LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes with median overall survival less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to the rapid disease progression and provide novel therapeutic selection for these ultra-high-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients with survival of less than two years (EM24). Notably, an enrichment of LILRB4high pre-matured plasma-cell cluster was observed in the patients in EM24 compared to patients with durable remission. This cluster exhibited aggressive proliferation and drug-resistance phenotype. High-level LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/refractory MM patients. The ATAC-seq analysis identified that high chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of MDSCs, and further rescued T cell dysfunction in MM microenvironment. The more infiltration of myeloid-derived suppressive cells (MDSCs) was observed in EM24 patients as well. Therefore, we innovatively generated a TCR-based chimeric antigen receptor (CAR) T cell, LILRB4-STAR-T. Cytotoxicity experiment demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSCs function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.

Identification of clinically relevant subsets CD39+PD-1+CD8+ T cells and CD39+ regulatory T cells in intrahepatic cholangiocarcinoma using single-cell CyTOF.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy with limited treatment options and a dismal prognosis. The tumor immune microenvironment (TIME) is crucial for iCCA progression, yet its comprehensive characterization remains incomplete. This study utilized mass cytometry by time of flight (CyTOF) to comprehensively analyze immune cell populations in fresh iCCA tumor samples and adjacent peritumor liver tissues. Notably, NK cell percentages significantly decreased in iCCA lesions compared to peritumor liver tissues. Conversely, an enrichment of immunosuppressive CD39+Foxp3+CD4+ regulatory T cells (CD39+T-regs) and exhausted-like CD8+T cells (with pronounced CD39 and PD-1 expression) within TIME was identified and confirmed by multiplex immunofluorescence staining in an independent patient cohort (n = 140). Crucially, tumor-infiltrating CD39+T-regs and CD39+PD-1+CD8+T cells emerged as independent prognostic indicators associated with an unfavorable prognosis in iCCA. These findings unveil the intricate immune landscape within iCCA, offering valuable insights for disease management and novel cancer immunotherapies.

Controlling nonlinear collapse of ellipticity and orientation of a co-variant vector optical field.

A vector optical field with inhomogeneous spatial polarization distribution offers what we believe to be a new paradigm to form controllable filaments. However, it is challenging to steer multiple performances (e.g. number, orientation, and interval) of filaments in transparent nonlinear media at one time. Herein, we theoretically self-design and generate a kind of believed to be novel ellipticity and orientation co-variant vector optical field to interact with Kerr medium to solve this issue. The collapsing behaviors of such a new hybrid vector optical field reveal that, by judiciously adjusting the inherent topological charge and initial phase of incident optical field, we are able to give access to stable collapsing filamentation with tunable numbers, orientations and interval. Additionally, the collapsing patterns presented are immune nearly to the extra random noise. The relevant mechanism behind the collapse of the vector optical field is elucidated as well. The findings in this work may have huge potential in optical signal processing, laser machining, and other related applications.

The effect and mechanism of volatile oil emulsion from leaves of Clausena lansium (Lour.) Skeels on Staphylococcus aureus in vitro.

This study aimed to develop a suitable dosage form of volatile oil from wampee leaves and to explore its antibacterial mechanism in vitro. The chemical composition of the volatile oil from wampee leaves was determined by gas chromatography-mass spectrometry (GC-MS). Different microemulsion ratios were tested and their stabilities were investigated to determine the optimal ratio. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the wampee leaves volatile oil emulsion (WVOE) against Salmonella typhimurium (S. typhimurium) and Staphylococcus aureus (S. aureus) were determined using double-dilution and plate-counting methods, respectively. Morphological changes in these two bacteria were observed using scanning electron microscopy. Death, ultrastructural morphology, and biofilm formation were also assessed for S. aureus. Finally, we established an S. aureus-infected Lewis lung carcinoma (LLC) cell model to evaluate the protective effects of the volatile oil emulsion and the associated mechanisms. The volatile oil extracted from wampee leaves contained 37 compounds, of which 96.49% were aromatic hydrocarbons, terpenoids, and their oxygen-containing derivatives. The emulsion was most stable at 1:1 in the oil phase and 1:9 in the water phase. WVOE had poor antibacterial activity against S. typhimurium, but the MIC and MBC against S. aureus were 312.5 and 2,500 µg/mL, respectively. S. aureus survival rates were 84.6%, 14.5%, and 12.8% in the 1/2, 1, and 4 × MIC groups, respectively, compared with 97.2% in the control group. S. typhimurium survival was not affected by WVOE treatment. WVOE administration induced cavity formation and abnormal binary fission, and significantly inhibited biofilm formation in S. aureus cells. The WVOE notably reduced the number of S. aureus and inhibited TLR4, NLRP3, NF-κB, IL-6, IL-18, and TNF-α gene expression in S. aureus-infected LLC cells. The WVOE had a significant inhibitory effect on S. aureus and altered its cell membrane permeability. Moreover, it alleviated inflammation by inhibiting the NF-κB-NLRP3 pathway in S. aureus-infected LLC cells.

Three different routes of EHEC O157:H7 infection were used to establish EHEC broiler model.

In order to study the prevention and control EHEC disease measures in poultry, the infection process and development of this disease and the pathological changes of various organs were to be observed. In this study, chickens were infected with different doses of enterohemorrhagic Escherichia coli (EHEC) O157:H7 using different routes of administration to establish EHEC broiler model. A total of 195 14-day-old broilers were randomly divided into 13 groups: including control group, Enema-drip groups (1010, 1011, 1012, 1013 CFUs E. coli O157:H7), gavage groups (P.O) (1011, 1012, 1013, 1014 CFUs E. coli O157:H7), and intraperitoneal injection group (I.P.) (108, 109, 1010, 1011 CFUs E. coli O157:H7). Escherichia coli (E. coli) was given using enema-drip, gavage or intraperitoneal infection. Then the feed intake, weight changes, stool and clinical symptoms of the chicks were recorded during the experiment. 7 d after E. coli infection, blood was collected from the jugular vein and serological tests were carried out. The liver, spleen, and colon of the chicks were extracted to get the organ index, bacteria load, and their histopathological changes. After infection with E. coli, some chicks feces were green or red watery stool, sometimes accompanied by foam, and the material to weight ratio of broilers in I.P. group increased significantly (P < 0.05), the 108 CFUs group were 1.3 times as large as control group. Three modeling methods can result in abnormal serum lipid metabolism and liver function indexes (increase of AST, TBA, T-Bil and TC level; decrease of ALB, TG, and TP level). Infection of chicks with O157:H7 by all 3 methods resulted in its detection in the liver, spleen, and colon. Three modeling methods significantly decreased liver index, and inflammatory cell infiltration and hyperemia were observed in liver. The spleen index in E. coli broilers by gavage and enema-drip was significantly decreased, splenic hyperemia and periarteriolar hyalinosis were observed. The spleen was enlarged with purplish-black spheroids in I.P. group broilers, and the spleen histological changes was more serious. The colon villi of broilers in gavage and enema-drip groups were thinner, more prone to rupture, intestinal lamina propria hyperemia, and inflammatory cell infiltration. Moreover, the number of goblet cells in the mucosal epithelium increased. E. coli O157:H7 can induce liver, spleen and intestinal damage and reduce growth performance of chicks. By comparing these 3 methods, we found that chicks infected with O157:H7 by gavage had more severe liver and intestinal damage, the enema-drip method caused most serious intestinal damage, and I.P. method significantly damaged the liver and spleen of chickens.

[Neonate-onset ornithine transcarbamylase deficiency]. / æ–°ç”Ÿå„¿é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡.

The male neonate in this case study was admitted to the hospital at 15 hours of age due to respiratory distress for 15 hours and poor response for 3 hours after resuscitation from asphyxia. The neonate was highly unresponsive, with central respiratory failure and seizures. Serum ammonia was elevated (>1 000 µmol/L). Blood tandem mass spectrometry revealed a significant decrease in citrulline. Rapid familial whole genome sequencing revealed OTC gene mutations inherited from the mother. Continuous hemodialysis filtration and other treatments were given. Neurological assessment was performed by cranial magnetic resonance imaging and electroencephalogram. The neonate was diagnosed with ornithine transcarbamylase deficiency combined with brain injury. He died at 6 days of age after withdrawing care. This article focuses on the differential diagnosis of neonatal hyperammonemia and introduces the multidisciplinary management of inborn error of metabolism.

Acetaminophen-induced hepatotoxicity predominantly via inhibiting Nrf2 antioxidative pathway and activating TLR4-NF-κB-MAPK inflammatory response in mice.

To explore the action time and molecular mechanism underlying the effect of acetaminophen (APAP) on liver injury. APAP was used to establish drug-induced liver injury (DILI) model in mice. Mice in the model group were intraperitoneally injected 300 mg/kg APAP for 6, 12, and 24 h respectively, and control group mice were given the same volume of normal saline. The mice were anesthetized through intravenous injection of sodium pentobarbital at 6, 12, and 24 h after APAP poisoning. Analysis of ALT, AST and ALP in serum, liver histopathological observation, oxidative damage and western blot were performed. The livers in APAP exposed mice were pale, smaller, with a rough texture, and poorly arranged cells. Lesions, large areas of hyperemia, inflammation, swelling, poorly cell arrangement, necrosis, and apoptosis of liver cells were obvious in the liver tissue sections. Serum ALT, AST and ALP levels were significantly enhanced at 12 h of APAP adminstration mice than that of in control group mice (P＜0.05). The histopathological alterations and proinflammatory cytokines (IL-1ß, TNF-α and IL-6) levels were most severe at 12 h of APAP-induced hepatotoxicity. APAP treatment induced oxidative stress by decreasing hepatic activities of superoxide dismutase (SOD) and glutathione (GSH) (P＜0.05), and enhancing malondialdehyde (MDA) content (P＜0.05). Moreover, APAP inhibited erythroid 2-related factor 2 (Nrf2) antioxidative pathway with decreased of Nrf2 and HO-1 proteins levels. Furthermore, APAP aggravated the activation of NLRP3 inflammasome by increasing of NLRP3, caspase-1, ASC, IL-1ß and IL-18 proteins levels. Finally, APAP further significantly activated the toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. This study demonstrated that APAP-induced hepatotoxicity by inhibiting of Nrf2 antioxidative pathway and promoting TLR4-NF-κB-MAPK inflammatory response and NLRP3 inflammasome activation.

Resveratrol relieves chronic heat stress-induced liver oxidative damage in broilers by activating the Nrf2-Keap1 signaling pathway.

Heat stress (HS) affects poultry production and welfare, causing enormous damage to poultry. Resveratrol, an antioxidant and anti-inflammatory natural plant polyphenol, is widely used in agriculture for the prevention of oxidative stress-related diseases. This study aimed to explore the effects and potential mechanism of resveratrol on liver oxidative damage in heat-stressed broilers. Sixty SPF chickens were randomly divided into control, heat stress (HS) and HS+ resveratrol (resveratrol) groups. Broilers were exposed to 35 ± 2 â„ƒ (8 h/d) for 7 consecutive days to induce HS, and the other 16 h/d were kept at 23 ± 2 â„ƒ, similar to the control group. Broilers received 400 mg/kg resveratrol in the basic diet 2 days before exposure to HS and for the following 7 days. The results showed that resveratrol improved growth performance by increasing the average daily gain (ADG) and reducing the feed conversion ratio (FCR), compared with the HS group. Heat stress reduced liver weight and index, increased inflammatory cell infiltration in the liver, enhanced serum AST levels, and decreased TP and ALB II levels, which resulted in liver injury in broilers, and resveratrol effectively alleviated liver injury. Moreover, supplementation with resveratrol enhanced the activities of liver antioxidant enzymes resulting in higher GPX and SOD levels than those in the heat-stressed broilers, and decreased MDA levels. Furthermore, resveratrol alleviated liver oxidative stress by activating the gene and protein levels of Nrf2 and HO-1, enhancing NQO1 and SOD1 gene levels, and decreasing protein levels of HSP70, p62, and Keap1, and thereby alleviated the liver injury of heat-stressed broilers. Compared with the HS group, Nrf2 immunofluorescence was significantly up-regulated in the livers of resveratrol group. These results suggest that resveratrol can enhance the liver antioxidant function by activating the Nrf2-Keap1 signaling pathway to promote growth performance in broilers under HS.

Effects of glucagon-like peptide-1 on male reproductive function / 中华内分泌代谢杂志

With the younger onset of diabetes, the reproductive dysfunction caused by diabetes has received widespread attention. Hyperglycemia and insulin resistance, the main features of diabetes, are high-risk factors for male reproductive dysfunction. Obesity, the common co-morbidity of diabetes, may aggravate the progression of reproductive dysfunction. Glucagon-like peptide-1(GLP-1) and its receptor agonists improve the overall health status by lowering blood glucose, reducing body weight, and inhibiting inflammatory response, which indirectly exerts protective effects on the reproductive system. GLP-1 also protects reproductive function by regulating the neuroendocrine function, and directly acting on the supporting cells and interstitial cells of the testis. However, some studies did not find the protective effects. High-quality clinical studies are needed. GLP-1 receptor agonists may be a therapeutic option to improve reproductive dysfunction in diabetic men.

Effects and mechanism of p53 gene deletion on energy metabolism during the pluripotent transformation of spermatogonial stem cells / 生理学报

Previous studies have shown that long-term spermatogonial stem cells (SSCs) have the potential to spontaneously transform into pluripotent stem cells, which is speculated to be related to the tumorigenesis of testicular germ cells, especially when p53 is deficient in SSCs which shows a significant increase in the spontaneous transformation efficiency. Energy metabolism has been proved to be strongly associated with the maintenance and acquisition of pluripotency. Recently, we compared the difference in chromatin accessibility and gene expression profiles between wild-type (p53+/+) and p53 deficient (p53-/-) mouse SSCs using the Assay for Targeting Accessible-Chromatin with high-throughput sequencing (ATAC-seq) and transcriptome sequencing (RNA-seq) techniques, and revealed that SMAD3 is a key transcription factor in the transformation of SSCs into pluripotent cells. In addition, we also observed significant changes in the expression levels of many genes related to energy metabolism after p53 deletion. To further reveal the role of p53 in the regulation of pluripotency and energy metabolism, this paper explored the effects and mechanism of p53 deletion on energy metabolism during the pluripotent transformation of SSCs. The results of ATAC-seq and RNA-seq from p53+/+ and p53-/- SSCs revealed that gene chromatin accessibility related to positive regulation of glycolysis and electron transfer and ATP synthesis was increased, and the transcription levels of genes encoding key glycolytic enzymes and regulating electron transport-related enzymes were markedly increased. Furthermore, transcription factors SMAD3 and SMAD4 promoted glycolysis and energy homeostasis by binding to the chromatin of the Prkag2 gene which encodes the AMPK subunit. These results suggest that p53 deficiency activates the key enzyme genes of glycolysis in SSCs and enhances the chromatin accessibility of genes associated with glycolysis activation to improve glycolysis activity and promote transformation to pluripotency. Moreover, SMAD3/SMAD4-mediated transcription of the Prkag2 gene ensures the energy demand of cells in the process of pluripotency transformation and maintains cell energy homeostasis by promoting AMPK activity. These results shed light on the importance of the crosstalk between energy metabolism and stem cell pluripotency transformation, which might be helpful for clinical research of gonadal tumors.

Neonate-onset ornithine transcarbamylase deficiency / 中国当代儿科杂志

The male neonate in this case study was admitted to the hospital at 15 hours of age due to respiratory distress for 15 hours and poor response for 3 hours after resuscitation from asphyxia. The neonate was highly unresponsive, with central respiratory failure and seizures. Serum ammonia was elevated (>1 000 μmol/L). Blood tandem mass spectrometry revealed a significant decrease in citrulline. Rapid familial whole genome sequencing revealed OTC gene mutations inherited from the mother. Continuous hemodialysis filtration and other treatments were given. Neurological assessment was performed by cranial magnetic resonance imaging and electroencephalogram. The neonate was diagnosed with ornithine transcarbamylase deficiency combined with brain injury. He died at 6 days of age after withdrawing care. This article focuses on the differential diagnosis of neonatal hyperammonemia and introduces the multidisciplinary management of inborn error of metabolism.

The protective effects and underlying mechanisms of dapagliflozin on diabetes-induced testicular dysfunction / 亚洲男科学杂志(英文版)

Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9-39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9-39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9-39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.

Efficacy of pp65-specific TCR-T cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection remains a major cause of mortality after hematopoietic stem cell transplantation (HSCT). Current treatments, including antiviral drugs and adoptive cell therapy with CMV-specific cytotoxic T lymphocytes (CTLs), only show limited benefits in patients. T-cell receptor (TCR)-T cell therapy offers a promising option to treat CMV infections. Here, using tetramer-based screening and single-cell TCR cloning technologies, we identified various CMV antigen-specific TCRs from healthy donors, and generated TCR-T cells targeting multiple pp65 epitopes corresponding to three major HLA-A alleles. The TCR-T cells showed efficient cytotoxicity toward epitope-expressing target cells in vitro. After transfer into immune-deficient mice bearing pp65+ HLA+ tumor cells, TCR-T cells induced dramatic tumor regression and exhibited long-term persistence. In a phase I clinical trial (NCT04153279), CMV TCR-T cells were applied to treat patients with CMV reactivation after HSCT. Except one patient who withdrew at early treatment stage, all other six patients were well-tolerated and achieved complete response (CR), no more than grade 2 cytokine release syndrome (CRS) and other adverse events were observed. CMV TCR-T cells persisted up to 3 months. Among them, two patients have survived for more than 1 year. This study demonstrates the great potential in the treatment and prevention of CMV infection following HSCT or other organ transplantation.

Extracellular vesicles enclosed-miR-421 suppresses air pollution (PM2.5 )-induced cardiac dysfunction via ACE2 signalling.

Air pollution, via ambient PM2.5, is a big threat to public health since it associates with increased hospitalisation, incidence rate and  mortality of cardiopulmonary injury. However, the potential mediators of pulmonary injury in PM2.5 -induced cardiovascular disorder are not fully understood. To investigate a potential cross talk between lung and heart upon PM2.5 exposure, intratracheal instillation in vivo, organ culture ex vivo and human bronchial epithelial cells (Beas-2B) culture in vitro experiments were performed respectively. The exposed supernatants of Beas-2B were collected to treat primary neonatal rat cardiomyocytes (NRCMs). Upon intratracheal instillation, subacute PM2.5 exposure caused cardiac dysfunction, which was time-dependent secondary to lung injury in mice, thereby demonstrating a cross-talk between lungs and heart potentially mediated via small extracellular vesicles (sEV). We isolated sEV from PM2.5 -exposed mice serum and Beas-2B supernatants to analyse the change of sEV subpopulations in response to PM2.5 . Single particle interferometric reflectance imaging sensing analysis (SP-IRIS) demonstrated that PM2.5 increased CD63/CD81/CD9 positive particles. Our results indicated that respiratory system-derived sEV containing miR-421 contributed to cardiac dysfunction post-PM2.5 exposure. Inhibition of miR-421 by AAV9-miR421-sponge could significantly reverse PM2.5 -induced cardiac dysfunction in mice. We identified that cardiac angiotensin converting enzyme 2 (ACE2) was a downstream target of sEV-miR421, and induced myocardial cell apoptosis and cardiac dysfunction. In addition, we observed that GW4869 (an inhibitor of sEV release) or diminazene aceturate (DIZE, an activator of ACE2) treatment could attenuate PM2.5 -induced cardiac dysfunction in vivo. Taken together, our results suggest that PM2.5 exposure promotes sEV-linked miR421 release after lung injury and hereby contributes to PM2.5 -induced cardiac dysfunction via suppressing ACE2.

A novel adoptive synthetic TCR and antigen receptor (STAR) T-Cell therapy for B-Cell acute lymphoblastic leukemia.

We developed a T-cell-receptor (TCR) complex-based chimeric antigen receptor (CAR) named Synthetic TCR and Antigen Receptor (STAR). Here, we report pre-clinical and phase I clinical trial data (NCT03953599) of this T-cell therapy for refractory and relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) patients. STAR consists of two protein modules each containing an antibody light or heavy chain variable region and TCR α or ß chain constant region fused to the co-stimulatory domain of OX40. T-cells were transduced with a STAR-OX40 lentiviral vector. A leukemia xenograft mouse model was used to assess the STAR/STAR-OX40 T cell antitumor activity. Eighteen patients with R/R B-ALL were enrolled into the clinical trial. In a xenograft mouse model, STAR-T-cells exhibited superior tumor-specific cytotoxicity compared with conventional CAR-T cells. Incorporating OX40 into STAR further improved the proliferation and persistence of tumor-targeting T-cells. In our clinical trial, 100% of patients achieved complete remission 4 weeks post-STAR-OX40 T-cell infusion and 16/18 (88.9%) patients pursued consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twelve of 16 patients (75%) remained leukemia-free after a median follow-up of 545 (433-665) days. The two patients without consolidative allo-HSCT relapsed on Day 58 and Day 186. Mild cytokine release syndrome occurred in 10/18 (55.6%) patients, and 2 patients experienced grade III neurotoxicity. Our preclinical studies demonstrate super anti-tumor potency of STAR-OX40 T-cells compared with conventional CAR-T cells. The first-in-human clinical trial shows that STAR-OX40 T-cells are tolerable and an effective therapeutic platform for treating R/R B-ALL.

Effects of delayed HIF-1α expression in astrocytes on myelination following hypoxia-ischaemia white matter injury in immature rats.

BACKGROUND: The underlying cause of neurological sequelae after immature cerebral hypoxia-ischaemia (HI) white matter injury is impaired myelination. Previous studies have indicated that astrocyte activation is closely related to impaired myelination. However, the mechanism of reactive gliosis in white matter injury post-HI remains poorly understood. METHODS: Studies using adult ischaemic animal models demonstrated that hypoxia inducible factor-1α (HIF-1α) expression was involved in the formation of reactive astrocytes. Here, we investigated the temporal expression of HIF-1α and its impact on reactive gliosis and further myelination using a perinatal HI white matter injury model induced in rats at postnatal day 3. The temporal pattern of HIF-1α expression post-HI injury was tested by western blotting and immunofluorescence. Rats were treated with a HIF-1α inhibitor at 72 hours post-HI injury. Reactive gliosis and myelination were assessed with western blotting, immunofluorescence and electron microscopy, and neurological functions were examined by behavioural testing. RESULTS: Our results showed that the expression of HIF-1α was upregulated in neurons at 24 hours and in astrocytes at 7 days post-HI. Inhibiting delayed HIF-1α expression post-HI injury could restrain reactive gliosis, ameliorate hypomyelination, and improve the performance of rats in the Morris water maze test. CONCLUSIONS: Our findings suggest that a delayed increase in HIF-1α in astrocytes is involved in glial scar formation and leads to arrested oligodendrocyte maturation, impaired myelination, and long-term neurological function after experimental white matter injury in immature rats.

Rapid identification of chemical constituents in the dried stem bark of Asparagus officinalis L. based on UPLC-Q-TOF-MS/MS / 药学学报

Ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF-MS/MS) coupled with a molecular network analysis strategy was used to identify the chemical constituents of the stem bark of two kinds of asparagus. The chemical constituents were identified by determining an accurate molecular weight, the fragmentation pathway, and comparison with the mass spectrometry data from the references. A molecular network was established based on the similarity of MS/MS fragmentation patterns. A total of 107 compounds were identified or tentatively deduced, which included 46 saponins, 13 flavonoids, and 48 other compounds. The chemical compounds identified in the stem bark of white and green asparagus differed greatly: the white asparagus was rich in saponins, while the green asparagus was rich in flavonoids. In conclusion, the chemical constituents of asparagus stem bark were characterized rapidly using UPLC-Q-TOF-MS/MS and molecular network analysis, with 10 compounds and 45 targets determined from the HIT 2.0 herbal ingredients' targets platform. This work will provide a theoretical basis for the resource utilization of asparagus.

Remote whispering metamaterial for non-radiative transceiving of ultra-weak sound.

Transceiving ultra-weak sound typically relies on signal pre-amplification at the transmitting end via active electro-acoustic devices, which inherently perturbs the environment in the form of noise that inevitably leads to information leakage. Here we demonstrate a passive remote-whispering metamaterial (RWM) enabling weak airborne sound at audible frequencies to reach unprecedented signal enhancement without altering the detected ambient soundscape, which is based on the extraordinary scattering properties of a metamaterial formed by a pair of self-resonating subwavelength Mie meta-cavities, constituting the acoustic analogy of Förster resonance energy transfer. We demonstrate efficient non-radiative sound transfer over distances hundreds times longer than the radius of the meta-cavities, which enables the RWM to recover weak sound signals completely overwhelmed by strong noise with enhanced signal-to-noise ratio from -3 dB below the detection limit of 0 dB in free space to 17.7 dB.

Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors.

Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated high response rate and durable disease control for the treatment of B cell malignancies. However, in the case of solid tumors, CAR-T cells have shown limited efficacy, which is partially attributed to intrinsic defects in CAR signaling. Here, we construct a double-chain chimeric receptor, termed as synthetic T cell receptor (TCR) and antigen receptor (STAR), which incorporates antigen-recognition domain of antibody and constant regions of TCR that engage endogenous CD3 signaling machinery. Under antigen-free conditions, STAR does not trigger tonic signaling, which has been reported to cause exhaustion of traditional CAR-T cells. Upon antigen stimulation, STAR mediates strong and sensitive TCR-like signaling, and STAR-T cells exhibit less susceptibility to dysfunction and better proliferation than traditional 28zCAR-T cells. In addition, STAR-T cells show higher antigen sensitivity than CAR-T cells, which holds potential to reduce the risk of antigen loss-induced tumor relapse in clinical use. In multiple solid tumor models, STAR-T cells prominently outperformed BBzCAR-T cells and generated better or equipotent antitumor effects to 28zCAR-T cells without causing notable toxicity. With these favorable features endowed by native TCR-like signaling, STAR-T cells may provide clinical benefit in treating refractory solid tumors.