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Chlorocholine chloride (CCC) is a plant growth regulator used worldwide that is detectable in cereals, fruits and animal products. The health effects of CCC exposure have raised public concern. Our previous research showed that CCC exposure decreased testosterone synthesis in pubertal rats. However, little is known about whether and how pubertal CCC exposure impacts spermatogenesis. In this study, we used BALB/c mice and spermatogonia-derived GC-1 cells to examine CCC-induced spermatogenic dysfunction. In vivo , pubertal CCC exposure led to decreased testicular weight, decreased testicular germ cells and poor sperm quality. This effect worsened after cessation of CCC exposure for the next 30 days. RNA-seq and western blot analysis revealed that CCC induced aryl hydrocarbon receptor (AhR) signaling, endoplasmic reticulum stress (ERS) and ferritinophagy. Increased iron content and lipid peroxidation levels were also observed in CCC-treated testes. In vitro , it was identified that iron overload mediated by enhanced ferritinophagy occurred in CCC-treated GC-1 cells, which might be attributed to the PERK pathway in ERS. Further, for the first time, our study elucidated the involvement of AhR in CCC-induced iron overload, which aggravated testicular oxidative damage via lipid peroxidation. Considering the adverse impact of CCC exposure on rodents, supportive evidence from GC-1 cells, and the critical importance of spermatogenesis on male development, the effects of CCC on the male reproduction warrant increased attention. [Display omitted] • CCC pubertal exposure led to spermatogenesis disorders which remained after cessation of CCC exposure for the next 30 days. • CCC-induced iron overload by ferritinophagy activation contributed to lipid peroxidation in GC-1 cells. • PERK pathway in endoplasmic reticulum stress triggered ferritinophagy activation in CCC-treated cells. • AhR was involved in CCC-induced ROS production and PERK-dependent iron overload, which caused testicular oxidative damage. [ABSTRACT FROM AUTHOR]

Black carbon (BC) is an important component of atmospheric PM 2.5 and the second largest contributor to global warming. 1,4-naphthoquinone-coated BC (1,4 NQ-BC) is a secondary particle with great research value, so we chose 1,4 NQ-BC as the research object. In our study, mitochondria and lysosomes were selected as targets to confirm whether they were impaired by 1,4 NQ-BC, label free proteomics technology, fluorescent probes, qRT-PCR and western blots were used to investigate the mechanism of 1,4 NQ-BC toxicity. We found 494 differentially expressed proteins (DEPs) in mitochondria and 86 DEPs in lysosomes using a proteomics analysis of THP1 cells after 1,4 NQ-BC exposure for 24 h. Through proteomics analysis and related experiments, we found that 1,4 NQ-BC can damage THP-1-M cells by obstructing autophagy, increasing lysosomal membrane permeability, disturbing the balance of ROS, and reducing the mitochondrial membrane potential. It is worth noting that 1,4 NQ-BC prevented the removal of FTL by inhibiting autophagy, and increased IL-33 level by POR/FTL/IL-33 axis. We first applied proteomics to study the damage mechanism of 1,4 NQ-BC on THP1 cells. Our research will enrich knowledge of the mechanism by which 1,4 NQ-BC damages human macrophages and identify important therapeutic targets and adverse outcome pathways for 1,4 NQ-BC-induced damage. [Display omitted] • PM 2.5 is a mixture, and 1,4 NQ-BC is a major component of PM 2.5. • 1,4 NQ-BC is a form of simulating the aging of BC in nature, which is more realistic. • We first applied proteomics to study the damage mechanism of 1,4 NQ-BC on THP1 cells. • 1,4 NQ-BC prevented the removal of FTL by inhibiting autophagy. • 1,4 NQ-BC increased IL-33 level by POR/FTL/IL-33 axis. [ABSTRACT FROM AUTHOR]

This study explored the effects of 1, 2-bis (2,4, 6-tribromophenoxy) ethane (BTBPE) and bis (2-ethylhexyl) tetrabromophthalate (TBPH) on serum metabolites and lipids in male Sprague-Dawley (SD) rats. Rats were orally gavaged 250 mg/kg bw of BTBPE and 500 mg/kg bw of TBPH for 28 consecutive days. Serum samples were collected for metabolomics and lipidomics analysis. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to explore changes in rat metabolic patterns. Least absolute shrinkage and selection operator (LASSO) regression models were established using serum levels of total thyroxine (TT4), free thyroxine (FT4), and rats' grouping information as variables to screen for robust differential substances. SuperPred was the database to obtain potential targets. The metabolomics and lipidomics results showed that BTBPE and TBPH had an impact on rat metabolic patterns, affecting pathways such as vitamin B6 synthesis. For BTBPE treatment, pyridoxal and ceramide (Cer) 24:0;4O were selected as differential substances related to thyroid hormones. For TBPH treatment, dehydroascorbic acid, acylcarnitine (CAR) 19:0, and diglyceride (DG) 38:4 were selected as differential substances related to thyroid hormones. Serotonin 2c receptor and cyclooxygenase-2 were chosen as potential targets of BTBPE and TBPH, respectively. In conclusion, this study found that BTBPE and TBPH impacted the metabolism of rats, and this effect may be related to changes in thyroid function. • BTBPE and TBPH change the metabolic pattern of male SD rats. • BTBPE and TBPH affect pathways such as vitamin B6 and vitamin C synthesis. • Pyridoxal and Cer 24:0;4O are differential substances for BTBPE. • Dehydroascorbic acid, CAR 19:0, and DG 38:4 are differential substances for TBPH. [ABSTRACT FROM AUTHOR]

Abstract: Survivability is an important issue to ensure the service continuity in optical network. At the same time, with the granularity of traffic demands ranging from sub-wavelength-level to wavelength-level, traffic demands need to be aggregated and carried over the network in order to utilize resources effectively. Therefore, multi-granularity grooming is proposed to save the cost and reduce the number of switching ports in Optical-Cross Connects (OXCs). However, current works mostly addressed the survivable wavelength or waveband grooming. Therefore, in this paper, we propose three heuristic algorithms called Multi-granularity Dedicated Protection Grooming (MDPG), Multi-granularity Shared Protection Grooming (MSPG) and Multi-granularity Mixed Protection Grooming (MMPG), respectively. All of them are performed based on the Survivable Multi-granularity Integrated Auxiliary Graph (SMIAG) that includes one Wavelength Integrated Auxiliary Graph (WIAG) for wavelength protection and one waveBand Integrated Auxiliary Graph (BIAG) for waveband protection. Numerical results show that MMPG has the lowest average port-cost, the best resource utilization ratio and the lowest blocking probability among these three algorithms. Compared with MDPG, MSPG has lower average port-cost, better resource utilization ratio and lower blocking probability. [Copyright &y& Elsevier]

PM2.5 still poses a threat to public health even at very low levels. Black carbon (BC) is a key component of PM2.5. Macrophage extracellular traps (METs) are a means by which macrophages capture and destroy invading pathogens. Necroptosis is an inflammatory programmed cell death. However, there is no research on the crosstalk mechanism between necroptosis and METs after BC exposure. In our study, fluorescence labeling, fluorescent probes, qPCR, and immunofluorescence were applied. Our research found that under normal physiological conditions, when macrophages receive external stimuli (in our experiment, phorbol 12-myristate 13-acetate (PMA)), they will form METs, thus exhibiting innate immune function. However, exposure to BC can cause necroptosis in macrophages accompanied by increased levels of ROS and cytosolic calcium ions as well as altered expression of inflammatory factors and chemokines that prevent the formation of METs, and weakening innate immune function. Notably, inhibition of necroptosis restored the formation of METs, indicating that necroptosis inhibits the formation of METs. Our experiment will enrich the understanding of the mechanism of macrophage injury caused by BC exposure, provide a new direction for studying harmful atmospheric particle toxicity, and propose new therapeutic insights for diseases caused by atmospheric particulate matter. This study is the first to explore the crosstalk mechanism between necroptosis and METs after BC exposure. [Display omitted] • Black carbon (BC) can cause necroptosis in macrophages. • BC can prevent the formation of macrophage extracellular traps (METs). • BC induced necroptosis inhibits the formation of METs. • Necroptosis and METs could interconvert. • This study is the first to investigate the crosstalk mechanism between necroptosis and METs after BC exposure. [ABSTRACT FROM AUTHOR]

The exponential growth of the demand for broadband services has imposed great challenges on the design of spectrum-efficient optical transmission system in Passive Optical Network (PON). Recently, an innovative Orthogonal Frequency Division Multiplexing (OFDM) scheme, called Polar-OFDM (P-OFDM), has emerged as a promising solution to boost the spectral efficiency of optical transmission in PON. However, the traditional P-OFDM does not yet perform best in spectral efficiency as it only uses half of the total subcarriers. In this paper, we verify a promising complementation between Polarization Multiplexing (POLMUX) and P-OFDM aiming at higher spectral efficiency. We then propose the full-subcarriers P-OFDM by loading data on the even-indexed subcarriers of X polarization and the odd-indexed subcarriers of Y polarization, respectively. Thus, all of the subcarriers will be utilized for effective data transmission, which can double the spectral efficiency. More importantly, because the subcarriers are interlaced on different polarizations, the cross-polarization interference can be significantly mitigated, which enables the independent channel estimation and equalization at the receiver to recover the data carried on each polarization. Our evaluation results demonstrate that the proposed system realizes the double spectral efficiency of the traditional P-OFDM with reasonable Bit Error Rate (BER) performance loss. [ABSTRACT FROM AUTHOR]

Th17 cells, which have been implicated in autoimmune diseases including rheumatoid arthritis (RA), require the JAK-STAT3 pathway for their differentiation and functions. Recently, JAK inhibitors have been developed as a therapeutic drug for RA. However, the current JAK inhibitors are not optimized to STAT3 compared with other STATs. In this study, we found a new lead compound of a small molecule JAK-STAT inhibitor, 2-[(3-Carbamoyl-2-thienyl)amino]-2-oxoethyl (2,6-dichlorophenyl)acetate, which inhibits STAT3 as efficiently as other STATs. This compound, named JI069, was selected by STAT3 reporter assay in combination with an in silico docking model. JI069 inhibited gp130 signaling by inducing dissociation between gp130 and JAK1. In HEK293T cells and primary T cells, JI069 suppressed STAT3 activation as efficiently as other STATs, including STAT1, STAT5, and STAT6. JI069 effectively suppressed Th1, Th2, and Th17 differentiation while strongly promoted iTreg differentiation. JI069 suppressed symptoms of the collagen-induced arthritis (CIA) model in mice, and inhibited the cytokine production from T cells as well as the STAT3 phosphorylation of synovial cells. These data suggest that JI069 is a new type of JAK inhibitor which has potential for the treatment of immunological disorders. [ABSTRACT FROM AUTHOR]

Highlights: [•] MAP4K4 is required for the proliferation and activation of CD4+ T cells. [•] MAP4K4 deletion in CD4+ T cells suppresses the IL-2 and IFN-γ production. [•] MAP4K4 is essential for promoting the development of CD25+ CD4+ Tregs. [•] MAP4K4 deficiency prevents the phosphorylation of Erk, Jnk, p38 and PKC-θ. [ABSTRACT FROM AUTHOR]

Abstract: Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. Several Smad-independent pathways including the JNK and the RhoA-ROCK pathways have been implicated in the induction of RORγt, the master regulator of Th17, however, molecular mechanisms underlying Smad-independent pathway remain largely unknown. To identify novel pathways involved in Th17 differentiation, we screened 285 chemical inhibitors for known signaling pathways. Among them, we found that Kenpaullone, a GSK3-β and CDK inhibitor, efficiently suppressed TGF-β-mediated RORγt induction and enhanced Foxp3 induction in primary T cells. Another CDK inhibitor, Roscovitine, but not other GSK3-β inhibitors, suppressed Th17 differentiation and enhanced iTreg development. Kenpaullone and Roscovitine suppressed experimental autoimmune encephalomyelitis (EAE), a typical Th17-mediated autoimmune disease model. These two compounds enhanced STAT5 phosphorylation and restored IL-2 production in the presence of TGF-β. These data suggest that CDK inhibitors modulate TGF-β-signaling pathways, which restore TGF-β-mediated suppression of IL-2 production, thereby modifying the Th17/iTreg balance. [Copyright &y& Elsevier]

Abstract: In this paper, we propose a novel robust routing algorithm based on Valiant load-balancing under the model of polyhedral uncertainty (i.e., hose uncertainty model) for WDM (wavelength division multiplexing) mesh networks. Valiant load-balanced robust routing algorithm constructs the stable virtual topology on which any traffic patterns under the hose uncertainty model can be efficiently routed. Considering there are multi-granularity connection requests in WDM mesh networks, we propose the method called hose-model separation to solve the problem for the proposed algorithm. Our goal is to minimize total network cost when constructing the stable virtual topology that assures robust routing for the hose model in WDM mesh networks. A mathematical formulation (integer linear programming, ILP) about Valiant load-balanced robust routing algorithm is presented. Two fast heuristic approaches are also proposed and evaluated. We compare the network throughput of the virtual topology constructed by the proposed algorithm with that of the traditional traffic grooming algorithm under the same total network cost by computer simulation. [Copyright &y& Elsevier]

Occupational exposure to trichloroethylene (TCE) has been associated with severe, generalized contact hypersensitivity (CHS) skin disorder, which is considered a delayed-type hypersensitivity reaction mediated by antigen-specific T cells. Transforming growth factor-β activated kinase-1 (TAK1) is essential for regulating the development and effector function of T cells. We hypothesized that disrupting TAK1 activity might inhibit TCE-induced CHS response. In this study, a local lymph node assay was employed to build a CHS model induced by TCE combined with the inducible-TAK1 deletion system to study the effect of TAK1 on it. It was observed that TAK1 deficiency ameliorated the TCE-induced CHS response and was associated with defective T cell expansion and activation and IFN-γ production in vivo. Furthermore, we investigated the effects of TCE and its metabolites trichloroacetic acid (TCA) and dichloroacetic acid (DCA) on CD4+ T cell function and the effect of TAK1 on it in vitro. The results showed that TCE, TCA and DCA augmented the proliferation, activation and differentiation of CD4+ T cells through Jnk MAPK and NF-κB pathways. TAK1 deletion significantly attenuated these effects induced by TCE, TCA or DCA on CD4+ T cells. In conclusion, it is suggested that TAK1 plays a critical role both in TCE-induced CHS response in vivo and in TCE and its metabolite-induced CD4+ T cell activation in vitro. Local inhibition of TAK1 might offer a promising alternative feasible strategy for TCE-induced CHS. • Local disruption of TAK1 inhibited the CHS response induced by TCE. • Intact TAK1 was critical to promote T-cell effector function in TCE-induced CHS. • Loss of TAK1 suppressed the activation of CD4+ T cells induced by TCE, TCA and DCA. • TAK1 deletion abolished MAPK and NF-κB pathway in TCE,TCA,DCA-treated CD4+ T cells. [ABSTRACT FROM AUTHOR]