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Immunotherapy has emerged as a potent and effective treatment for multiple cancer types. For example, the engineering of T cells through the expression of chimeric antigen receptor (CAR) against tumors has shown remarkable potential. This review outlines clinical applications of CAR-T cell therapy in hematological malignancies and solid tumors, with a focus on the main challenges related to the safety and efficacy of the current CAR-T cell therapy and the promising strategies to maximize antitumor efficacy while minimizing adverse events. Finally, we present the future outlook of CAR-T cell therapy for the treatment against malignancies. We believe that potential problems can be overcome by strategies to further facilitate effective clinical translation and improve the efficacy, especially through the combination of different approaches.

Rationale: TCR-T cell therapy plays a critical role in the treatment of malignant cancers. However, it is unclear how TCR-T cells are affected by PD-L1 molecule in the tumor environment. We performed an in-depth evaluation on how differential expressions of tumor PD-L1 can affect the functionality of T cells. Methods: We used MART-1-specific TCR-T cells (TCR-TMART-1), stimulated with MART-127-35 peptide-loaded MEL-526 tumor cells, expressing different proportions of PD-L1, to perform cellular assays and high-throughput single-cell RNA sequencing. Results: Different clusters of activated or cytotoxic TCR-TMART-1 responded divergently when stimulated with tumor cells expressing different percentages of PD-L1 expression. Compared to control T cells, TCR-TMART-1 were more sensitive to exhaustion, and secreted not only pro-inflammatory cytokines but also anti-inflammatory cytokines with increasing proportions of PD-L1+ tumor cells. The gene profiles of chemokines were modified by increased expression of tumor PD-L1, which concurrently downregulated pro-inflammatory and anti-inflammatory transcription factors. Furthermore, increased expression of tumor PD-L1 showed distinct effects on different inhibitory checkpoint molecules (ICMs). In addition, there was a limited correlation between the enrichment of cell death signaling in tumor cells and T cells and increased tumor PD-L1 expression. Conclusion: Overall, though the effector functionality of TCR-T cells was suppressed by increased expression percentages of tumor PD-L1 in vitro, scRNA-seq profiles revealed that both the anti-inflammatory and pro-inflammatory responses were triggered by a higher expression of tumor PD-L1. This suggests that the sole blockade of tumor PD-L1 might inhibit not only the anti-inflammatory response but also the pro-inflammatory response in the complicated tumor microenvironment. Thus, the outcome of PD-L1 intervention may depend on the final balance among the highly dynamic and heterogeneous immune regulatory circuits.

Cancer patients have been treated with various types of therapies, including conventional strategies like chemo‐, radio‐, and targeted therapy, as well as immunotherapy like checkpoint inhibitors, vaccine and cell therapy etc. Among the therapeutic alternatives, T‐cell therapy like CAR‐T (Chimeric Antigen Receptor Engineered T cell) and TCR‐T (T Cell Receptor Engineered T cell), has emerged as the most promising therapeutics due to its impressive clinical efficacy. However, there are many challenges and obstacles, such as immunosuppressive tumor microenvironment, manufacturing complexity, and poor infiltration of engrafted cells, etc still, need to be overcome for further treatment with different forms of cancer. Recently, the antitumor activities of CAR‐T and TCR‐T cells have shown great improvement with the utilization of CRISPR/Cas9 gene editing technology. Thus, the genome editing system could be a powerful genetic tool to use for manipulating T cells and enhancing the efficacy of cell immunotherapy. This review focuses on pros and cons of various gene delivery methods, challenges, and safety issues of CRISPR/Cas9 gene editing application in T‐cell‐based immunotherapy.

Additional file 3: Figure S1. Heatmap of differential expression between the severe and critical groups in our transcriptome (A), proteome (B), lipidome (C), and metabolome (D) results.

Additional file 1: Table S1. Baseline characteristics clinical parameters of recruited COVID-19 patients.

Additional file 4: Figure S2. (A) Heatmap of differential expressed genes (logFC > 1) between Cluster 1 and Cluster 2. Individual effect and sampling day are considered as confounding factors. (B) Soft clustering of longitudinal gene dynamics in six patients containing Cluster 1-to-2 transition (FDR

Additional file 2: Table S2. RBC and Hb characteristics of participants in discovery and validation groups.

As an important pro-inflammatory cytokine, IL-1β exerts its pro-inflammatory function by promoting inflammatory cytokines...

Background: Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, which recently attracts great interest for immune therapeutic development. In this context, in-depth understanding of TNBC immune landscape is highly demanded.Results: Here we report full-length single-cell RNA sequencing results of 9683 tumor-infiltrated immune cells isolated from 14 treatment naïve TNBC tumors, where 22 immune cell subsets, including T cells, macrophages, B cells, and DCs have been characterized. We identify a new T cell subset, CD8+CXCL8+ T cell, which associates with poor survival, and a subset of “pre-exhaustion” T cell cluster, which is predictive of favorable prognosis. A novel immune cell subset comprised of TCR+ macrophages, is found to be widely distributed in TNBC tumors. Further analyses reveal an up-regulation of molecules associated with TCR signaling and cytotoxicity in these immune cells.Conclusions: Altogether, our study provides a valuable resource to understand the immune ecosystem of TNBC. The novel immune cell subsets reported herein might be functionally important in cancer immunity. These data will be helpful for the immunotherapeutic strategy design of this disease.

PD-L1 expression levels in tumors do not consistently predict cancer patients’ response to PD-(L)1 inhibitors. We therefore evaluated how tumor PD-L1 levels affect the anti-PD-(L)1 efficacy and T cell function. We used MART-1-specific TCR-T cells (TCR-TMART-1) stimulated with MART-127-35peptide-loaded MEL-526 tumor cells with different proportions of them expressing PD-L1 to perform cellular assays and high-throughput single-cell RNA sequencing. Compared to control T cells, TCR-TMART-1were more sensitive to exhaustion and secreted lower pro-inflammatory but higher anti-inflammatory cytokines with increasing proportions of PD-L1+tumor cells. The colocalization of T cells and tumor cells in gene clusters correlated negatively with the proportion of PD-L1+tumor cells and positively with immune cell cytotoxicity. Moreover, elevated proportion of PD-L1+tumor cells increased PD-L1 expression and decreased PD-1 expression on T cells and enhanced T cell death. The expression of PD-1 and PD-L1 in T cells and macrophages also correlated positively with COVID-19 severity.

SummarySystem-wide molecular characteristics of COVID-19, especially in those patients without comorbidities, have not been fully investigated. We compared extensive molecular profiles of blood samples from 231 COVID-19 patients, ranging from asymptomatic to critically ill, importantly excluding those with any comorbidities. Amongst the major findings, asymptomatic patients were characterized by highly activated anti-virus interferon, T/natural killer (NK) cell activation, and transcriptional upregulation of inflammatory cytokine mRNAs. However, given very abundant RNA binding proteins (RBPs), these cytokine mRNAs could be effectively destabilized hence preserving normal cytokine levels. In contrast, in critically ill patients, cytokine storm due to RBPs inhibition and tryptophan metabolites accumulation contributed to T/NK cell dysfunction. A machine-learning model was constructed which accurately stratified the COVID-19 severities based on their multi-omics features. Overall, our analysis provides insights into COVID-19 pathogenesis and identifies targets for intervening in treatment.

SUMMARY COVID-19 is a severe infectious disease that is a current global health threat. However, little is known about its hallmarks compared to other infectious diseases. Here, we report the single-cell transcriptional landscape of longitudinally collected peripheral blood mononuclear cells (PBMCs) in both COVID-19 and influenza A virus (IAV)-infected patients. We observed increase of plasma cells in both COVID-19 and IAV patients, and XAF1-, TNF- and FAS-induced T cell apoptosis in COVID-19 patients. Further analyses revealed distinct signaling pathways activated in COVID-19 (STAT1 and IRF3) vs. IAV (STAT3 and NFκB) patients and substantial differences in the expression of key factors. These factors include relatively increase of IL6R and IL6ST expression in COVID-19 patients, but similarly increased IL-6 concentrations compared to IAV patients, supporting the clinical observations of increased pro-inflammatory cytokines in COVID-19 patients. Thus, we provide the landscape of PBMCs and unveil distinct immune response pathways in COVID-19 and IAV patients., Graphical Abstract, Highlights ● We generated a single-cell atlas of PBMCs in both COVID-19 and influenza patients. ● Plasma cells increase significantly in both COVID-19 and influenza patients. ● COVID-19 is featured with XAF1-, TNF- and FAS-induced T cell apoptosis. ● Distinct pathways activate in COVID-19 (STAT1/IRF3) vs. influenza (STAT3/NFκB) patients., COVID-19 and influenza are both respiratory infections with cytokine release syndrome. Zhu et al. use single-cell RNA sequencing of longitudinally collected PBMCs in both patients to reveal distinct immune response landscapes of the two diseases and identify virus-specific cell composition and immune response pathways.

A few animals have been suspected to be intermediate hosts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a large-scale single-cell screening of SARS-CoV-2 target cells on a wide variety of animals is missing. Here, we constructed the single-cell atlas for 11 representative species in pets, livestock, poultry, and wildlife. Notably, the proportion of SARS-CoV-2 target cells in cat was found considerably higher than other species we investigated and SARS-CoV-2 target cells were detected in multiple cell types of domestic pig, implying the necessity to carefully evaluate the risk of cats during the current COVID-19 pandemic and keep pigs under surveillance for the possibility of becoming intermediate hosts in future coronavirus outbreak. Furthermore, we screened the expression patterns of receptors for 144 viruses, resulting in a comprehensive atlas of virus target cells. Taken together, our work provides a novel and fundamental strategy to screen virus target cells and susceptible species, based on single-cell transcriptomes we generated for domesticated animals and wildlife, which could function as a valuable resource for controlling current pandemics and serve as an early warning system for coping with future infectious disease threats.

Of the ~80 putative toxin‐antitoxin (TA) modules encoded by the bacterial pathogen Mycobacterium tuberculosis (Mtb), three contain antitoxins essential for bacterial viability. One of these, Rv0060 (DNA ADP‐ribosyl glycohydrolase, DarGMtb), functions along with its cognate toxin Rv0059 (DNA ADP‐ribosyl transferase, DarTMtb), to mediate reversible DNA ADP‐ribosylation (Jankevicius et al., 2016). We demonstrate that DarTMtb‐DarGMtb form a functional TA pair and essentiality of darGMtb is dependent on the presence of darTMtb, but simultaneous deletion of both darTMtb‐darGMtb does not alter viability of Mtb in vitro or in mice. The antitoxin, DarGMtb, forms a cytosolic complex with DNA‐repair proteins that assembles independently of either DarTMtb or interaction with DNA. Depletion of DarGMtb alone is bactericidal, a phenotype that is rescued by expression of an orthologous antitoxin, DarGTaq, from Thermus aquaticus. Partial depletion of DarGMtb triggers a DNA‐damage response and sensitizes Mtb to drugs targeting DNA metabolism and respiration. Induction of the DNA‐damage response is essential for Mtb to survive partial DarGMtb‐depletion and leads to a hypermutable phenotype., DarT and DarG form a toxin‐antitoxin pair in M. tuberculosis. In the absence of DarG, the toxin ADP‐ribosylates DNA leading to cell death. In the presence of DarG, DarG binds to and neutralizes the toxin, and plausibly also recruits DNA repair machinery to remove the ADP‐ribosyl moiety and repair the DNA.

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis. Electronic supplementary material The online version of this article (10.1007/s13238-018-0505-z) contains supplementary material, which is available to authorized users.

Adoptive cell transfer of T-cell receptor (TCR)-engineered T cells has emerged as a powerful and potentially curative therapy for cancers and infectious diseases. However, how to rapidly identify and obtain therapeutic TCRs remains a major challenge in this field. Here, we simultaneously performed deep single-cell RNA and TCR V(D)J sequencing on 879 single T cells from in vitro stimulated CMV pp65NLV-specific CD8+ T cells. The correlation analysis of single-cell transcriptome and TCR V(D)J sequences revealed a differential distribution of T cell transcriptomic profiles among TCR clones. Two distinct cell types were identified in the T cell population. TYPE I T cell subtype, which represents the gene signatures of T cell activation and cytotoxicity, mainly includes TCR clone 1, 2 & 4, while TYPE II subtype, which represents the gene signatures of naïve status, mainly includes TCR clone 3 and other low frequency clones. Based on their temporal phases of T cell activation, the selected TCR sequences from clone 1 (TCRZWX1) and clone 3 (TCRZWX3) were functionally validated by constructing TCR-engineered T cells in vitro. The two clones showed distinct cell stages corresponding to their transcriptome patterns. TCRZWX1 transgenic T cells displayed effector functions including secretion of pro-inflammatory cytokines, IFN-γ and TNF-α, and cytotoxicity in response to CMV pp65NLV peptide. However, TCRZWX3 transgenic T cells displayed non-detectable levels of IFN-γ, which might correlate with a low affinity TCR. Our results provide a novel approach using correlative analysis of the single-cell transcriptome and TCR V(D)J sequences for rapidly identifying potential therapeutic TCRs for T cell therapy. Citation Format: Linnan Zhu, Fei Wang, Qumiao Xu, Hai-Xi Sun, Ziyi Li, Yanling Liang, Zhenkun Zhuang, Ying Gu, Cheng-chi Chao. Rapid generation of TCR-engineered T lymphocytes by linking the single cell transcriptome to its corresponding T cell receptor in antigen specific T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6600.

T cell function can be compromised when continuously exposed to tumor antigens by immune checkpoint signaling. Immunotherapies with T cells and inhibitors of repressive checkpoint molecules such as PD-1, CTLA-4, etc. have been shown promising results in cancer clinical trials. Inhibitors of checkpoint molecules have been solely used to block or suppress the corresponding pathways to improve the functionality of T cells and enhance the anti-tumor immunity. However, few reports combined disruption of repressive checkpoint molecules with TCR-T cell therapy for the treatment of cancer patients. In our study, new TCR sequence was attained from T cells stimulated by Melan-A (aa27-35) peptide, but the cytotoxicity of MART-1-specific TCR-T cells was found to be inhibited by expression of PD-L1 in target cells. To overcome this PD(L)-1-mediated suppression, Cas9 mRNA and gRNA were electroporated into primary T cells infected by MART-1 TCR lentivirus. CRISPR/Cas9-mediated PD-1 disruption in MART-1 TCR-T cells recovered T cell cytotoxicity inhibited by PD-L1 overexpression in target cells. In addition, secretion of IFNγ and IL-2 was also increased in PD-1-damaged TCR-T cells. Furthermore, the differences between wild-type and PD-1-disrupted TCR-T cells were characterized by single-cell RNA (scRNA) sequencing. In summary, our study illustrates enhanced therapeutic efficacy and different features of PD-1-eliminated TCR-T cells compared to the control, providing an alternative strategy for current cell therapy. Citation Format: Qianqian Gao, Renpeng Ding, Huanyi Chen, Qumiao Xu, Linnan Zhu, Xuan Dong, Ying Gu, Cheng-chi Chao. Enhancing anti-tumor efficacy of MART-1-specific TCR-T cells by CRISPR-Cas9-based PD-1 disruption [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2204.

Neutrophils are involved in the pathogenesis of allergy. However, the contribution of the different functionally polarized neutrophils in allergy needs to be clarified. We sought to define the characteristics of interleukin (IL)-33-induced neutrophils and the involvement of this subset of polarized neutrophils in allergic pathogenesis. Freshly isolated neutrophils were treated with different cytokines and the cytokine expression levels were detected by real-time PCR. The gene expression profile of IL-33-induced neutrophils was determined by microarray assay. Adoptive transfer assay was used to investigate the function of IL-33-induced neutrophils in an ovalbumin (OVA)-induced allergic asthma model. IL-33-treated neutrophils selectively produced IL-4, IL-5, IL-9 and IL-13 (referred as to N(IL-33) cells) and displayed a distinctive gene expression profile in sharp contrast to resting and lipopolysaccharide (LPS)-treated neutrophils. IL-33-induced neutrophils expressed high Levels of IL-1R2 on cell surface, whereas resting and LPS-treated neutrophils did not, indicating IL-1R2 might be used as a biomarker for N(IL-33) cells. Importantly, N(IL-33) neutrophils exist in the lungs of OVA-induced allergic asthma mice. Adoptive transfer of N(IL-33) neutrophils significantly promotes the severity of the lung pathogenesis in this model. IL-33 induces neutrophil polarization through c-Jun N-terminal kinase- and nuclear factor-κB-dependent pathways. A previously unappreciated neutrophil polarization driven by IL-33 with unique cell surface markers and cytokine/chemokine-producing gene profile was defined. The newly identified N(IL-33) subpopulation may have significant contribution to IL-33-related pathogenesis.

Molecular mechanisms of microgravity-caused immunosuppression are not fully elucidated. In the present study, we investigated the effects of simulated microgravity on macrophage functions and tried to identify the related intracellular signal pathways.Primary mouse macrophages were used in the present study. The gene expression and function of IL-4-treated mouse macrophages were detected after simulated microgravity or 1 g control.Freshly isolated primary mouse macrophages were cultured in a standard simulated microgravity situation using a rotary cell culture system (RCCS-1) and 1 g control conditions. Real-time PCR, western blots and flow cytometry were used to investigate the related intracellular signals and molecule expression.The arginase mRNA and protein levels in freshly isolated primary mouse macrophages under simulated microgravity using RCCS-1 were significantly higher than those under normal gravity. Meanwhile, simulated microgravity induced over-expression of C/EBPβ, a transcription factor of arginase promoter, and activation of p38 MAPK, which could increase C/EBPβ expression. Furthermore, up-regulation of Interleukin-6 (IL-6) and down-regulation of IL-12 p40 (IL-12B) in LPS-stimulated macrophages were also detected after simulated microgravity, which is regulated by C/EBPβ.Simulated microgravity activates a p38 MAPK-C/EBPβ pathway in macrophages to up-regulate arginase and IL-6 expression and down-regulate IL-12B expression. Both increased arginase expression and decreased IL-12B expression in macrophages during inflammation could result in immunosuppression under microgravity.

Macrophages are a functionally heterogeneous cell population that is mainly shaped by a variety of microenvironmental stimuli. Interferon γ (IFN-γ), interleukin-1β (IL-1β), and lipopolysaccharide (LPS) induce a classical activation of macrophages (M1), whereas IL-4 and IL-13 induce an alternative activation program in macrophages (M2). Reprogramming of intracellular metabolisms is required for the proper polarization and functions of activated macrophages. Similar to the Warburg effect observed in tumor cells, M1 macrophages increase glucose consumption and lactate release and decreased oxygen consumption rate. In comparison, M2 macrophages mainly employ oxidative glucose metabolism pathways. In addition, fatty acids, vitamins, and iron metabolisms are also related to macrophage polarization. However, detailed metabolic pathways involved in macrophages have remained elusive. Understanding the bidirectional interactions between cellular metabolism and macrophage functions in physiological and pathological situations and the regulatory pathways involved may offer novel therapies for macrophage-associated diseases.

Microgravity environments in space can cause major abnormalities in human physiology, including decreased immunity. The underlying mechanisms of microgravity-induced inflammatory defects in macrophages are unclear.RAW264.7 cells and primary mouse macrophages were used in the present study. Lipopolysaccharide (LPS)-induced cytokine expression in mouse macrophages was detected under either simulated microgravity or 1g control.Freshly isolated primary mouse macrophages and RAW264.7 cells were cultured in a standard simulated microgravity situation using a rotary cell culture system (RCCS-1) and 1g control conditions. The cytokine expression was determined by real-time PCR and ELISA assays. Western blots were used to investigate the related intracellular signals.LPS-induced tumor necrosis factor-α (TNF-α) expression, but not interleukin-1β expression, in mouse macrophages was significantly suppressed under simulated microgravity. The molecular mechanism studies showed that LPS-induced intracellular signal transduction including phosphorylation of IKK and JNK and nuclear translocation of NF-κB in macrophages was identical under normal gravity and simulated microgravity. Furthermore, TNF-α mRNA stability did not decrease under simulated microgravity. Finally, we found that heat shock factor-1 (HSF1), a known repressor of TNF-α promoter, was markedly activated under simulated microgravity.Short-term treatment with microgravity caused significantly decreased TNF-α production. Microgravity-activated HSF1 may contribute to the decreased TNF-α expression in macrophages directly caused by microgravity, while the LPS-induced NF-κB pathway is resistant to microgravity.

Objective The protease HTRA-1 is closely associated with rheumatoid arthritis (RA). The molecular mechanisms that control HTRA-1 expression are currently unknown. This study was undertaken to determine the regulatory role of Toll-like receptors (TLRs) on HTRA-1 expression in mice with collagen-induced arthritis (CIA) and in synovial cells from RA patients. Methods HTRA-1 messenger RNA and protein production in mouse fibroblasts, mouse macrophages, and freshly isolated RA patient synovial cells treated with TLR ligands were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Arthritis incidence and severity were determined using clinical scores and histopathologic analysis. Involvement of HTRA-1 in lipopolysaccharide (LPS)–increased arthritis incidence and severity in mice was determined using anti–HTRA-1 monoclonal antibody. The signal pathways involved in HTRA-1 expression were accessed by specific inhibitors, RNA interference, dual-luciferase reporter, and chromatin immunoprecipitation methods. Results LPS and tenascin-C, but not the other TLR ligands tested, strongly induced HTRA-1 expression. LPS significantly increased HTRA-1 expression in the joint tissue as well as arthritis incidence and severity in mice with CIA. Blocking HTRA-1 by antibody significantly decreased LPS-promoted CIA severity. Inhibiting NF-κB significantly decreased LPS-induced HTRA-1 expression in mouse and human cells. Dual-luciferase reporter assay and ChIP analysis showed that p65 directly binds to HTRA-1 promoter (amino acid 347). Conclusion Our findings indicate that TLR-4 activation increases HTRA-1 expression through the NF-κB pathway in fibroblasts and macrophages. HTRA-1 expression is involved in the enhancing effects of LPS on CIA. This study offers new insights into the regulation of HTRA-1 expression via LPS/TLR-4 and the role of HTRA-1 in RA pathogenesis.

Neutrophils are heterogeneous with distinct subsets, and can switch phenotypes to exert regulatory functions on immunity. We herein demonstrate that IL-23-treated neutrophils selectively produce IL-17A, IL-17F and IL-22, and display a distinct gene expression profile in contrast to resting and lipopolysaccharide-treated neutrophils. IL-17(+) neutrophils are present in the colons of mice with dextran sulfate sodium-induced colitis. Adoptive transfer of IL-23-treated neutrophils significantly promotes pathogenesis in this model. IL-23 induces neutrophil polarization through STAT3-dependent RORγt and BATF pathways. Thus, IL-23-induced neutrophil polarization expresses a unique cytokine-producing profile, which may contribute to IL-23-mediated inflammatory diseases.

This paper proposes a lightweight deep model to recognize age and gender from a face image. Though simple, our network architecture is able to complete the two tasks effectively and efficiently. Moreover, different from existing methods, we simultaneously perform the age and gender recognition tasks via a joint regression model. Specifically, our model employs a multi-task learning scheme to learn shared features for these two correlated tasks in an end-to-end manner. Extensive experimental results on the recent Adience benchmark demonstrate that our model achieves competitive recognition accuracy with the state-of-the-art methods but with much faster speed, i.e., about 10 times faster in the testing phase. Our model can be easily adopted and extended to other facial applications.

The understanding that mankind should reasonably exploit and utilize earth resources and effectively protect the planet on which we live, is now widely accepted. However, effective actions can only be conducted if we better understand and visualize the earth. To meet this need, digital earth science and technology have been put forward and developed. This paper introduces the evolution and development process of digital earth, and presents an overview by reviewing and analyzing the 1999 and 2009 Beijing Declaration on Digital Earth, the scientific and commercial digital earth systems, global and regional digital earth research, and some existing platforms of digital earth science. It also presents some thoughts about digital earth's future development.

The interaction between the nervous and immune systems during aging is an area of avid interest, but many aspects remain unclear. This is due, not only to the complexity of the aging process, but also to a mutual dependency and reciprocal causation of alterations and diseases between both the nervous and immune systems. Aging of the brain drives whole body systemic aging, including aging-related changes of the immune system. In turn, the immune system aging, particularly immunosenescence and T cell aging initiated by thymic involution that are sources of chronic inflammation in the elderly (termed inflammaging), potentially induces brain aging and memory loss in a reciprocal manner. Therefore, immunotherapeutics including modulation of inflammation, vaccination, cellular immune therapies and "protective autoimmunity" provide promising approaches to rejuvenate neuroinflammatory disorders and repair brain injury. In this review, we summarize recent discoveries linking the aging immune system with the development of neurodegeneration. Additionally, we discuss potential rejuvenation strategies, focusing aimed at targeting the aging immune system in an effort to prevent acute brain injury and chronic neurodegeneration during aging.

The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR), which serves as a key regulator of inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Previous studies have shown that TSC1 knockout (KO) macrophages produced increased inflammatory responses including tumor necrosis factor-α (TNF-α) and IL-12 to pro-inflammatory stimuli, but whether and how TSC1 regulates pro-IL-1β expression remains unclear. Here using a mouse model in which myeloid lineage-specific deletion of TSC1 leads to constitutive mTORC1 activation, we found that TSC1 deficiency resulted in impaired expression of pro-IL-1β in macrophages following lipopolysaccharide stimulation. Such decreased pro-IL-1β expression in TSC1 KO macrophages was rescued by reducing mTORC1 activity with rapamycin or deletion of mTOR. Rictor deficiency has no detectable effect on pro-IL-1β synthesis, suggesting that TSC1 positively controls pro-IL-1β expression through mTORC1 pathway. Moreover, mechanism studies suggest that mTORC1-mediated downregulation of the CCAAT enhancer-binding protein (C/EBPβ) critically contributes to the defective pro-IL-1β expression. Overall, these findings highlight a critical role of TSC1 in regulating innate immunity by control of the mTOR1-C/EBPβ pathway.

Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses, but the mechanisms that regulate the macrophage polarization are poorly defined. Here we show that tuberous sclerosis complex 1 (TSC1) is a critical regulator of M1 and M2 phenotypes of macrophages. Mice with myeloid-specific deletion of TSC1 exhibit enhanced M1 response and spontaneously develop M1-related inflammatory disorders. However, TSC1-deficient mice are highly resistant to M2-polarized allergic asthma. Inhibition of the mammalian target of rapamycin (mTOR) fails to reverse the hypersensitive M1 response of TSC1-deficient macrophages, but efficiently rescues the defective M2 polarization. Deletion of mTOR also fails to reverse the enhanced inflammatory response of TSC1-deficient macrophages. Molecular studies indicate that TSC1 inhibits M1 polarization by suppressing the Ras GTPase-Raf1-MEK-ERK pathway in mTOR-independent manner, whereas TSC1 promotes M2 properties by mTOR-dependent CCAAT/enhancer-binding protein-β pathways. Overall, these findings define a key role for TSC1 in orchestrating macrophage polarization via mTOR-dependent and independent pathways.

The high temperature requirement A1 (HTRA1) is a potent protease involved in many diseases, including rheumatoid arthritis (RA). However, the regulatory mechanisms that control HTRA1 expression need to be determined. In this study, we demonstrated that IFN-γ significantly inhibited the basal and LPS-induced HTRA1 expression in fibroblasts and macrophages, which are two major cells for HTRA1 production in RA. Importantly, the inhibitory effect of IFN-γ on HTRA1 expression was evidenced in collagen-induced arthritis (CIA) mouse models and in human RA synovial cells. In parallel with the enhanced CIA incidence and pathological changes in IFN-γ–deficient mice, HTRA1 expression in the joint tissues was also increased as determined by real-time PCR and Western blots. IFN-γ deficiency increased the incidence of CIA and the pathological severity in mice. Neutralization of HTRA1 by Ab significantly reversed the enhanced CIA frequency and severity in IFN-γ–deficient mice. Mechanistically, IFN-γ negatively controls HTRA1 expression through activation of p38 MAPK/STAT1 pathway. Dual luciferase reporter assay and chromatin immunoprecipitation analysis showed that STAT1 could directly bind to HTRA1 promoter after IFN-γ stimulation. This study offers new insights into the molecular regulation of HTRA1 expression and its role in RA pathogenesis, which may have significant impact on clinical therapy for RA and possibly other HTRA1-related diseases, including osteoarthritis, age-related macular degeneration, and cancer.

Cell metabolism is closely related to the host immunity in many respects. We herein briefly summarized the recent progress on the roles of cellular metabolism in T-cell development, homeostasis, differentiation and functions. Relatively quiescent naive T cells only require energy for survival and migration, and they mainly metabolize glucose to carbon dioxide through oxidative phosphorylation. However, activated T cells engage in robust cell proliferation, produce of a range of effector molecules and migrate through peripheral tissues, so they utilizes glycolysis to convert glucose to lactate (termed aerobic glycolysis) to meet the significantly increased metabolic demands. Importantly, the differentiation of T-cell subsets and memory T cells (Tm) was also significantly shaped by distinct cellular metabolic pathways including glucose, amino acids (AA), fatty acids (FA), and others. Understanding the regulatory metabolic networks on immunity may offer new insights into the immune-related disorders and open novel potential therapies to prevent and treat immune diseases.

In this paper, in order to determine the initial stresses of tunnels in cold regions before earthquake occurs, a mathematical mechanical model and the governing differential equations of the coupled problem of temperature, seepage and stress fields, with phase change, are first derived from the theory of heat transfer, the theory of seepage and frozen soil mechanics. Then, the finite element formulae of this problem are obtained from Galerkin's method. Secondly, the visco-plastic constitutive equations of frozen soil for dynamic computation are given. Finally, an illustrative example is provided. The example shows that the effect of seepage field and stress field on the frozen depth of cold region tunnels is large and the influence of frost-heaving force on the stresses of the tunnel lining is very large. This example also indicates that the influence of initial stresses of tunnels in cold regions on the time stress response of tunnels to earthquake is large. So the effects of these factors on the tunnel lining should be taken into account in cold regions engineering design.