Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of PrLGlu activity.

Methamphetamine (METH), an abused psychostimulant, impairs cognition through prolonged or even single-dose exposure, but animal experiments have shown contradictory effects on memory deficits. In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory (ORM) in mice. We showed that single-dose METH administration (2 mg/kg, i.p.) significantly impaired ORM retrieval in mice. Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons (PrLGlu) was significantly reduced during ORM retrieval. Chemogenetic activation of PrLGlu or glutamatergic projections from ventral CA1 to PrL (vCA1Glu-PrL) rescued ORM retrieval impairment. Fiber photometry recording revealed that dopamine (DA) levels in PrL of METH-treated mice were significantly increased, and micro-infusion of the D2 receptor (D2R) antagonist sulpiride (0.25 µg/side) into PrL rescued ORM retrieval impairment. Whole-cell recordings in brain slices containing the PrL revealed that PrLGlu intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice, and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice. Thus, the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrLGlu activity, possibly due to excessive DA activity on D2R. Selective activation of PrLGlu or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.

Domain Switching Characteristics in Ga-Doped HfO2 Ferroelectric Thin Films with Low Coercive Field.

The gallium-doped hafnium oxide (Ga-HfO2) films with different Ga doping concentrations were prepared by adjusting the HfO2/Ga2O3 atomic layer deposition cycle ratio for high-speed and low-voltage operation in HfO2-based ferroelectric memory. The Ga-HfO2 ferroelectric films reveal a finely modulated coercive field (Ec) from 1.1 (HfO2/Ga2O3 = 32:1) to an exceptionally low 0.6 MV/cm (HfO2/Ga2O3 = 11:1). This modulation arises from the competition between domain nucleation and propagation speed during polarization switching, influenced by the intrinsic domain density and phase dispersion in the film with specific Ga doping concentrations. Higher Ec samples exhibit a nucleation-dominant switching mechanism, while lower Ec samples undergo a transition from a nucleation-dominant to a propagation-dominant reversal mechanism as the electric field increases. This work introduces Ga as a viable dopant for low Ec and offers insights into material design strategies for HfO2-based ferroelectric memory applications.

In vivo imaging reveals a synchronized correlation among neurotransmitter dynamics during propofol and sevoflurane anesthesia.

General anesthesia is widely applied in clinical practice. However, the precise mechanism of loss of consciousness induced by general anesthetics remains unknown. Here, we measured the dynamics of five neurotransmitters, including γ-aminobutyric acid, glutamate, norepinephrine, acetylcholine, and dopamine, in the medial prefrontal cortex and primary visual cortex of C57BL/6 mice through in vivo fiber photometry and genetically encoded neurotransmitter sensors under anesthesia to reveal the mechanism of general anesthesia from a neurotransmitter perspective. Results revealed that the concentrations of γ-aminobutyric acid, glutamate, norepinephrine, and acetylcholine increased in the cortex during propofol-induced loss of consciousness. Dopamine levels did not change following the hypnotic dose of propofol but increased significantly following surgical doses of propofol anesthesia. Notably, the concentrations of the five neurotransmitters generally decreased during sevoflurane-induced loss of consciousness. Furthermore, the neurotransmitter dynamic networks were not synchronized in the non-anesthesia groups but were highly synchronized in the anesthetic groups. These findings suggest that neurotransmitter dynamic network synchronization may cause anesthetic-induced loss of consciousness.

Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist ß-amyloid peptides (Aß) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Conjunctive encoding of exploratory intentions and spatial information in the hippocampus.

The hippocampus creates a cognitive map of the external environment by encoding spatial and self-motion-related information. However, it is unclear whether hippocampal neurons could also incorporate internal cognitive states reflecting an animal's exploratory intention, which is not driven by rewards or unexpected sensory stimuli. In this study, a subgroup of CA1 neurons was found to encode both spatial information and animals' investigatory intentions in male mice. These neurons became active before the initiation of exploration behaviors at specific locations and were nearly silent when the same fields were traversed without exploration. Interestingly, this neuronal activity could not be explained by object features, rewards, or mismatches in environmental cues. Inhibition of the lateral entorhinal cortex decreased the activity of these cells during exploration. Our findings demonstrate that hippocampal neurons may bridge external and internal signals, indicating a potential connection between spatial representation and intentional states in the construction of internal navigation systems.

Propofol Alleviates Anxiety-Like Behaviors Associated with Pain by Inhibiting the Hyperactivity of PVNCRH Neurons via GABAA Receptor ß3 Subunits.

Pain, a comorbidity of anxiety disorders, causes substantial clinical, social, and economic burdens. Emerging evidence suggests that propofol, the most commonly used general anesthetic, may regulate psychological disorders; however, its role in pain-associated anxiety is not yet described. This study investigates the therapeutic potential of a single dose of propofol (100 mg kg-1) in alleviating pain-associated anxiety and examines the underlying neural mechanisms. In acute and chronic pain models, propofol decreased anxiety-like behaviors in the elevated plus maze (EPM) and open field (OF) tests. Propofol also reduced the serum levels of stress-related hormones including corticosterone, corticotropin-releasing hormone (CRH), and norepinephrine. Fiber photometry recordings indicated that the calcium signaling activity of CRH neurons in the paraventricular nucleus (PVNCRH) is reduced after propofol treatment. Interestingly, artificially activating PVNCRH neurons through chemogenetics interfered with the anxiety-reducing effects of propofol. Electrophysiological recordings indicated that propofol decreases the activity of PVNCRH neurons by increasing spontaneous inhibitory postsynaptic currents (sIPSCs). Further, reducing the levels of γ-aminobutyric acid type A receptor ß3 (GABAAß3) subunits in PVNCRH neurons diminished the anxiety-relieving effects of propofol. In conclusion, this study provides a mechanistic and preclinical rationale to treat pain-associated anxiety-like behaviors using a single dose of propofol.

Canakinumab in the treatment of systemic juvenile idiopathic arthritis: a retrospective single center study in China.

Objective: Systemic juvenile idiopathic arthritis (sJIA) is characterized by excessive production of proinflammatory cytokines. As an anti-IL-1 agent, canakinumab has been approved in the USA and Europe for the treatment of sJIA patients aged ≥2 years. However, the use of canakinumab has never been reported in China. In this study, we aimed to assess the efficacy and safety of canakinumab in Chinese patients with sJIA. Methods: A total of 11 patients with sJIA who were treated with canakinumab were included in this study. Clinical data were collected retrospectively from medical records. Efficacy was evaluated by the systemic juvenile arthritis disease activity score (sJADAS). The follow-up was performed at canakinumab initiation, at months 1, 3, 6, 9 and 12, or at the last follow-up. Results: Of the 11 patients enrolled, 91.0% (10/11) had previously received treatment with tocilizumab. The mean duration of canakinumab was 9 (3-18) months. 45.5% (5/11) of patients showed complete response, 45.5% (5/11) showed partial response, and 9.0% (1/11) showed no response. 18.2% (2/11) experienced disease flare during the treatment with canakinumab. 81.8% (9/11) of patients successfully reduced the dose of corticosteroids, with six discontinuing corticosteroids. 45.6% (5/11) of patients experienced infection. No serious adverse events occurred during the treatment with canakinumab. Conclusions: Canakinumab may be effective and tolerable for Chinese sJIA patients, helping to reduce the dosage of corticosteroids. However, additional researches on large samples are required to evaluate its efficacy and safety.

Compact Modeling of Advanced Gate-All-Around Nanosheet FETs Using Artificial Neural Network.

As the architecture of logic devices is evolving towards gate-all-around (GAA) structure, research efforts on advanced transistors are increasingly desired. In order to rapidly perform accurate compact modeling for these ultra-scaled transistors with the capability to cover dimensional variations, neural networks are considered. In this paper, a compact model generation methodology based on artificial neural network (ANN) is developed for GAA nanosheet FETs (NSFETs) at advanced technology nodes. The DC and AC characteristics of GAA NSFETs with various physical gate lengths (Lg), nanosheet widths (Wsh) and thicknesses (Tsh), as well as different gate voltages (Vgs) and drain voltages (Vds) are obtained through TCAD simulations. Subsequently, a high-precision ANN model architecture is evaluated. A systematical study on the impacts of ANN size, activation function, learning rate, and epoch (the times of complete pass through the entire training dataset) on the accuracy of ANN models is conducted, and a shallow neural network configuration for generating optimal ANN models is proposed. The results clearly show that the optimized ANN model can reproduce the DC and AC characteristics of NSFETs very accurately with a fitting error (MSE) of 0.01.

Costunolide attenuates LPS-induced inflammation and lung injury through inhibiting IKK/NF-κB signaling.

Inflammation is an important pathological process of many acute and chronic diseases, such as sepsis, arthritis, and cancer. Many factors can lead to an inflammatory state of the body, among which bacterial infection plays an important role. Bacterial infection often leads to sepsis, acute lung injury (ALI), or its more serious form of acute respiratory distress syndrome, which are the main fatal diseases in intensive care units. Costunolide has been reported to possess excellent anti-inflammatory activity; however, whether it can affect inflammation induced by gram-negative bacterial is still unclear. Lipopolysaccharide (LPS) stimulated mouse peritoneal macrophages (MPMs) to release proinflammatory cytokines was used as the cell model. The mouse model of sepsis and ALI was built through injecting intravenously and intratracheally of LPS. In the present study, costunolide inhibited LPS-induced inflammatory response through IKK/NF-κB signaling pathway in macrophages. In vivo, costunolide attenuated LPS-induced septic death in mice. Meanwhile, costunolide treatment alleviated LPS-induced lung injury and inflammation via inhibiting the infiltration of inflammatory cells and the expression of inflammatory cytokines. Taken together, these results demonstrated that costunolide could attenuate gram-negative bacterial induced inflammation and diseases and might be a potential candidate for the treatment of inflammatory diseases.

Feasibility analysis of low-dose CT with asynchronous quantitative computed tomography to assess vBMD.

BACKGROUND: To explore the feasibility of low-dose computed tomography (LDCT) with asynchronous quantitative computed tomography (asynchronous QCT) for assessing the volumetric bone mineral density (vBMD). METHODS: 416 women patients, categorized into 4 groups, were included and underwent chest CT examinations combined with asynchronous QCT, and CT scanning dose protocols (LDCT or CDCT) were self-determined by the participants. Radiation dose estimations were retrieved from patient protocols, including volume CT dose index (CTDIvol) and dose-length-product (DLP), and then calculated effective dose (ED). Delimiting ED by 1.0 mSv, chest CT examinations were categorized into 2 groups, LDCT group and CDCT group. vBMD of T12-L2 was obtained by transferring the LDCT and CDCT images to the QCT workstation, without extra radiation. RESULTS: There was no difference of vBMD among 4 age groups in LDCT group (P = 0.965), and no difference in CDCT group (P = 0.988). In LDCT group and CDCT group, vBMD was not correlated to mAs, CTDIvol and DLP (P > 0.05), respectively. Between LDCT group and CDCT group, there was no difference of vBMD (P ≥ 0.480), while differences of mAs, CTDIvol and DLP. CONCLUSION: There was no difference of vBMD between LDCT group and CDCT group and vBMD was not correlated to mAs. While screening for diseases such as lung cancer and mediastinal lesions, LDCT combined with asynchronous QCT can be also used to assess vBMD simultaneously with no extra imaging equipment, patient visit time, radiation dose and no additional economic cost.

Elevated serum IFN-γand IFN-γ/IL-6 ratio in Kikuchi-Fujimoto disease.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is typically a benign, self-limiting inflammatory disease. The diagnosis of KFD can be challenging for nonspecific symptoms, laboratory or imaging findings. In this study, we aimed to describe the clinical manifestations of patients with KFD and to access the potential role of serum cytokines in the diagnosis of this disease. METHODS: Patients with KFD were retrospectively enrolled from January 2015 to November 2021 at Shenzhen Children's Hospital. Clinical data were collected from inpatient or outpatient medical records. Serum cytokines were detected by the Flowcytomix technique. Serum levels of cytokines were compared between patients with KFD and SJIA, or patients with KFD and KD. The data of patients without MAS were further analyzed. A receiver operating characteristic (ROC) curve analysis was further performed to access the potential role of serum cytokines in the diagnosis of KFD. RESULTS: Serum cytokines were detected in 25 (43.8%, 25/57) patients with a histological diagnosis of KFD. Compared to SJIA or KD patients, the KFD group had a significantly higher IFN-γ/IL-6 ratio and much lower levels of serum IL-6. The median level of serum IFN-γ in KFD was 41.65 pg/ml (range, 21.04-70.74 pg/ml), which was much higher than that in SJIA (median: 3.33 pg/ml, p = 0.16) or KD (median: 2.6 pg/ml, p = 0.01). After excluding patients with MAS, there was statistical significance in all comparisons of serum IFN-γ, IFN-γ/IL-6 ratio, and serum IL-6. The cutoff values of serum IFN-γ, IL-6, and IFN-γ/IL-6 ratio for differentiating KFD from SJIA were > 8.48 pg/ml, < 47.42 pg/ml, and > 0.45, respectively. The cutoff values of serum IFN-γ, IL-6, and IFN-γ/IL-6 ratio for differentiating KFD from KD were > 8.56 pg/ml, < 50.45 pg/ml, and > 0.45, respectively. The specificity of all those cutoff values for differentiating KFD from SJIA or KD was ≥ 94.7%. CONCLUSIONS: For patients with fever of unknown etiology and lymphadenopathy, after excluding HLH or MAS, serum IFN-γ > 8.56 pg/mL and IFN-γ/IL-6 ratio > 0.45 may highly suggest the diagnosis of KFD; serum IL-6 > 50.45 pg/mL indicates that the probability of KFD may be small, and sJIA, KD, and acute infection should be excluded first.

Feasibility of diffusion kurtosis imaging in evaluating cervical spinal cord injury in multiple sclerosis.

This research aimed to assess gray matter (GM), white matter (WM), lesions of multiple sclerosis (MS) and the therapeutic effect using diffusion kurtosis imaging (DKI). From January 2018 to October 2019, 78 subjects (48 of MS and 30 of health) perform routine MR scan and DKI of cervical spinal cord. The MS patients were divided into 2 groups according to the presence or absence of T2 hyperintensity. DKI-metrics were measured in the lesions, normal-appearing GM and WM. Significant differences were detected in DKI metrics between MS and healthy (P < .05) and between patients with cervical spinal cord T2-hyperintense and without T2-hyperintense (P < .001). Compared to healthy, GM-mean kurtosis (MK), GM-radial kurtosis, and WM-fractional anisotropy, WM-axial diffusion were statistically reduced in patients without T2-hyperintense (P < .05). Significant differences were observed in DKI metrics between patients with T2-hyperintense after therapy (P < .05), as well as GM-MK and WM-fractional anisotropy, WM-axial diffusion in patients without T2-hyperintense (P < .05); Expanded Disability Status Scale was correlated with MK values, as well as Expanded Disability Status Scale scores and MK values after therapy. Our results indicate that DKI-metrics can detect and quantitatively evaluate the changes in cervical spinal cord micropathological structure.

ANP32B suppresses B-cell acute lymphoblastic leukemia through activation of PU.1 in mice.

ANP32B, a member of the acidic leucine-rich nuclear phosphoprotein 32 kDa (ANP32) family of proteins, is critical for normal development because its constitutive knockout mice are perinatal lethal. It is also shown that ANP32B acts as a tumor-promoting gene in some kinds of cancer such as breast cancer and chronic myelogenous leukemia. Herein, we observe that ANP32B is lowly expressed in B-cell acute lymphoblastic leukemia (B-ALL) patients, which correlates with poor prognosis. Furthermore, we utilized the N-myc or BCR-ABLp190 -induced B-ALL mouse model to investigate the role of ANP32B in B-ALL development. Intriguingly, conditional deletion of Anp32b in hematopoietic cells significantly promotes leukemogenesis in two B-ALL mouse models. Mechanistically, ANP32B interacts with purine rich box-1 (PU.1) and enhances the transcriptional activity of PU.1 in B-ALL cells. Overexpression of PU.1 dramatically suppresses B-ALL progression, and highly expressed PU.1 significantly reverses the accelerated leukemogenesis in Anp32b-deficient mice. Collectively, our findings identify ANP32B as a suppressor gene and provide novel insight into B-ALL pathogenesis.

Propofol exerts anti-anhedonia effects via inhibiting the dopamine transporter.

Lasker's award-winning drug propofol is widely used in general anesthesia. The recreational use of propofol is reported to produce a well-rested feeling and euphoric state; yet, the neural mechanisms underlying such pleasant effects remain unelucidated. Here, we report that propofol actively and directly binds to the dopamine transporter (DAT), but not the serotonin transporter (SERT), which contributes to the rapid relief of anhedonia. Then, we predict the binding mode of propofol by molecular docking and mutation of critical binding residues on the DAT. Fiber photometry recording on awake freely moving mice and [18F] FP-CIT-PET scanning further establishes that propofol administration evokes rapid and lasting dopamine accumulation in nucleus accumbens (NAc). The enhanced dopaminergic tone drives biased activation of dopamine-receptor-1-expressing medium spiny neurons (D1-MSNs) in NAc and reverses anhedonia in chronically stressed animals. Collectively, these findings suggest the therapeutic potential of propofol against anhedonia, which warrants future clinical investigations.

FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia.

BACKGROUND: Selectively targeting leukemia stem cells (LSCs) is a promising approach in treating acute myeloid leukemia (AML), for which identification of such therapeutic targets is critical. Increasing lines of evidence indicate that FBXO22 plays a critical role in solid tumor development and therapy response. However, its potential roles in leukemogenesis remain largely unknown. METHODS: We established a mixed lineage leukemia (MLL)-AF9-induced AML model with hematopoietic cell-specific FBXO22 knockout mice to elucidate the role of FBXO22 in AML progression and LSCs regulation, including self-renewal, cell cycle, apoptosis and survival analysis. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis, Western blotting and rescue experiments were performed to study the mechanisms underlying the oncogenic role of FBXO22. RESULTS: FBXO22 was highly expressed in AML, especially in MLL-rearranged (MLLr) AML. Upon FBXO22 knockdown, human MLLr leukemia cells presented markedly increased apoptosis. Although conditional deletion of Fbxo22 in hematopoietic cells did not significantly affect the function of hematopoietic stem cells, MLL-AF9-induced leukemogenesis was dramatically abrogated upon Fbxo22 deletion, together with remarkably reduced LSCs after serial transplantations. Mechanistically, FBXO22 promoted degradation of BACH1 in MLLr AML cells, and overexpression of BACH1 suppressed MLLr AML progression. In line with this, heterozygous deletion of BACH1 significantly reversed delayed leukemogenesis in Fbxo22-deficient mice. CONCLUSIONS: FBXO22 promotes MLLr AML progression by targeting BACH1 and targeting FBXO22 might be an ideal strategy to eradicate LSCs without influencing normal hematopoiesis.

Atypical antipsychotics antagonize GABAA receptors in the ventral tegmental area GABA neurons to relieve psychotic behaviors.

Psychosis is an abnormal mental condition that can cause patients to lose contact with reality. It is a common symptom of schizophrenia, bipolar disorder, sleep deprivation, and other mental disorders. Clinically, antipsychotic medications, such as olanzapine and clozapine, are very effective in treatment for psychosis. To investigate the neural circuit mechanism that is affected by antipsychotics and identify more selective therapeutic targets, we employed a strategy by using these effective antipsychotics to identify antipsychotic neural substrates. We observed that local injection of antipsychotics into the ventral tegmental area (VTA) could reverse the sensorimotor gating defects induced by MK-801 injection in mice. Using in vivo fiber photometry, electrophysiological techniques, and chemogenetics, we found that antipsychotics could activate VTA gamma-aminobutyric acid (GABA) neurons by blocking GABAA receptors. Moreover, we found that the VTAGABA nucleus accumbens (NAc) projection was crucially involved in such antipsychotic effects. In summary, our study identifies a novel therapeutic target for the treatment of psychosis and underscores the utility of a 'bedside-to-bench' approach for identifying neural circuits that influence psychotic disorders.

GMP development and preclinical validation of CAR-T cells targeting a lytic EBV antigen for therapy of EBV-associated malignancies.

Introduction: Epstein-Barr virus (EBV) is a widely spread pathogen associated with lymphoproliferative diseases, B/ T/ NK cell lymphomas, nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). EBV lytic reactivations contribute to the genomic instability, inflammation and tumorigenesis of NPC, promoting cancer progression. Patients with NPC refractory to standard therapies show dismal survival. EBV gp350 is an envelope protein detectable in NPC specimens intracellularly and on the cell membrane of malignant cells, and is a potential viral antigen for T cell-directed immunotherapies. The potency of T cells engineered with a chimeric antigen receptor (CAR) targeting gp350 against EBV+ lymphoproliferative disease was previously shown. Methods: Here, we advanced towards preclinical and non-clinical developments of this virus-specific CAR-T cell immunotherapy against NPC. Different gp350CAR designs were inserted into a lentiviral vector (LV) backbone. Results: A construct expressing the scFv 7A1-anti-gp350 incorporating the CD8 transmembrane and CD28.CD3ζ signaling domain (ZT002) was selected. High titer ZT002 (~1x108 TU/ml) was manufactured in HEK 293T/17 suspension cells in serum free media as large-scale production under good manufacturing practices (GMP). A LV multiplicity of infection (MOI) of 1 resulted in high frequencies of functional gp350CAR+ T cells (>70%) at a low (<2) vector copy numbers in the genome. ZT002 was therefore used to establish gp350CAR-T batch run production methods. GMP upscaling and validation of T cell transduction and expansion in several runs resulted in average 3x109 gp350CAR-T cells per batch. >80% CD3+ gp350CAR-T cells bound to purified gp350 protein. In vitro cytotoxicity and cytokine secretion assays (IFN-γ and TNF-α) confirmed the specificity of gp350CAR-T cells against gp350+ NPC, GC and lymphoma cell targets. Immunocompromised B-NDG mice (NOD.CB17-PrkdcscidIl2rgtm1/Bcgen) were challenged s.c. with a EBV+ NPC C666.1 cell line expressing gp350 and then treated with escalating doses of gp350CAR-T cells or with non-transduced T cells. gp350CAR-T cells promoted antitumor responses, bio-distributed in several tissues, infiltrated in tumors and rejected gp350+ tumor cells. Discussion: These results support the use of gp350CAR-T cells generated with ZT002 as an Innovative New Drug to treat patients with solid and liquid EBV-associated malignancies.

Macrophage activation syndrome in children with Kikuchi-Fujimoto disease.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is typically a benign, self-limiting inflammatory disease. However, some patients may have a prolonged or recurrent disease course, or present with life-threatening complications such as macrophage activation syndrome (MAS). In this study, we aimed to describe the incidence and clinical features of MAS in KFD and to access potential laboratory markers for the diagnosis of KFD-associated MAS. METHODS: Patients with KFD were retrospectively enrolled from January 2015 to November 2021 at Shenzhen Children's Hospital. Clinical data were collected from inpatient or outpatient medical records. Data collected included clinical manifestations, laboratory and imaging findings, treatment, and clinical outcomes. Data were analyzed using GraphPad Prism 8.0 statistical software (GraphPad Software Inc., La Jolla, CA, USA). A receiver operating characteristic (ROC) curve analysis was further performed to access the potential predictors for the KFD-MAS diagnosis. RESULTS: Of 58 patients with a histological diagnosis of KFD, 15 (25.9%) patients had MAS. Compared to patients without MAS, patients with KFD-MAS presented with a higher proportion of skin rash (26.7%, p = 0.01), glucocorticoid treatment (80%, p = 0.003), and disease recurrence (33.3%, p = 0.04). KFD-MAS patients had lower absolute peripheral white blood cell (WBC, p = 0.02), platelet (p = 0.002), serum albumin levels (p = 0.01), and lymphocyte count (p < 0.0001), and higher lactate dehydrogenase (LDH) levels (p < 0.0001). ROC curve analysis showed that the cutoff values of absolute lymphocyte count, an absolute platelet count, serum albumin level, and serum LDH level for KFD-MAS diagnosis were < 1235/µL, < 171 × 106/µL, < 35.6 g/L, and > 679 IU/mL, respectively. CONCLUSIONS: The presence of KFD-MAS in children may be more common than previously expected, especially in those with skin rash. KFD-MAS may be associated with a higher recurrence rate. An extremely elevated serum LDH level and moderate to severe lymphopenia may be useful diagnostic markers for MAS in KFD. TRIAL REGISTRATION: Not applicable; this was a retrospective study.

Piperlongumine mitigates LPS-induced inflammation and lung injury via targeting MD2/TLR4.

PURPOSE: Acute lung injury (ALI) is a fatal acute inflammatory illness with restricted therapeutic choices clinically. Piperlongumine (PL) is recognized as an alkaloid separated from Piper longum L, which was suggested to exhibit multiple pharmacological activities (e.g., anti-inflammatory activity). However, the effects of PL on LPS-triggered ALI and its anti-inflammatory target remain unclear. This paper intended to assess the roles of PL in LPS-triggered ALI, as well as its underlying mechanism and target. METHODS: In vivo, ALI was induced by intratracheal injection of LPS to evaluate protective effects of PL and assessed by the changes of histopathological. In vitro, the anti-inflammatory activity and mechanism of PL were investigated by ELISA, RT-qPCR, transcription factor enrichment analysis, Western blotting and Immunofluorescence assay. The binding affinity of PL to MD2 was analyzed using computer docking, surface plasmon resonance, ELISA and immunoprecipitation assay. RESULTS: It was reported here that PL treatment alleviated LPS-induced pulmonary damage, inflammatory cells infiltration and inflammatory response in mice. In culture cells, PCR array showed that PL significantly inhibited LPS-induced inflammatory cytokines, chemokines, and type I IFNs genetic expression, along with the inhibition of TAK1 and TBK1 pathway. It is noteworthy that PL is capable of straightly binding to MD2 and inhibiting MD2/TLR4 complex formation and TLR4 dimerization. CONCLUSIONS: As revealed from this study, PL directly binding to MD2 to block cytokines expression by inhibiting the activation of TAK1 and TBK1 pathway, which then exerted its pulmonary protective activity. Accordingly, PL may act as an underlying candidate for treating LPS-triggered ALI.

Talaromyces marneffei Infections in 8 Chinese Children with Inborn Errors of Immunity.

PURPOSE: Talaromyces marneffei (TM) is an opportunistic fungus leading to multi-organ damages and poor prognosis in immunocompromised individuals. TM infections in children are rare and our knowledge to TM infection is insufficient. To investigate the clinical characteristics of TM-infected children and to explore the underlying mechanisms for host against TM, we analysed TM-infected patients diagnosed in our hospital. METHODS: Eight patients with TM infections have been identified in Shenzhen Children's Hospital during 2017-2021. Clinical data were collected from medical records. Immunological features were evaluated by flow cytometry. Literatures were also reviewed to summarize the reported inborn errors of immunity (IEIs) with TM infections. RESULTS: All 8 children were HIV-negative. The most common symptom of TM infections was fever (8/8), followed by weight loss (7/8), pneumonia (7/8), hepatomegaly (7/8), splenomegaly (6/8), anemia (6/8), lymphadenopathy (5/8), thrombocytopenia (3/8), diarrhea (3/8), rashes or skin lesions (3/8), and osteolytic lesions (1/8). Five children died during the follow-ups. CD3+ T cells were decreased in 6 patients. Eight patients had reduced natural killer cells. All patients went gene sequencing and were finally diagnosed as IEIs, including STAT1 gain-of-function, IL-2 receptor common gamma chain deficiency, adenosine deaminase deficiency, CD40 ligand deficiency, and STAT3 deficiency. Another 4 types of IEIs (CARD9, IFN-γ receptor 1, RelB, and NFKB2 deficiency), have been reported with TM infections based on literature review. CONCLUSION: TM infections resulted in systemic injuries and high mortality. The spectrum of IEIs underlying TM infections indicated that T cell-mediated immunity, IFN-γ, IL-17 signalings and NF-κB pathways were important for host responses against TM infection. In reverse, for HIV-negative children without other secondary immunodeficiencies, IEIs should be considered in TM-infected children.