Cancer Immunosurveillance by Tissue-Resident Innate Lymphoid Cells and Innate-like T Cells.

Malignancy can be suppressed by the immune system in a process termed immunosurveillance. However, to what extent immunosurveillance occurs in spontaneous cancers and the composition of participating cell types remains obscure. Here, we show that cell transformation triggers a tissue-resident lymphocyte response in oncogene-induced murine cancer models. Non-circulating cytotoxic lymphocytes, derived from innate, T cell receptor (TCR)αß, and TCRγδ lineages, expand in early tumors. Characterized by high expression of NK1.1, CD49a, and CD103, these cells share a gene-expression signature distinct from those of conventional NK cells, T cells, and invariant NKT cells. Generation of these lymphocytes is dependent on the cytokine IL-15, but not the transcription factor Nfil3 that is required for the differentiation of tumor-infiltrating NK cells, and IL-15 deficiency, but not Nfil3 deficiency, results in accelerated tumor growth. These findings reveal a tumor-elicited immunosurveillance mechanism that engages unconventional type-1-like innate lymphoid cells and type 1 innate-like T cells.

Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways.

Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.

Triple Synergism Effect of Ammonium Nitrilotriacetate on the Chemical Mechanical Polishing Performance of Ruthenium Barrier Layers.

As the feature size of integrated circuits continues to decrease, ruthenium (Ru) has been suggested as the successor to traditional Ta/TaN bilayers for barrier layer materials due to its unique properties. This research delves into the effects of ammonium nitrilotriacetate (NTA(NH4)3) on the chemical mechanical polishing (CMP) performance of Ru in H2O2-based slurry. The removal rate (RR) of Ru surged from 47 to 890 Å min-1, marking an increase of about 17 times. The essence of this mechanism lies in the triple synergistic effects of NTA(NH4)3 in promoting ruthenium (Ru) removal: 1) The interaction between NH 4 + ${\mathrm{NH}}_{\mathrm{4}}^{\mathrm{+}}$ from NTA(NH4)3 and SiO2 abrasives; 2) The chelating action of [(NH4)N(CH2COO)3]2- from NTA(NH4)3 on Ru and its oxides; 3) The ammoniation and chelation of Ru and its oxides by NH 4 + ${\mathrm{NH}}_{\mathrm{4}}^{\mathrm{+}}$ from NTA(NH4)3, which enhance the dissolution and corrosion of oxidized Ru, making its removal during the barrier layer CMP process more efficient through mechanical means. This research introduces a synergistic approach for the effective removal of Ru, shedding light on potential applications of CMP in the field of the integrated circuits.

Dynamic Covalent Bonds Regulate Zinc Plating/Stripping Behaviors for High-Performance Zinc Ion Batteries.

Artificial interfaces provide a comprehensive approach to controlling zinc dendrite and surface corrosion in zinc-based aqueous batteries (ZABs). However, due to consistent volume changes during zinc plating/stripping, traditional interfacial layers cannot consistently adapt to the dendrite surface, resulting in uncontrolled dendrite growth and hydrogen evolution. Herein, dynamic covalent bonds exhibit the Janus effect towards zinc deposition at different current densities, presenting a holistic strategy for stabilizing zinc anode. The PBSC intelligent artificial interface consisting of dynamic B-O covalent bonds is developed on zinc anode to mitigate hydrogen evolution and restrict dendrite expansion. Owing to the reversible dynamic bonds, PBSC exhibits shape self-adaptive characteristics at low current rates, which rearranges the network to accommodate volume changes during zinc plating/stripping, resisting hydrogen evolution. Moreover, the rapid association of B-O dynamic bonds enhances mechanical strength at dendrite tips, presenting a shear-thickening effect and suppressing further dendrite growth at high current rates. Therefore, the assembled symmetrical battery with PBSC maintains a stable cycle of 4500 hours without significant performance degradation and the PBSC@Zn||V2O5 pouch cell demonstrates a specific capacity exceeding 170 mAh g-1. Overall, the intelligent interface with dynamic covalent bonds provides innovative approaches for zinc anode interfacial engineering and enhances cycling performance.

Clinical characteristics of early-onset paediatric systemic lupus erythematosus in a single centre in China.

OBJECTIVES: We sought to investigate the sex distribution, clinical presentations, disease outcomes and genetic background of early-onset paediatric SLE (eo-pSLE) in a single centre in China to help enable early diagnosis and timely treatment. METHODS: The clinical data of children aged less than 5 years old with SLE (n = 19) from January 2012 to December 2021 were reviewed and analysed. We performed DNA sequencing in 11 out of 19 patients to survey the genetic aetiologies. RESULTS: Our study included 6 males and 13 females. The mean age at onset was 3.73 years. The median diagnostic delay was 9 months and was longer in male patients (P = 0.02). Four patients had an SLE-relevant family history. The most common clinical manifestations at diagnosis were fever, rash and hepatosplenomegaly. ANA positivity and low C3 were identified in all children. The renal (94.74%), mucocutaneous (94.74%), haematological (89.47%), respiratory (89.47%), digestive (84.21%), cardiovascular (57.89%) and neuropsychiatric (52.63%) systems were involved to varying degrees. We identified 13 SLE-associated gene mutations in 9 out of 11 patients: TREX1, PIK3CD, LRBA, KRAS, STAT4, C3, ITGAM, CYBB, TLR5, RIPK1, BACH2, CFHR5 and SYK. One male patient showed a 47, XXY chromosomal abnormality. CONCLUSION: Early-onset (<5 years) pSLE is characterized by an insidious onset, typical immunological patterns, and the involvement of multiple organs. Immunological screening and genetic testing should be performed as soon as feasible in patients with an early onset of multisystemic autoimmune diseases to confirm the diagnosis.

Evaluation of belimumab in treatment of Chinese childhood-onset systemic lupus erythematosus: a prospective analysis from multicenter study.

OBJECTIVE: The aim of this study is to identify whether low lupus disease activity status (LLDAS) and clinical remission (CR) of belimumab plus standard of care (SoC) therapy are achievable goals in childhood-onset SLE (cSLE). METHODS: This multicentre, one arm pre-post intervention study was conducted at 15 centers in China. The primary end point was to describe the proportion of patients who achieved LLDAS and CR after 3, 6, and 12 months after treatment with belimumab plus SoC therapy. A multiple regression model was used to impute missing data. A Poisson regression model was used to calculate the effect of belimumab treatment on the reduced risk of serious diseases and the incidence of new damage. RESULT: 193 (92.2% female) with active cSLE from 15 centers were included. At 3, 6 and 12 months, the proportion of LLDAS (CR) was 12.4% (1.0%), 25.6% (4.5%) and 70.3% (29.7%), respectively. The mean SELENA-SLEDAI score decreased from 11.0 at baseline to 3.7, 2.9 and 1.7 at 3, 6, and 12 months. At baseline, all patients received steroids at a mean (SD) prednisone equivalent dose of 31.0 (18.2) mg/day, which decreased to 19.4 (10.8) mg/day at month 3, 12.6 (7.2) mg/day at month 6 and 6.7 (5.3) mg/day at month 12. The symptoms and immunological indicators were also significantly improved. CONCLUSION: This is the first and largest sample size prospective clinical intervention study of cSLE patients treated with belimumab in China. LLDAS and CR were attainable treat-to-target of belimumab plus SoC therapy in cSLE.

Pelargonidin ameliorates inflammatory response and cartilage degeneration in osteoarthritis via suppressing the NF-κB pathway.

Pelargonidin (PG), a derivative of anthocyanins, has anti-oxidant and anti-inflammatory properties. Herein, the protective effect and the mechanism of PG in counteract the osteoarthritis (OA) progression were needed to further evaluate. In the current study, C57BL/6 mice was induced by destabilization of medial meniscus (DMM) surgery to establish the OA model. Primary chondrocytes were acquired from the knee cartilage of newborn mice. Then, PG was administrated to OA mice and IL-1ß-stimulated chondrocytes to evaluate its protective effects, respectively. Results uncovered that no conspicuous cytotoxic effects were observed when chondrocytes were treated with PG at a concentration lower than 40 µM for 24-72 h. Thus, 10 µM, 20 µM, and 40 µM PG were chosen for subsequent experiments in vitro. Then, we observed that 10, 20, and 40 µM PG reduced the levels of IL-6, TNF-α, COX-2 and iNOS in chondrocytes. In line, PG inhibited the IL-1ß-induced ECM catabolism in chondrocytes, as evidenced by deepening toluidine blue staining, increased expression of Collagen II, and decreased expressions of ADAMTS5 and MMP13. Moreover, PG also reduced the IL-1ß-stimulated p-p65 overexpression and nuclear translocation of p65 in chondrocytes. In vivo, Safranin O/Fast green and HE staining showed that articular cartilage surface morphology was basically smooth and complete after PG treatment for 8 weeks. Similarly, OARSI scores and MMP13 expression were apparently decreased, whereas Aggrecan expression was elevated in PG-treated mice 8 weeks after DMM surgery. In conclusion, PG can effectively ameliorate inflammatory reactions and cartilage degeneration via suppressing the NF-κB pathway, thereby restraining the OA progression.

[Role of CD4+NKG2D+ T cells in the disease activity of juvenile idiopathic arthritis]. / CD4+NKG2D+ Tç»†èƒžåœ¨å¹¼å¹´ç‰¹å‘æ€§å ³èŠ‚ç‚Žç–¾ç— æ´»åŠ¨ä¸­çš„ä½œç”¨.

OBJECTIVES: To study the expression levels of CD4+NKG2D+ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. METHODS: Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4+NKG2D+ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4+NKG2D+ T cells, sMICA and sMICB in the disease activity of JIA. RESULTS: The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4+NKG2D+ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. CONCLUSIONS: The percentage of CD4+NKG2D+ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4+NKG2D+ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.

Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity.

Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.

A spiral cystic fibroma originating from left ventricular fascicular muscle: a case report.

BACKGROUND: In adults, cardiac fibromas are fairly rare, mostly round in shape, and few cases of ventricular fibromas of other morphology have been reported. CASE PRESENTATION: We report a case of a 47-year-old male patient admitted with recurrent nocturnal paroxysmal dyspnea, diagnosed by transthoracic cardiac ultrasound, transesophageal ultrasound, and computed tomography (CT) as a left ventricular occupancy with a spiral shape resembling a conch with a fixed base and a free distal end. CONCLUSION: This case reports a rare but noteworthy morphological features of the adult uncommon ventricular tumor pathological type. Furthermore, the patient had no notable postoperative issues and was followed up on for a year following surgery, with no residual tumors or arrhythmias discovered during the examination.

Coordinated Adsorption and Catalytic Conversion of Polysulfides Enabled by Perovskite Bimetallic Hydroxide Nanocages for Lithium-Sulfur Batteries.

Catalysis is an effective remedy for the fast capacity decay of lithium-sulfur batteries induced by the shuttling of lithium polysulfides (LiPSs), but too strong adsorption ability of many catalysts toward LiPSs increases the risk of catalyst passivation and restricts the diffusion of LiPSs for conversion. Herein, perovskite bimetallic hydroxide (CoSn(OH)6 ) nanocages are prepared, which are further wrapped by reduced graphene oxide (rGO) as the catalytic host for sulfur. Because of the coordinated valence state of Co and Sn and the intrinsic defect of the perovskite structure, such bimetallic hydroxide delivers moderate adsorption ability and enhanced catalytic activity toward LiPS conversion. Coupled with the hollow structure and the wrapped rGO as double physical barriers, the redox reaction kinetics, and sulfur utilization are effectively improved with such a host. The assembled battery delivers a good rate performance with a high capacity of 644 mAh g-1 at 2 C and long stability with a capacity decay of 0.068% per cycle over 600 cycles at 1 C. Even with a higher sulfur loading of 3.2 mg cm-2 and a low electrolyte/sulfur ratio of 5 µL mg-1 , the battery still shows high sulfur utilization and good cycling stability.

Combined 4-1BB and ICOS co-stimulation improves anti-tumor efficacy and persistence of dual anti-CD19/CD20 chimeric antigen receptor T cells.

Chimeric antigen receptor (CAR) T-cell therapy is a promising therapeutic strategy against lymphoma. However, post-treatment relapses due to antigen loss remain a challenge. Here the authors designed a novel bicistronic CAR construct and tested its functions in vitro and in vivo. The CAR construct consisted of individual anti-CD19 and anti-CD20 single-chain fragment variables equipped with ICOS-CD3ζ and 4-1BB-CD3ζ intracellular domains, respectively. The CD19 and CD20 bicistronic CAR T cells exhibited tumor lytic capacities equivalent to corresponding monospecific CAR T cells. Moreover, when stimulated with CD19 and CD20 simultaneously, the bicistronic CAR T cells showed prolonged persistence and enhanced cytokine generation compared with single stimulations. Interestingly, the authors found that the 4-1BB signal was predominant in the signaling profiles of ICOS and 4-1BB doubly activated CAR T cells. In vivo study using a CD19/CD20 double-positive tumor model revealed that the bicistronic CAR T cells were more efficient than monospecific CD19 CAR T cells in eradicating tumors and prolonging mouse survival. The authors' novel bicistronic CD19/CD20 CAR T cells demonstrate improved anti-tumor efficacy in response to dual antigen stimulations. These data provide optimism that this novel bicistronic CAR construct can improve treatment outcomes in patients with relapsed/refractory B cell malignancy.

Density- and moisture-dependent effects of arbuscular mycorrhizal fungus on drought acclimation in wheat.

Arbuscular mycorrhizal fungus (AMF) is widely viewed as an ecosystem engineer to help plants adapt to adverse environments. However, a majority of the previous studies regarding AMF's eco-physiological effects are mutually inconsistent. To clarify this fundamental issue, we conducted an experiment focused on wheat (Triticum aestivum L.) plants with or without AMF (Funneliformis mosseae) inoculation. Two water regimes (80% and 40% field water capacity, FWC80 (CK) and FWC40 (drought stress) and four planting densities (6 or 12 plants per pot as low densities, 24 or 48 plants per pot as high densities) were designed. AMF inoculation did not show significant effects on shoot biomass, grain yield, and water use efficiency (WUE) under the low densities, regardless of water regimes. However, under the high densities, AMF inoculation significantly decreased shoot biomass, grain yield and WUE in FWC80, while it significantly increased these parameters in FWC40, showing density and/or moisture-dependent effects of AMF on wheat performance. In FWC40, the relationships between reproductive biomass (y-axis) vs. vegetative biomass (x-axis) (R-V), and between grain biomass (y-axis, sink) vs. leaf biomass (x-axis, source) fell into a typical allometric pattern (α > 1, P < 0.001), and the AMF inoculation significantly increased the values of α. Yet in FWC80, they were in an isometric pattern (α ≈ 1, P < 0.001) and AMF addition had no significant effects on α. Similarly, AMF did not significantly change the isometric relationship between leaf biomass (i.e., metabolic rate) and shoot biomass (body size) in FWC80, while it significantly decreased the α of allometric relationship between both of them in FWC40 (α > 1, P < 0.001). We therefore, sketched a generalized model of R-V and sink-source relationships as affected by AMF, in which AMF inoculation might enhance the capabilities of sink acquisition and utilization under drought stress, while having no significant effect under the well watered conditions. Our findings demonstrate dual density- and moisture-dependent effects of AMF on plant development and provide new insights into current ecological applications of AMF as an ecosystem engineer.

Retromer associates with the cytoplasmic amino-terminus of polycystin-2.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic human disease, with around 12.5 million people affected worldwide. ADPKD results from mutations in either PKD1 or PKD2, which encode the atypical G-protein coupled receptor polycystin-1 (PC1) and the transient receptor potential channel polycystin-2 (PC2), respectively. Although altered intracellular trafficking of PC1 and PC2 is an underlying feature of ADPKD, the mechanisms which govern vesicular transport of the polycystins through the biosynthetic and endosomal membrane networks remain to be fully elucidated. Here, we describe an interaction between PC2 and retromer, a master controller for the sorting of integral membrane proteins through the endo-lysosomal network. We show that association of PC2 with retromer occurs via a region in the PC2 cytoplasmic amino-terminal domain, independently of the retromer-binding Wiskott-Aldrich syndrome and scar homologue (WASH) complex. Based on observations that retromer preferentially interacts with a trafficking population of PC2, and that ciliary levels of PC1 are reduced upon mutation of key residues required for retromer association in PC2, our data are consistent with the identification of PC2 as a retromer cargo protein.This article has an associated First Person interview with the first author of the paper.

Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin-1 and regulates polycystin-1 trafficking.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder causing renal failure. Mutations of polycystic kidney disease 1 (PKD1) account for most ADPKD cases. Defective ciliary localization of polycystin-1 (PC1), a large integral membrane protein encoded by PKD1, underlies the pathogenesis of a subgroup of patients with ADPKD. However, the mechanisms by which PC1 and other ciliary proteins traffic to the primary cilium remain poorly understood. A ciliary targeting sequence (CTS) that resides in ciliary receptors is considered to function in the process. It has been reported that the VxP motif in the intracellular C-terminal tail of PC1 functions as a CTS in an ADP ribosylation factor 4 (Arf4)/ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1)-dependent manner. However, other recent studies have revealed that this motif is dispensable for PC1 trafficking to cilia. In this study, we identified a novel CTS consisting of 8 residues (RHKVRFEG) in the PC1 C tail. We found that this motif is sufficient to bind protein phosphatase 1 (PP1)α, a ubiquitously expressed phosphatase in the phosphoprotein phosphatase (PPP) family. Mutations in this CTS motif disrupt binding with PP1α and impair ciliary localization of PC1. Additionally, short hairpin RNA-mediated knockdown of PP1α results in reduced ciliary localization of PC1 and elongated cilia, suggesting a role for PP1α in the regulation of ciliary structure and function.-Luo, C., Wu, M., Su, X., Yu, F., Brautigan, D. L., Chen, J., Zhou, J. Protein phosphatase 1α interacts with a novel ciliary targeting sequence of polycystin-1 and regulates polycystin-1 trafficking.

[A rapid identification of authenticity and specifications of Chinese medicine Fritillariae Cirrhosae Bulbus based on E-eye technology].

The quality of traditional Chinese medicine tablets is correlated with clinical efficacy and drug safety, and plays a great role in promoting the development of traditional Chinese medicine. However, the existing traditional artificial identification and modern instrument detection in terms of accuracy and timeliness have both advantages and disadvantages. Therefore, how to quickly and accurately identify the quality of traditional Chinese medicine tablets has become a high-profile issue. The purpose of this paper is to explore the feasibility of the application of electronic eye technology in the study of rapid identification of traditional Chinese medicine quality. A total of 80 batches of samples were collected and tested by Fritillariae Cirrhosae Bulbus for traditional empirical identification(M_1) and modern pharmacopeia(M_2). The optical data was collected from electronic eyes, and the chemical metrology was used to establish suitable discrimination models(M_3). Four authenticity and commodity specification models, namely identification analysis(DA), minimum bidirectional support vector machine(LS-SVM), partial minimum two-multiplier analysis(PLS-DA), main component analysis identification analysis(PCA-DA), were established, respectively. The accuracies of the authenticity identification models were 82.5%, 90.0%, 96.2% and 93.8%, while the accuracies of the commodity specification identification models were 89.3%, 96.0%, 90.7% and 97.3%, respectively. The models were well judged, the authenticity identification was based on the final identification model of PLS-DA, and the commodity specification was based on the final identification model of PCA-DA. There was no significant difference between its accuracy and M_1, and the time of determination was much shorter than M_2(P<0.01). Therefore, electronic-eye technology could be used for the rapid identification of the quality of Fritillariae Cirrhosae Bulbus.

Foxo transcription factors in T cell biology and tumor immunity.

The evolutionally conserved forkhead box O (Foxo) family of transcription factors is pivotal in the control of nutrient sensing and stress responses. Recent studies have revealed that the Foxo proteins have been rewired to regulate highly specialized T cell activities. Here, we review the latest advances in the understanding of how Foxo transcription factors control T cell biology, including T cell trafficking, naive T cell homeostasis, effector and memory responses, as well as the differentiation and function of regulatory T cells. We also discuss the emerging evidence on Foxo-mediated regulation in antitumor immunity. Future work will further explore how the Foxo-dependent programs in T cells can be exploited for cancer immunotherapy.

Disruption of polycystin-L causes hippocampal and thalamocortical hyperexcitability.

Epilepsy or seizure disorder is among the least understood chronic medical conditions affecting over 65 million people worldwide. Here, we show that disruption of the polycystic kidney disease 2-like 1 (Pkd2l1 or Pkdl), encoding polycystin-L (PCL), a non-selective cation channel, increases neuronal excitability and the susceptibility to pentylenetetrazol-induced seizure in mice. PCL interacts with ß2-adrenergic receptor (ß2AR) and co-localizes with ß2AR on the primary cilia of neurons in the brain. Pkdl deficiency leads to the loss of ß2AR on neuronal cilia, which is accompanied with a remarkable reduction in cAMP levels in the central nervous system (CNS). The reduction of cAMP levels is associated with a reduction in the activation of cAMP response element-binding protein, but not the activation of Ca(2+)/calmodulin-dependent protein kinase II, Akt or mitogen-activated protein kinases. Our data, thus, indicate for the first time that a ciliary protein complex is required for the control of neuronal excitability in the CNS.

Novel Foxo1-dependent transcriptional programs control T(reg) cell function.

Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T(reg) cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T(reg) cell function.

Different Biological Characteristics of Macrophages from BALB/c Mice and Severe Combined Immunodeficient Mice.

BACKGROUND: Our previous research has found that absence of lymphocytes during development may affect innate activity of immune cells. To better understand the effect of lymphocyte defects on macrophages during development, we compared the biological characteristics of peritoneal macrophages (PMa) from BALB/c and severe combined immunodeficient (SCID) mice. METHODS: Cytokines such as TNF-α, IL-6, and IL-10 produced by PMa and mRNA of those cytokines of PMa, phagocytosis of chicken red cells by PMa, and cell surface markers of PMa from BALB/c and SCID mice were tested. LPS was used as the stimulator. RESULTS: Compared with PMa from BALB/c mice, PMa from SCID mice produced more TNF-α, IL-6, and less IL10 after LPS stimulation in vitro and exhibited decreased phagocytosis in vivo or in vitro. The MFI of cell surface markers, including TLR4, MHC-II and CD80/CD86, on PMa increased markedly after LPS injection in vivo, but was not significantly different between the two mouse strains. CONCLUSIONS: Lymphocyte defects during development lead to increased inflammatory potential and decreased phagocytosis of PMa. If BALB/c and SCID mice are used as models to compare differences in infections and inflammation, the different biological characteristics of macrophages should be considered.