c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells.

The c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc's targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature.

Calcium and energy: making the cake and eating it too?

Mitochondrial calcium ions promote a number of events that sustain ATP levels in the cell. Cardenas et al. (2010) now demonstrate that the inositol 1,4,5-triphosphate receptor at the endoplasmic reticulum constitutively provides calcium for mitochondria. In the absence of this calcium transfer, cells use autophagy to sustain survival.

Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy.

Tumor immunotherapy has emerged as an efficacious therapeutic approach that mobilizes the patient's immune system to achieve durable tumor suppression. Here, we design a photodynamic therapy-motivated nanovaccine (Dex-HDL/ALA-Fe3O4) co-delivering 5-aminolevulinic acid and Fe3O4 nanozyme that demonstrate a long-term durable immunotherapy strategy. After vaccination, the nanovaccine exhibits obvious tumor site accumulation, lymph node homing, and specific and memory antitumor immunity evocation. Upon laser irradiation, Dex-HDL/ALA-Fe3O4 effectively generates reactive oxygen species at the tumor site not only to induce the immunogenic cell death-cascade but also to trigger the on-demand release of full types of tumor antigens. Intriguingly, Fe3O4 nanozyme-catalyzed hydrogen peroxide generated oxygen for alleviating tumor hypoxia and modifying the inhibitory tumor microenvironment, thereby exhibiting remarkable potential as a sensitizer. The intravenous administration of nanovaccines in diverse preclinical cancer models has demonstrated remarkable tumor regression and inhibition of postoperative tumor recurrence and metastasis, thereby enabling personalized treatment strategies against highly heterogeneous tumors.

Unconventional Activation of IRE1 Enhances Th17 Responses and Promotes Airway Neutrophilia.

Heightened unfolded protein responses (UPRs) are associated with the risk for asthma, including severe asthma. Treatment-refractory severe asthma manifests a neutrophilic phenotype with T helper (Th)17 responses. However, how UPRs participate in the deregulation of Th17 cells leading to neutrophilic asthma remains elusive. This study found that the UPR sensor IRE1 is induced in the murine lung with fungal asthma and is highly expressed in Th17 cells relative to naive CD4+ T cells. Cytokine (e.g., IL-23) signals induce the IRE1-XBP1s axis in a JAK2-dependent manner. This noncanonical activation of the IRE1-XBP1s pathway promotes UPRs and cytokine secretion by both human and mouse Th17 cells. Ern1 (encoding IRE1) deficiency decreases the expression of endoplasmic reticulum stress factors and impairs the differentiation and cytokine secretion of Th17 cells. Genetic ablation of Ern1 leads to alleviated Th17 responses and airway neutrophilia in a fungal airway inflammation model. Consistently, IL-23 activates the JAK2-IRE1-XBP1s pathway in vivo and enhances Th17 responses and neutrophilic infiltration into the airway. Taken together, our data indicate that IRE1, noncanonically activated by cytokine signals, promotes neutrophilic airway inflammation through the UPR-mediated secretory function of Th17 cells. The findings provide a novel insight into the fundamental understanding of IRE1 in Th17-biased TH2-low asthma.

Metabolic checkpoints in activated T cells.

The immunological process of clonal selection requires a rapid burst in lymphocyte proliferation, and this involves a metabolic shift to provide energy and the building blocks of new cells. After activation, naive and memory T cells switch from the oxidation of free fatty acids to glycolysis and glutaminolysis to meet these demands. Beyond this, however, the availability of specific metabolites and the pathways that process them interconnect with signaling events in the cell to influence cell cycle, differentiation, cell death and immunological function. Here we define 'metabolic checkpoints' that represent such interconnections and provide examples of how these checkpoints sense metabolic status and transduce signals to affect T lymphocyte responses.

Tumor Metabolism: A New Field for the Treatment of Glioma.

The clinical treatment of glioma remains relatively immature. Commonly used clinical treatments for gliomas are surgery combined with chemotherapy and radiotherapy, but there is a problem of drug resistance. In addition, immunotherapy and targeted therapies also suffer from the problem of immune evasion. The advent of metabolic therapy holds immense potential for advancing more efficacious and tolerable therapies against this aggressive disease. Metabolic therapy alters the metabolic processes of tumor cells at the molecular level to inhibit tumor growth and spread, and lead to better outcomes for patients with glioma that are insensitive to conventional treatments. Moreover, compared with conventional therapy, it has less impact on normal cells, less toxicity and side effects, and higher safety. The objective of this review is to examine the changes in metabolic characteristics throughout the development of glioma, enumerate the current methodologies employed for studying tumor metabolism, and highlight the metabolic reprogramming pathways of glioma along with their potential molecular mechanisms. Importantly, it seeks to elucidate potential metabolic targets for glioblastoma (GBM) therapy and summarize effective combination treatment strategies based on various studies.

Novel Corrugated Long Period Grating Surface Balloon-Shaped Heterocore-Structured Plastic Optical Fibre Sensor for Microalgal Bioethanol Production.

A novel long period grating (LPG) inscribed balloon-shaped heterocore-structured plastic optical fibre (POF) sensor is described and experimentally demonstrated for real-time measurement of the ultra-low concentrations of ethanol in microalgal bioethanol production applications. The heterocore structure is established by coupling a 250 µm core diameter POF between two 1000 µm diameter POFs, thus representing a large core-small core-large core configuration. Before coupling as a heterocore structure, the sensing region or small core fibre (SCF; i.e., 250 µm POF) is modified by polishing, LPG inscription, and macro bending into a balloon shape to enhance the sensitivity of the sensor. The sensor was characterized for ethanol-water solutions in the ethanol concentration ranges of 20 to 80 %v/v, 1 to 10 %v/v, 0.1 to 1 %v/v, and 0.00633 to 0.0633 %v/v demonstrating a maximum sensitivity of 3 × 106 %/RIU, a resolution of 7.9 × 10-6 RIU, and a limit of detection (LOD) of 9.7 × 10-6 RIU. The experimental results are included for the intended application of bioethanol production using microalgae. The characterization was performed in the ultra-low-level ethanol concentration range, i.e., 0.00633 to 0.03165 %v/v, that is present in real culturing and production conditions, e.g., ethanol-producing blue-green microalgae mixtures. The sensor demonstrated a maximum sensitivity of 210,632.8 %T/%v/v (or 5 × 106 %/RIU as referenced from the RI values of ethanol-water solutions), resolution of 2 × 10-4%v/v (or 9.4 × 10-6 RIU), and LOD of 4.9 × 10-4%v/v (or 2.3 × 10-5 RIU). Additionally, the response and recovery times of the sensor were investigated in the case of measurement in the air and the ethanol-microalgae mixtures. The experimentally verified, extremely high sensitivity and resolution and very low LOD corresponding to the initial rate of bioethanol production using microalgae of this sensor design, combined with ease of fabrication, low cost, and wide measurement range, makes it a promising candidate to be incorporated into the bioethanol production industry as a real-time sensing solution as well as in other ethanol sensing and/or RI sensing applications.

Dynamic metabolic reprogramming in dendritic cells: An early response to influenza infection that is essential for effector function.

Infection with the influenza virus triggers an innate immune response that initiates the adaptive response to halt viral replication and spread. However, the metabolic response fueling the molecular mechanisms underlying changes in innate immune cell homeostasis remain undefined. Although influenza increases parasitized cell metabolism, it does not productively replicate in dendritic cells. To dissect these mechanisms, we compared the metabolism of dendritic cells to that of those infected with active and inactive influenza A virus and those treated with toll-like receptor agonists. Using quantitative mass spectrometry, pulse chase substrate utilization assays and metabolic flux measurements, we found global metabolic changes in dendritic cells 17 hours post infection, including significant changes in carbon commitment via glycolysis and glutaminolysis, as well as mitochondrial respiration. Influenza infection of dendritic cells led to a metabolic phenotype distinct from that induced by TLR agonists, with significant resilience in terms of metabolic plasticity. We identified c-Myc as one transcription factor modulating this response. Restriction of c-Myc activity or mitochondrial substrates significantly changed the immune functions of dendritic cells, such as reducing motility and T cell activation. Transcriptome analysis of inflammatory dendritic cells isolated following influenza infection showed similar metabolic reprogramming occurs in vivo. Thus, early in the infection process, dendritic cells respond with global metabolic restructuring, that is present in inflammatory lung dendritic cells after infection, and this is important for effector function. These findings suggest metabolic switching in dendritic cells plays a vital role in initiating the immune response to influenza infection.

Direct femtosecond laser inscription of Bragg gratings in Ho3+/Pr3+ co-doped AlF3-based glass fibers for a 2.86†µm laser.

In this Letter, we report the fabrication of fiber Bragg gratings (FBGs) in home-made Ho3+/Pr3+ co-doped single-cladding fluoroaluminate (AlF3) glass fibers and its application in watt-level lasing at the mid-infrared (MIR) wavelength of 2.86 µm. The FBGs were inscribed using an 800 nm femtosecond (fs) laser direct-writing technique. The FBG properties were investigated for different pulse energies, inscription speeds, grating orders, and transversal lengths. A second-order FBG with a high reflectivity of 99% was obtained at one end of a 16.5-cm-long gain fiber. Under 1150 nm laser pumping, this fiber yielded a power exceeding 1 W at 2863.9 nm with an overall laser efficiency of 17.7%. The fiber laser showed a FWHM bandwidth of 0.46 nm and long-term spectral stability.

Metabolic maintenance of cell asymmetry following division in activated T lymphocytes.

Asymmetric cell division, the partitioning of cellular components in response to polarizing cues during mitosis, has roles in differentiation and development. It is important for the self-renewal of fertilized zygotes in Caenorhabditis elegans and neuroblasts in Drosophila, and in the development of mammalian nervous and digestive systems. T lymphocytes, upon activation by antigen-presenting cells (APCs), can undergo asymmetric cell division, wherein the daughter cell proximal to the APC is more likely to differentiate into an effector-like T cell and the distal daughter is more likely to differentiate into a memory-like T cell. Upon activation and before cell division, expression of the transcription factor c-Myc drives metabolic reprogramming, necessary for the subsequent proliferative burst. Here we find that during the first division of an activated T cell in mice, c-Myc can sort asymmetrically. Asymmetric distribution of amino acid transporters, amino acid content, and activity of mammalian target of rapamycin complex 1 (mTORC1) is correlated with c-Myc expression, and both amino acids and mTORC1 activity sustain the differences in c-Myc expression in one daughter cell compared to the other. Asymmetric c-Myc levels in daughter T cells affect proliferation, metabolism, and differentiation, and these effects are altered by experimental manipulation of mTORC1 activity or c-Myc expression. Therefore, metabolic signalling pathways cooperate with transcription programs to maintain differential cell fates following asymmetric T-cell division.

CT, MRI, and 18F-FDG PET/CT imaging features of seven cases of adult pancreatoblastoma.

OBJECTIVE: This study mainly analysed the imaging data for seven cases of adult pancreatoblastoma (PB) and summarized additional imaging features of this disease based on a literature review, aiming to improve the understanding and diagnosis rate of this disease. MATERIALS AND METHODS: The imaging data for seven adult patients pathologically diagnosed with adult PB were retrospectively analysed. Among the seven patients, six underwent computed tomography (CT) scans, two patients underwent abdominal magnetic resonance imaging (MRI), and five patients underwent 18F-FDG PET/CT. RESULTS: The tumours were located in the head of the pancreas in three cases, in the tail of the pancreas in two cases, and in the gastric antrum and neck of the pancreas in one case. Six tumours showed blurred edges, and an incomplete envelope was observed in only two cases when enhanced, which showed extruded growth and cyst-solid masses; one tumour was a solid mass with ossification. Showing mild or significant enhancement in the arterial phase (AP) for six cases. In the MRI sequence, isointensity was found on suppressed T1-weighted imaging, and hyperintensity was noted on suppressed T2-weighted imaging in two cases, with significant enhancement. Pancreatic duct dilatation was found in four cases. Tumour 18F-FDG PET/CT imaging exhibited high uptake in five cases. CONCLUSION: Adult PB involves a single tumour and commonly manifests as cystic-solid masses with blurred edges. Capsules are rare, ossification is an important feature, tumours can also present in ectopic pancreatic tissues, with mild or strengthening in the AP, and 18F-FDG uptake is high. These features are relatively specific characteristics in adult PB.

A Review of Optical Fibre Ethanol Sensors: Current State and Future Prospects.

A range of optical fibre-based sensors for the measurement of ethanol, primarily in aqueous solution, have been developed and are reviewed here. The sensing approaches can be classified into four groups according to the measurement techniques used, namely absorption (or absorbance), external interferometric, internal fibre grating and plasmonic sensing. The sensors within these groupings can be compared in terms of their characteristic performance indicators, which include sensitivity, resolution and measurement range. Here, particular attention is paid to the potential application areas of these sensors as ethanol production is globally viewed as an important industrial activity. Potential industrial applications are highlighted in the context of the emergence of the internet of things (IoT), which is driving widespread utilization of these sensors in the commercially significant industrial and medical sectors. The review concludes with a summary of the current status and future prospects of optical fibre ethanol sensors for industrial use.

Ultra-compact in-core-parallel-written FBG and Mach-Zehnder interferometer for simultaneous measurement of strain and temperature.

An ultra-compact in-core-parallel-written fiber Bragg grating (FBG) and Mach-Zehnder interferometer (MZI) for simultaneous measurement of strain and temperature is described. The FBG and MZI are written spatially parallel in the same section of fiber core using a femtosecond laser, forming an ultra-compact device, which is different from the previously developed axial cascade of different structures. Due to the weak coupling between the FBG and the MZI, their individual extinction ratios are traded off by optimizing their writing position and separation, and extinction ratios of 5.9 dB for the FBG and 10 dB for the MZI are achieved. Experimental results show that the FBG and MZI have different sensitivities for strain and temperature, allowing this device to measure strain and temperature simultaneously. In addition, since both the FBG and MZI are written in the fiber core, this ultra-compact device is proven to be impervious to ambient humidity, making it a promising candidate for accurate industrial strain and temperature measurements.

CD4+CD126low/- Foxp3+ Cell Population Represents a Superior Subset of Regulatory T Cells in Treating Autoimmune Diseases.

CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining homeostasis and preventing autoimmune diseases. Nonetheless, we and others have previously reported that natural Treg cells are unstable and dysfunctional in the inflamed environment with a high-salt diet, limiting the Treg function in disease control. In this study, we made an innovative observation showing a high degree of heterogeneity within the Treg pool. We identified that CD126, interleukin (IL)-6 receptor alpha chain, contributed to Treg cell instability. Using a series of in vitro and in vivo experimental approaches, we demonstrated that CD126Lo/- Treg cells presented greater function and were more stable than CD126Hi nTreg cells, even in the presence of IL-6 and inflammation. Blockade of programmed death-1 (PD-1) interrupted CD126Lo/- nTreg cell stability. Additionally, CD126Lo/- Treg cells can treat colitis and established collagen-induced arthritis, while the CD126Hi cell population failed to do this. Moreover, we noted that CD126 expression of Treg cells had a positive correlation to rheumatoid arthritis (RA) severity and the stability of Treg cells. Our results strongly suggest that the manipulation of CD126Lo/- nTreg cells could be a novel strategy for the treatment of autoimmune diseases and for other conditions associated with a deficit of Treg cells.

The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation.

To fulfill the bioenergetic and biosynthetic demand of proliferation, T cells reprogram their metabolic pathways from fatty acid ß-oxidation and pyruvate oxidation via the TCA cycle to the glycolytic, pentose-phosphate, and glutaminolytic pathways. Two of the top-ranked candidate transcription factors potentially responsible for the activation-induced T cell metabolic transcriptome, HIF1α and Myc, were induced upon T cell activation, but only the acute deletion of Myc markedly inhibited activation-induced glycolysis and glutaminolysis in T cells. Glutamine deprivation compromised activation-induced T cell growth and proliferation, and this was partially replaced by nucleotides and polyamines, implicating glutamine as an important source for biosynthetic precursors in active T cells. Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines. Therefore, a Myc-dependent global metabolic transcriptome drives metabolic reprogramming in activated, primary T lymphocytes. This may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.

Synergistic inhibition of metastatic breast cancer by dual-chemotherapy with excipient-free rhein/DOX nanodispersions.

BACKGROUND: The management of metastatic cancer remains a major challenge in cancer therapy worldwide. The targeted delivery of chemotherapeutic drugs through rationally designed formulations is one potential therapeutic option. Notably, excipient-free nanodispersions that are entirely composed of pharmaceutically active molecules have been evaluated as promising candidates for the next generation of drug formulations. Formulated from the self-assembly of drug molecules, these nanodispersions enable the safe and effective delivery of therapeutic drugs to local disease lesions. Here, we developed a novel and green approach for preparing nanoparticles via the self-assembly of rhein (RHE) and doxorubicin (DOX) molecules, named RHE/DOX nanoparticles (RD NPs); this assembly was associated with the interaction force and did not involve any organic solvents. RESULTS: According to molecular dynamics (MD) simulations, DOX molecules tend to assemble around RHE molecules through intermolecular forces. This intermolecular retention of DOX was further improved by the nanosizing effect of RD NPs. Compared to free DOX, RD NPs exerted a slightly stronger inhibitory effect on 4T1 cells in the scratch healing assay. As a dual drug-loaded nanoformulation, the efficacy of RD NPs against tumor cells in vitro was synergistically enhanced. Compared to free DOX, the combination of DOX and RHE in nanoparticles exerted a synergistic effect with a combination index (CI) value of 0.51 and showed a stronger ability to induce cell apoptosis. Furthermore, the RD NP treatment not only effectively suppressed primary tumor growth but also significantly inhibited tumor metastasis both in vitro and in vivo, with a better safety profile. CONCLUSIONS: The generation of pure nanodrugs via a self-assembly approach might hold promise for the development of more efficient and novel excipient-free nanodispersions, particularly for two small molecular antitumor drugs that potentially exert synergistic antiproliferative effects on metastatic breast cancer.

Education-dependent activation of glycolysis promotes the cytolytic potency of licensed human natural killer cells.

BACKGROUND: The mechanism by which natural killer (NK) cell education results in licensed NK cells with heightened effector function against missing self-targets is not known. OBJECTIVE: We sought to identify potential mechanisms of enhanced function in licensed human NK cells. METHODS: We used expanded human NK cells from killer immunoglobulin-like receptor (KIR)/HLA-genotyped donors sorted for single-KIR+ cells to generate pure populations of licensed and unlicensed NK cells. We performed proteomic and gene expression analysis of these cells before and after receptor cross-linking and performed functional and metabolic analysis before and after interference with selected metabolic pathways. We verified key findings using freshly isolated and sorted NK cells from peripheral blood. RESULTS: We confirmed that licensed human NK cells are greater in number in peripheral blood and proliferate more in vitro than unlicensed NK cells. Using high-throughput protein analysis, we found that unstimulated licensed NK cells have increased expression of the glycolytic enzyme pyruvate kinase muscle isozyme M2 and after KIR cross-linking have increased phosphorylation of the metabolic modulators p38-α and 5' adenosine monophosphate-activated protein kinase α. After cytokine expansion and activation, unlicensed NK cells depended solely on mitochondrial respiration for cytolytic function, whereas licensed NK cells demonstrated metabolic reprogramming toward glycolysis and mitochondrial-dependent glutaminolysis, leading to accumulation of glycolytic metabolites and depletion of glutamate. As such, blocking both glycolysis and mitochondrial-dependent respiration was required to suppress the cytotoxicity of licensed NK cells. CONCLUSIONS: Collectively, our data support an arming model of education in which enhanced glycolysis in licensed NK cells supports proliferative and cytotoxic capacity.

Phosphorylation of CDC25C by AMP-activated protein kinase mediates a metabolic checkpoint during cell-cycle G2/M-phase transition.

From unicellular to multicellular organisms, cell-cycle progression is tightly coupled to biosynthetic and bioenergetic demands. Accumulating evidence has demonstrated the G1/S-phase transition as a key checkpoint where cells respond to their metabolic status and commit to replicating the genome. However, the mechanism underlying the coordination of metabolism and the G2/M-phase transition in mammalian cells remains unclear. Here, we show that the activation of AMP-activated protein kinase (AMPK), a highly conserved cellular energy sensor, significantly delays mitosis entry. The cell-cycle G2/M-phase transition is controlled by mitotic cyclin-dependent kinase complex (CDC2-cyclin B), which is inactivated by WEE1 family protein kinases and activated by the opposing phosphatase CDC25C. AMPK directly phosphorylates CDC25C on serine 216, a well-conserved inhibitory phosphorylation event, which has been shown to mediate DNA damage-induced G2-phase arrest. The acute induction of CDC25C or suppression of WEE1 partially restores mitosis entry in the context of AMPK activation. These findings suggest that AMPK-dependent phosphorylation of CDC25C orchestrates a metabolic checkpoint for the cell-cycle G2/M-phase transition.

Temperature-insensitive refractometer based on an RI-modulated singlemode-multimode-singlemode fibre structure.

A temperature-insensitive refractometer based on a refractive index (RI)-modulated singlemode-multimode-singlemode (RMSMS) fibre structure is proposed and experimentally demonstrated. In this investigation, a combination of no-core fibre (NCF) and multimode fibre (MMF) regions provides an RI modulation region due to the difference in RI between the NCF and the MMF. In effect, by periodically embedding the NCF within the MMF section of a singlemode-multimode-singlemode (SMS) fibre structure, a long-period grating (LPG) can be effectively introduced in the MMF section, and the excited cladding modes are therefore able to sense surrounding RI variation. The modulation parameters are determined from the numerical simulations, and the experimental results show the maximum RI sensitivity of the fabricated sample is as high as 206.96 nm/RIU. In addition, the proposed RMSMS fibre structure is proven to be unaffected by external temperature variation (in the wavelength domain), which is a very attractive feature in practical sensing applications.