriate amount of GT can inhibit the formation of initial micro-cracks in concrete, reduce the path of crack propagation in concrete, and prevent the dissipation of concrete energy. There were more defects in the matrix when GT replaced most of the sand, which was confirmed by mesoscopic analysis . The defConcrete refers to a multi-phase composite material composed of aggregate and hardened cement paste, and as such, defects such as pores, capillary pores, and material cracks inevitably exist in the process of mixing and vibration molding. Loading causes concrete stress to develop, limiting its volume change, and the concrete specimen will crack once the tensile stress exceeds the tensile strength of the concrete . ConcretAs depicted in Between the microscopic size of the nanometer level and the macroscopic size of the centimeter level, there are the microscopic sizes of the micrometer and the millimeter levels. Concrete has been considered a three-phase material consisting of aggregate at the mesoscopic level, cement stone, and the interfacial transition zone between them. Moreover, the mechanical properties of concrete can be recognized as a meso-homogeneous damage body. Concrete with different amounts of GT have different bleeding conditions, cement stone hardness, and interfacial bond strength, thus affecting the macroscopic mechanical properties of concrete .The specimens were dried before the flexural test. The mass and volume of the specimens were obtained by weighing and drainage methods, and the density of specimens was finally obtained . The dosAggregate crushing was identified in GT20~GT40. 120MPa compressive strength is the minimum standard for ultra-high-performance concrete according to the Chinese standard (T/CBMF37-2018) , whereas3S), dicalcium silicate (C2S), tricalcium aluminate (C3A), and tetracalcium ferric aluminate (C4AF), and the internal structure of concrete changed with the GT content. The mechanism of GT replacing sand was analyzed based on the above results from the four aspects, including the wettability of aggregates, the behavior of aggregates and bubbles during stirring and vibration, the reaction mechanism of cementitious materials, as well as the interface between aggregates and the cementitious matrix.The production process of concrete appears to be simple, whereas it exhibits a relatively complex internal structure. Concrete contains numerous non-uniform solid phase components, as well as some closed, semi-closed, or connected pores. Concrete in this study was composed of tricalcium silicate  expresses the correlation between bonding energy and surface energy.LGγ is basically the same in concrete with different GT contents, and Equation (8) suggests that the smaller the wetting angle θ, the stronger the adhesion between aggregate and slurry will be (Equation (8) can be obtained by Equations (6) and (7).  will be b. When aVibration is considered a necessary means and step for compacting concrete. The internal friction between aggregates temporarily disappeared during the vibration process, and the concrete mixture became fluid and tended to compact under the action of gravity a. Moreov2. Ca(OH)2 after cement hydration has an orientation parallel to aggregate surfaces [2 crystals exist in the aggregate–matrix interface, and the large Ca(OH)2 crystals parallel to aggregate surface are prone to cracking, resulting in the formation of weak regions of strength. A hydration reaction is the premise of the pozzolanic reaction, moreover, the pozzolanic reaction eliminates the negative effect of the hydration reaction and provides a guarantee for the strength of concrete [The main component of cement is CaO, and the main chemical component of silica fume is amorphous SiOsurfaces . Numerouconcrete ,62,63,643S and C2S formed thin films on the surface of cement particles, and Si and Al were enriched to form a thin film on the surface of silica fume (3S and C2S were hydrated to form C–S–H and Ca(OH)2. Ca–Si–Al film was formed on the surface of silica fume In general, GT and sand have similar chemical compositions, which lays a basis for GT to replace sand. Nevertheless, the differences in water absorption, crush value, and roughness make GT and sand have different mechanisms.(2)There is a threshold for the effect of GT content on the mechanical strength of concrete. Compared to GT00, the compressive strength and elastic modulus of GT30 increased by 12.68% and 96.42%, respectively, and the compressive strength and elastic modulus of GT100 decreased by 5.37% and 25.96%, respectively. The filling effect of GT on sand can inhibit the propagation of cracks and increase the energy required for concrete failure. A rate of 30% is recommended as the optimal GT replacement rate.(3)There are significant differences in concrete spalling degree (GT00~GT100). GT30 and GT40 have the lowest spalling degree (11.3% and 7.9%), and GT90 and GT100 have the largest spalling degree (51.1% and 54.3%). In the mesoscopic analysis, crushed aggregates are observed in the damaged specimens of GT20, GT30, and GT40, obvious defects were identified at the aggregate–matrix interface in GT80 and GT90, and numerous pores were observed in GT100. The above results suggest that the incorporation of an appropriate amount of GT can increase the bonding ability at the interface, and the skeleton effect of GT is significantly reduced when GT achieve the maximum value of 100%.(4)The characteristics of high water absorption, unreasonable particle size distribution, and large crushing value limit the feasibility of GT completely replacing sand. However, the wetting angle of GT is smaller, which is a good phenomenon for the bonding of GT to the matrix. There are still many places worth studying to increase the amount of GT.The results of this study can provide a reference for the mechanical mechanism of GT to prepare environment-friendly concrete. In the future, the amount of GT can serve as the basis for the ecological evaluation of concrete. Moreover, the experimental results of mechanical properties and durability can lay a basis for the feasibility evaluation of GT to replace sand. The correlation between GT content, mechanical properties, and durability can be developed, and the optimal solution can be applied to practical engineering.


Cross-modal human pose estimation has a wide range of applications. Traditional image-based pose estimation will not work well in poor light or darkness. Therefore, some sensors such as LiDAR or Radio Frequency (RF) signals are now using to estimate human pose. However, it limits the application that these methods require much high-priced professional equipment. To address these challenges, we propose a new WiFi-based pose estimation method. Based on the Channel State Information (CSI) of WiFi, a novel architecture CSI-former is proposed to innovatively realize the integration of the multi-head attention in the WiFi-based pose estimation network. To evaluate the performance of CSI-former, we establish a span-new dataset Wi-Pose. This dataset consists of 5 GHz WiFi CSI, the corresponding images, and skeleton point annotations. The experimental results on Wi-Pose demonstrate that CSI-former can significantly improve the performance in wireless pose estimation and achieve more remarkable performance over traditional image-based pose estimation. To better benefit future research on the WiFi-based pose estimation, Wi-Pose has been made publicly available. Pose estimation is a basic task of human behavior evaluation. It aims to analyze important joints of human bodies such as limbs and faces through a series of multimedia signals, and promote the recognition of human behaviors ,7,8,9,10In previous exploratory work, people have tried human pose estimation based on multiple signals. Adib et al.  try to uCompared with the above sensors, WiFi equipment has the advantages of lower costs and easy-to-layout. Therefore, using WiFi equipment for pose estimation is a good choice. Traditional WiF devices work under the wireless transmission standard protocol of the IEEE 802.11n . Under tMotivated by the work of Hao et al. , we atteConsequently, this paper addresses the above problems and attempts to design a novel network for paying more attention to the information-rich sub-carries. To achieve this, a novel multi-head attention-based network CSI-former is proposed for WiFi-based pose estimation. The proposed CSI-former is built in a teacher–student manner: a teacher network based on Alphapose and a student network based on Performer  and convTo demonstrate the performance of CSI-former, a reasonable and persuasive WiFi-based dataset is necessary. As the basis of establishing the dataset, it is significant for us to determine the WiFi frequency band. Most traditional CSI collection methods rely on a 2.4 GHz WiFi band. Nevertheless, the research of Yu et al.  demonstr1.We propose a novel architecture CSI-former that is composed of the attention mechanism and traditional convolutional neural network for WiFi-based pose estimation. To the best of our knowledge, CSI-former firstly realizes the effective integration of the multi-head attention to the field of cross-modal human pose estimation and significantly improves the performance.2.Differ from most previous methods, we establish the WiFi-based human body pose estimation dataset via a 5 GHz wireless WiFi signal and successfully demonstrate the effectiveness of 5 GHz WiFi in cross-modal pose estimation.3.We successfully established the novel WiFi-based pose estimation dataset Wi-Pose that is composed of 12 different actions such as bending, circling, crouching, pulling, running, walking, waving, etc. In addition, to ensure the rationality and persuasiveness of Wi-Pose, the invited 12 volunteers have different heights and weights.4.The proposed CSI-former has been evaluated on Wi-Pose and compared with the traditional network. The results demonstrate that CSI-former achieves state-of-the-art performance in WiFi-based pose estimation.The contributions of this paper are summarized as follows:https://github.com/NjtechCVLab/Wi-PoseDataset, accessed on 19 October 2022 to facilitate future research.In summary, we propose a WiFi-based pose estimation algorithm CSI-former in this paper to solve the performance defects and privacy problems of traditional image-based human pose estimation methods. Moreover, we present the attention mechanism-based network framework to improve the algorithm and achieve satisfactory performance. We also publish the new dataset Wi-Pose at The rest of the article is organized as follows. We introduce the related work for human pose estimation in Liu et al.  proposedJi et al.  uses a 3However, although these methods have achieved good results, they are still limited to pure image-based pose estimation. It indicates that these methods will not work well in poor light, so the application range is difficult to broaden.People are constantly exploring the cross-modal human body positioning. By the gyroscope sensor in the bracelet, we can monitor a person’s steps and heartbeat. Cui et al.  pointed Khan et al.  proposedWigest  performsWiHear  utilizesOverall, like most WiFi-based human body estimation networks, these methods can only perform rough human body positioning or crowd counting ,54,55,56CSI-former aims to realize WiFi-based pose estimation via a teacher–student network: a teacher network estimates human pose in videos by Alphapose, a student network learns human pose from CSI by Performer and convolutional neural network.Alphapose: Alphapose refers to a traditional two-step frame network for image-based human pose estimation. It achieves high-performance image-based pose estimation via the human detection framework YOlOv3  and the CSI: Channel State Information (CSI) refers to wireless state information obtained via Orthogonal Frequency Division Multiplexing (OFDM). OFDM converts the high-speed serial data stream into 30 low-speed parallel sub-data streams by decomposing the original channel into 30 mutually orthogonal sub-channels and modulates these sub-data streams to the orthogonal sub-channels for propagation. Each sub-data stream is called a sub-carrier. The amplitude and phase information of all sub-carriers constitute CSI. On this basis, the open-source tools  can obtaThe original CSI is captured by a three-antenna WiFi transmitter and a three-antenna receiver. The transmitter continuously broadcasts WiFi signals to the outside. When human bodies of different poses pass by, the receiver receives changed wireless signals and parses them into a tensor of m × 30 × 3 × 3 size. Where m represents the number of WiFi packets received, 30 represents the number of wireless sub-carriers, and 3 × 3 represents a 3 × 3 array composed of three transmitting antennas and three receiving antennas.Unfortunately, it is impossible to annotate real human poses with pure CSI. Thus, we use a camera parallel to the WiFi transmitting antenna to capture human pose images. Then, the captured images are processed by Alphapose of the teacher network to generate annotation information of human poses. Finally, under the supervision of the teacher work, the student network learns pose estimation from CSI.Inevitably, it tends to generate noise due to environmental influences during the collection of CSI. Under the impact of noise, the performance of the CSI-based pose estimation is bound to be restricted without effective denoising methods. For exploring denoising methods, it is significant to analyze the original CSI. As shown in Moreover, Wang et al.  also demInspired by the fact that the pose features cannot be concealed by noise and traditional filters have a poor performance in CSI denoising. It is reasonable to design a new network that can greatly dilute the influence of noise by paying more attention to the pose features. To this end, we propose an attention-guided denoising method (ADN) by CSI-former. Specifically, during the network training, the proposed CSI-former allocates more attention of the network to the sub-carriers that are more sensitive to poses through the parameter updating of the multi-head attention allocation algorithm. As In addition to ADN, we use multi-frame CSI to align a single-frame image to further dilute the possible impact of noise. In the system settings, the sampling rate of CSI is 100 Hz and the camera’s imaging frequency is 20 Hz. Through the synchronization of timestamps, every five CSI frames are aligned to one image frame. That is, for human body pose annotation information in each image frame, there is a corresponding CSI tensor with the size of 5 × 30 × 3 × 3.As the teacher network of CSI-former, Alphapose includes a two-step framework. First, a human body detector is used to form a human body detection box via the input images. After that, a pose estimation network will estimate the pose in the box. The pose skeleton points are finally output as annotation of the teacher network to the student network.The collected data includes pose images x and y generation rules are the same:With the original pose annotation n points . TherefoSAM enhances the generalization ability of the network via taking relative displacement between skeleton points as an additional constraint. However, it also greatly increases the number of parameters that the network needs to return, and most of the attention is still needs to be paid to the regression of SAM diagonal value. Therefore, the application of the attention mechanism can significantly enhance the performance of the entire network.Inspired by the SAM, the original pose annotation Apart from images, the parsed CSI CThe student network is composed of Performer and Convolutional Neural Network. The multi-head attention mechanism makes the student network improve the ability to extract pose features from CSI while learning annotations from the teacher network. Therefore, the student network includes three parts: encoder, feature extractor, and decoder.Then, the encoder directly uses bilinear interpolation to perform preliminary up-sampling on it, and expand it to The encoder can not only magnify the features of original data for easy extraction but also make it well adapted to the size of 18 skeleton points annotation from the teacher network.e ResNet . HoweverUnlike the traditional methods, CSI-former uses a multi-layer composite attention-based Performer as the feature extractor (PAFE). The PAFE can make the student network pay more attention to those information-rich CSI inputs to realize efficient feature extraction. In addition, considering that the network needs to pay more attention to diagonal elements while taking into account non-diagonal elements when learning SAM, the PAFE can help realize reasonable distribution of attention. After a series of parameter stripping comparison tests, a stack of 12-layers Performer was finally selected. After the encoding matrix Finally, the gradient backpropagation is used to continuously optimize the student network until CSI-former can independently estimate human poses. It should be noted that the trained CSI-former can estimate any individual pose without an entire pose sequence. That is, CSI-former is trained by every single pose rather than ranking different poses.i-th pose respectively. i-th skeleton point.Since CSI-former implements regression learning, the  network . The losTo establish a rational and persuasive data set under real scenarios, we invited 12 volunteers of different heights and weights to perform multi-action activities indoors while simultaneously using WiFi devices and cameras to capture their wireless status information and images. Each volunteer did 12 different actions  under guidance. Each action has a period of five seconds and repeats ten times. Since we cannot control the sampling time to exactly 5 s, the actual duration of each action is between 5 and 6 s. Moreover, our camera sampling rate is set to 20 Hz, thus the number of images per action is as follows:For data division in the experiment, 80% of the collected data were used for the training set and the remaining 20% for the testing set. The number of the training set and the testing set are 132,847 and 33,753, respectively.k-th body’s torso, k-th body’s right shoulder and left Hip coordinates respectively. The calculated Euclidean distance between these two points is approximated as torso diameter. The specific algorithm of PCK is as follows:j-th threshold of the algorithm, and the above formula i-th skeleton key point of the k-th human pose under the threshold, i-th joint point of the k-th person identified by the model and the ground truth of the joint point. After the normalization calculation and the discrimination of For evaluating the model, the percentage of correct key points (PCK) is one of the most persuasive evaluation algorithms for human pose key point detection models. It evaluates the CSI-former by calculating the ratio of the normalized distance between 18 detected key points and their corresponding ground truth that is less than the set threshold. The reference of normalized distance is developed via the torso diameter as follows:The threshold of PCK is usually set between 5 and 50. It should be noted that different thresholds are the evaluation standard of the model at different scales. Therefore, in this paper, we set the thresholds to various values between 5 and 50 to demonstrate the performance of our model from different evaluation scales. The larger the threshold is, the wider the error margin of skeleton point estimation is allowed. Thus, increasing the threshold may lead to higher PCK. However, lower thresholds represent more strict evaluation criteria, meaning lower thresholds can better demonstrate the model’s performance.CSI-former is implemented by Pytorch 1.7 and optimized by Adam optimizer. The batch size and epochs-number are eight and 50, respectively. The initial learning rate is set to 0.005 and is halved every ten epochs in the first 20 epochs and halved every 15 epochs in the last 30 epochs. We usually choose the model weights of the epoch which has the minimum loss. The epoch with minimum loss is generally between 45 to 50. The specific training details of the loss and the PCK are shown in In this section, we perform a series of ablation studies to analyze the impact of Performer layers on the performance of CSI-former. Under the strictly same training condition, four, eight, and twelve Performer layers were developed respectively to the feature extractor of CSI-former. The final result shown in CSI-former uses 12-layers superimposed Performer as the feature extractor of the network. In order to prove the effectiveness of the multi-head attention mechanism, we compared the effects of CSI-former with pose estimation network using 16-layers superimposed Resnet as the feature extractor. After training models under the same experimental condition, we evaluated the two models with the same testing set. As shown in Additionally, To observe the performance of CSI-former more directly, we estimate the poses of the testing set via CSI-former. Then, the estimated poses of CSI-former are drawn on the original images and compared with the pose estimation of the Alphapose-based teacher network, as shown in As shown in the above sections, we finalized CSI-former through a series of ablation studies. We compare CSI-former with existing Resnet-based networks in Nevertheless, due to the constraints of time cost and experimental environment, CSI-former is trained by 12 activities performed by 12 volunteers. It indicates that the pose estimation results may have deviations when CSI-former is applied to other complex activities. Thus, we will expand more poses in more environments to our dataset Wi-Pose in future research. Since there is no publicly available dataset for WiFi-based human pose estimation currently, we have published Wi-Pose to facilitate future research. Moreover, we will continue to study new algorithms to improve CSI-former and enable it to estimate multi-person poses.In this paper, we propose a WiFi-based pose estimation network CSI-former. Compared to traditional image-based pose estimation methods, CSI-former overcomes the disadvantages of cameras that cannot work in the dark and glare by using WiFi. Moreover, the WiFi-based method can solve the privacy concerns in human pose estimation well.We design the architecture of CSI-former by 12 layers of Performer with multi-head attention to make the network pay more attention to the information that includes more pose features. The experimental results in In addition, we successfully establish a novel WiFi-based human pose estimation dataset Wi-Pose and have published Wi-Pose to promote future research. CSI-former achieves state-of-the-art performance on Wi-Pose. Our future work will focus on further improving the structure of CSI-former to obtain better WiFi-based pose estimation capabilities.