A mutual regulatory loop between transcription factor Yin Yang 1 and hepatitis B virus replication influences chronic hepatitis B.

Hepatitis B virus (HBV) infections pose a major threat to human health. HBV can upregulate the expression of the transcription factor Yin Yang 1 (YY1) in in vitro cytological experiments, suggesting an association between YY1 and HBV infection. However, data on YY1 expression in chronic hepatitis B (CHB) patients are lacking. In this study, we aimed to assess the correlation between YY1 expression and HBV infection. We detected serum YY1 levels in 420 patients with chronic HBV infection, 30 patients with chronic hepatitis C virus infection, and 32 healthy controls using an enzyme-linked immunosorbent assay. The correlation between YY1 levels and clinical parameters was analyzed. Meanwhile, the changes of YY1 before and after interferon or entecavir treatment were analyzed. YY1 levels in the liver tissues were detected using immunofluorescence staining. The expression of YY1 in HBV-expressing cells was detected through western blotting. Meanwhile, we explored the effects of YY1 on HBV replication and gene expression. We found that YY1 was highly expressed in the serum and liver tissues of CHB patients. Serum YY1 levels positively correlated with HBV DNA and hepatitis B surface antigen (HBsAg). Additionally, HBV DNA levels increased but HBsAg levels decreased after HBV-expressing cells overexpress YY1. In conclusion, our study demonstrates that YY1 plays an important role in HBV replication and gene expression, providing a potential target for the treatment of CHB.

Mechanisms underlying morphological and functional changes of cilia in fibroblasts derived from patients bearing ARL3T31A and ARL3T31A/C118F mutations.

ARL3 is essential for cilia development, and mutations in ARL3 are closely associated with ciliopathies. In a previous study, we observed distinct phenotypes of retinal dystrophy in patients with heterozygous ARL3T31A and compound heterozygous ARL3T31A/C118F mutations, indicating that different mutation types may exert diverse effects on their functions. Here, we generated transformed immortal fibroblast cells from patients carrying heterozygous ARL3T31A and compound heterozygous ARL3T31A/C118F mutations, and systematically evaluated their cilia morphology and function, which were further validated in ARPE-19 cells. Results showed that both ARL3T31A and ARL3T31A/C118F mutations led to a decrease in cilium formation. The ARL3T31A/C118F mutations caused significantly elongated cilia and impaired retrograde transport, whereas the ARL3T31A mutation did not induce significant changes in fibroblasts. RNA-sequencing results indicated that compared to ARL3T31A , ARL3T31A/C118F fibroblasts exhibited a higher enrichment of biological processes related to neuron projection development, tissue morphogenesis, and extracellular matrix (ECM) organization, with noticeable alterations in pathways such as ECM-receptor interaction, focal adhesion, and TGF-ß signaling. Similar changes were observed in the proteomic results in ARPE-19 cells. Core regulated genes including IQUB, UNC13D, RAB3IP, and GRIP1 were specifically downregulated in the ARL3T31A/C118F group, and expressions of IQUB, NPM2, and SLC38A4 were further validated. Additionally, IQUB showed a rescuing effect on the overlong cilia observed in ARL3T31A/C118F fibroblasts. Our results not only enhance our understanding of ARL3-related diseases but also provide new insights into the analysis of heterozygous and compound heterozygous mutations in genetics.

Ag Nanoparticle-Induced Surface Chloride Immobilization Strategy Enables Stable Seawater Electrolysis.

Although hydrogen gas (H2 ) storage might enable offshore renewable energy to be stored at scale, the commercialization of technology for H2 generation by seawater electrolysis depends upon the development of methods that avoid the severe corrosion of anodes by chloride (Cl- ) ions. Here, it is revealed that the stability of an anode used for seawater splitting can be increased by more than an order of magnitude by loading Ag nanoparticles on the catalyst surface. In experiments, an optimized NiFe-layered double hydroxide (LDH)@Ag electrode displays stable operation at 400 mA cm-2 in alkaline saline electrolyte and seawater for over 5000 and 2500 h, respectively. The impressive long-term durability is more than 20 times that of an unmodified NiFe-LDH anode. Meticulous characterization and simulation reveals that in the presence of an applied electric field, free Cl- ions react with oxidized Ag nanoparticles to form stable AgCl species, giving rise to the formation of a Cl- -free layer near the anode surface. Because of its simplicity and effectiveness, it is anticipated that the proposed strategy to immobilize chloride ions on the surface of an anode has the potential to become a crucial technology to control corrosion during large-scale electrolysis of seawater to produce hydrogen.

TECO: A Unified Feature Map Compression Framework Based on Transform and Entropy.

The massive memory accesses of feature maps (FMs) in deep neural network (DNN) processors lead to huge power consumption, which becomes a major energy bottleneck of DNN accelerators. In this article, we propose a unified framework named Transform and Entropy-based COmpression (TECO) scheme to efficiently compress FMs with various attributes in DNN inference. We explore, for the first time, the intrinsic unimodal distribution characteristic that widely exists in the frequency domain of various FMs. In addition, a well-optimized hardware-friendly coding scheme is designed, which fully utilizes this remarkable data distribution characteristic to encode and compress the frequency spectrum of different FMs. Furthermore, the information entropy theory is leveraged to develop a novel loss function for improving the compression ratio and to make a fast comparison among different compressors. Extensive experiments are performed on multiple tasks and demonstrate that the proposed TECO achieves compression ratios of 2.31 × in ResNet-50 on image classification, 3.47 × in UNet on dark image enhancement, and 3.18 × in Yolo-v4 on object detection while keeping the accuracy of these models. Compared with the upper limit of the compression ratio for original FMs, the proposed framework achieves the compression ratio improvement of 21%, 157%, and 152% on the above models.

Concerning the stability of seawater electrolysis: a corrosion mechanism study of halide on Ni-based anode.

The corrosive anions (e.g., Cl-) have been recognized as the origins to cause severe corrosion of anode during seawater electrolysis, while in experiments it is found that natural seawater (~0.41 M Cl-) is usually more corrosive than simulated seawater (~0.5 M Cl-). Here we elucidate that besides Cl-, Br- in seawater is even more harmful to Ni-based anodes because of the inferior corrosion resistance and faster corrosion kinetics in bromide than in chloride. Experimental and simulated results reveal that Cl- corrodes locally to form narrow-deep pits while Br- etches extensively to generate shallow-wide pits, which can be attributed to the fast diffusion kinetics of Cl- and the lower reaction energy of Br- in the passivation layer. Additionally, for the Ni-based electrodes with catalysts (e.g., NiFe-LDH) loading on the surface, Br- causes extensive spalling of the catalyst layer, resulting in rapid performance degradation. This work clearly points out that, in addition to anti-Cl- corrosion, designing anti-Br- corrosion anodes is even more crucial for future application of seawater electrolysis.

Aucubin inhibits hepatic stellate cell activation through stimulating Nrf2/Smad7 axis.

AIM: Liver fibrosis may develop into end-stage liver disease if left unprevented. The study is attempting to identify a compound to ameliorate liver fibrosis progression with high efficiency and low toxicity, as well as to analyze its potential molecular mechanism. METHODS: The drug screening was performed using human hepatic stellate cell line LX-2 for identifying the compound as collagen I inhibitor. Primary Human hepatic stellate cells and LX-2 cell line were used to detect the antifibrotic function activity and molecular mechanism analysis in vitro. The CCl4-induced mouse experimental model was used to measure the amelioration in liver fibrosis. RESULTS: This study identified Aucubin, a natural compound, as a candidate for anti-liver fibrosis. Besides, Aucubin could inhibit the collagen I and α-SMA expressions in LX-2 cells and primary human hepatic stellate cells, as well as the cell proliferation. In terms of mechanism, Aucubin could upregulate Smad7 in hepatic stellate cells in a dose-dependent manner and block TGF-ß signaling. We also found that Nrf2 might be a direct target for the action of Aucubin, whose activation was necessary for Smad7 upregulation. In an in-vivo mouse model, Aucubin efficiency ameliorated the progression of CCl4-induced liver fibrosis, and reduced the hepatic levels of collagen deposition, transaminase and inflammatory cytokines. CONCLUSION: Capable of inhibiting the activation of hepatic stellate cells in vitro and in vivo, Aucubin may be a potential therapeutic candidate for liver fibrosis, which is dependent on the suppression of TGF-ß signaling through stimulating Nrf2/Smad7 axis.

Dopamine receptor-mediated roles on retinal ganglion cell hyperexcitability and injury in experimental glaucoma.

Extraordinary excitability (hyperexcitability) is closely related to retinal ganglion cell (RGC) injury in glaucoma. Dopamine (DA) and its receptors are involved in modulating RGC excitability. We investigated how DA system affects RGC injury in chronic ocular hypertension (COH) experimental glaucoma model. Western blotting and immunohistochemistry results revealed that expression of DA D2-like receptor (D2R) in RGCs was increased in COH retinas. Patch-clamp recordings showed that outward K+ currents were downregulated, while Na+ currents and NaV1.6 expression were upregulated in RGCs of COH retinas, which could be reversed by intravitreal pre-injection of the D2R antagonist sulpiride, but not by the D1-like receptor (D1R) antagonist SCH23390. However, pre-injection of the D1R agonist SKF81297 could partially reverse the increased expression of NaV1.6 proteins. Consistently, the numbers of evoked action potentials induced by current injections were increased in RGCs of COH retinas, indicating that RGCs may be in a condition of hyperexcitability. The increased frequency of evoked action potentials could be partially block by pre-injection of sulpiride, SKF81297 or DA, respectively. Furthermore, the increased number of TUNEL-positive RGCs in COH retinas could be partially reduced by intravitreal pre-injection of sulpiride, but not by pre-injection of SCH23390. Moreover, pre-injection of SKF81297 or DA could reduce the number of TUNEL-positive RGCs in COH retinas. All these results indicate that in COH retina, activation of D2R enhances RGC hyperexcitability and injury, while activation of D1R results in the opposite effects. Selective inhibition of D2R or activation of D1R may be an effective strategy for treatment of glaucoma.

Efficient Layer-Wise N:M Sparse CNN Accelerator with Flexible SPEC: Sparse Processing Element Clusters.

Recently, the layer-wise N:M fine-grained sparse neural network algorithm (i.e., every M-weights contains N non-zero values) has attracted tremendous attention, as it can effectively reduce the computational complexity with negligible accuracy loss. However, the speed-up potential of this algorithm will not be fully exploited if the right hardware support is lacking. In this work, we design an efficient accelerator for the N:M sparse convolutional neural networks (CNNs) with layer-wise sparse patterns. First, we analyze the performances of different processing element (PE) structures and extensions to construct the flexible PE architecture. Second, the variable sparse convolutional dimensions and sparse ratios are involved in the hardware design. With a sparse PE cluster (SPEC) design, the hardware can efficiently accelerate CNNs with the layer-wise N:M pattern. Finally, we employ the proposed SPEC into the CNN accelerator with flexible network-on-chip and specially designed dataflow. We implement hardware accelerators on Xilinx ZCU102 FPGA and Xilinx VCU118 FPGA and evaluate them with classical CNNs such as Alexnet, VGG-16, and ResNet-50. Compared with existing accelerators designed for structured and unstructured pruned networks, our design achieves the best performance in terms of power efficiency.

Modulation of Rac1/PAK1/connexin43-mediated ATP release from astrocytes contributes to retinal ganglion cell survival in experimental glaucoma.

Connexin43 (Cx43) is a major gap junction protein in glial cells. Mutations have been found in the gap-junction alpha 1 gene encoding Cx43 in glaucomatous human retinas, suggestive of the involvement of Cx43 in the pathogenesis of glaucoma. However, how Cx43 is involved in glaucoma is still unknown. We showed that increased intraocular pressure in a glaucoma mouse model of chronic ocular hypertension (COH) downregulated Cx43, which was mainly expressed in retinal astrocytes. Astrocytes in the optic nerve head where they gather and wrap the axons (optic nerve) of retinal ganglion cells (RGCs) were activated earlier than neurons in COH retinas and the alterations in astrocytes plasticity in the optic nerve caused a reduction in Cx43 expression. A time course showed that reductions of Cx43 expression were correlated with the activation of Rac1, a member of the Rho family. Co-immunoprecipitation assays showed that active Rac1, or the downstream signaling effector PAK1, negatively regulated Cx43 expression, Cx43 hemichannel opening and astrocyte activation. Pharmacological inhibition of Rac1 stimulated Cx43 hemichannel opening and ATP release, and astrocytes were identified to be one of the main sources of ATP. Furthermore, conditional knockout of Rac1 in astrocytes enhanced Cx43 expression and ATP release, and promoted RGC survival by upregulating the adenosine A3 receptor in RGCs. Our study provides new insight into the relationship between Cx43 and glaucoma, and suggests that regulating the interaction between astrocytes and RGCs via the Rac1/PAK1/Cx43/ATP pathway may be used as part of a therapeutic strategy for managing glaucoma.

Activation of retinal glial cells contributes to the degeneration of ganglion cells in experimental glaucoma.

Elevation of intraocular pressure (IOP) is a major risk factor for neurodegeneration in glaucoma. Glial cells, which play an important role in normal functioning of retinal neurons, are well involved into retinal ganglion cell (RGC) degeneration in experimental glaucoma animal models generated by elevated IOP. In response to elevated IOP, mGluR I is first activated and Kir4.1 channels are subsequently inhibited, which leads to the activation of Müller cells. Müller cell activation is followed by a complex process, including proliferation, release of inflammatory and growth factors (gliosis). Gliosis is further regulated by several factors. Activated Müller cells contribute to RGC degeneration through generating glutamate receptor-mediated excitotoxicity, releasing cytotoxic factors and inducing microglia activation. Elevated IOP activates microglia, and following morphological and functional changes, these cells, as resident immune cells in the retina, show adaptive immune responses, including an enhanced release of pro-inflammatory factors (tumor neurosis factor-α, interleukins, etc.). These ATP and Toll-like receptor-mediated responses are further regulated by heat shock proteins, CD200R, chemokine receptors, and metabotropic purinergic receptors, may aggravate RGC loss. In the optic nerve head, astrogliosis is initiated and regulated by a complex reaction process, including purines, transmitters, chemokines, growth factors and cytokines, which contributes to RGC axon injury through releasing pro-inflammatory factors and changing extracellular matrix in glaucoma. The effects of activated glial cells on RGCs are further modified by the interplay among different types of glial cells. This review is concluded by presenting an in-depth discussion of possible research directions in this field in the future.

A novel biosensing platform for detection of glaucoma biomarker GDF15 via an integrated BLI-ELASA strategy.

Glaucoma is a leading cause of irreversible blindness worldwide. Early discovery and prioritized intervention significantly impact its prognosis. Precise monitoring of the biomarker GDF15 contributes towards effective diagnosis and assessment of glaucoma. In this study, we demonstrate that GDF15 monitoring can also aid screening for glaucoma risk and early diagnosis. We obtained an aptamer (APT2TM) with high affinity, high specificity, and high stability for binding to both human-derived and rat-derived GDF15. Simulation results showed that the binding capabilities of APT2TM are mainly affected by the interplay between van der Waals forces and polar solvation energy, and that salt bridges and hydrogen bonds play critical roles. We then integrated an enzyme-linked aptamer sandwich assay (ELASA) into a biolayer interferometry (BLI) system to develop an automated, high-throughput, real-time monitoring BLI-ELASA biosensing platform. This platform exhibited a wide linear detection window (10-810 pg/mL range) and high sensitivity for GDF15 (detection limit of 5-6 pg/mL). Moreover, we confirmed its excellent performance when applied to GDF15 quantification in real samples from glaucomatous rats and clinical patients. We believe that this technology represents a robust, convenient, and cost-effective approach for risk screening, early diagnosis, and animal modeling evaluation of glaucoma in the near future.

EphA4/ephrinA3 reverse signaling induced Müller cell gliosis and production of pro-inflammatory cytokines in experimental glaucoma.

Previous work showed that ephrinA3/EphA4 forward signaling contributed to retinal ganglion cell (RGC) damage in experimental glaucoma. Since up-regulated patterns of ephrinA3 and EphA4 were observed in Müller cells and RGCs, an EphA4/ephrinA3 reverse signaling may exist in Müller cells of chronic ocular hypertension (COH) retina. We investigated effects of EphA4/ephrinA3 reverse signaling activation on Müller cells in COH retina. Intravitreal injection of the ephrinA3 agonist EphA4-Fc increased glial fibrillary acidic protein (GFAP) levels in normal retinas, suggestive of Müller cell gliosis, which was confirmed in purified cultured Müller cells treated with EphA4-Fc. These effects were mediated by intracellular STAT3 signaling pathway as phosphorylated STAT3 (p-STAT3) levels and ratios of p-STAT3/STAT3 were significantly increased in both COH retinas and EphA4-Fc intravitreally injected retinas, as well as in EphA4-Fc treated purified cultured Müller cells. The increase of GFAP protein levels in EphA4-Fc-injected retinas and EphA4-Fc treated purified cultured Müller cells could be partially eliminated by stattic, a selective STAT3 blocker. Co-immunoprecipitation results testified to the presence of interaction between ephrinA3 and STAT3/p-STAT3. In addition, intravitreal injection of EphA4-Fc or EphA4-Fc treatment of cultured Müller cells significantly up-regulated mRNA and protein contents of pro-inflammatory cytokines. Moreover, intravitreal injection of EphA4-Fc increased the number of apoptotic RGCs, which could be reversed by the tyrosine kinase blocker PP2. Overall, EphA4/ephrinA3 reverse signaling may induce Müller cell gliosis and increases release of pro-inflammatory factors, which could contribute to RGC death in glaucoma. Inhibition of EphA4/ephrinA3 signaling may provide an effective neuroprotection in glaucoma.

EphA4/ephrinA3 reverse signaling mediated downregulation of glutamate transporter GLAST in Müller cells in an experimental glaucoma model.

Deficiency of glutamate transporter GLAST in Müller cells may be culpable for excessive extracellular glutamate, which involves in retinal ganglion cell (RGC) damage in glaucoma. We elucidated how GLAST was regulated in rat chronic ocular hypertension (COH) model. Western blot and whole-cell patch-clamp recordings showed that GLAST proteins and GLAST-mediated current densities in Müller cells were downregulated at the early stages of COH. In normal rats, intravitreal injection of the ephrinA3 activator EphA4-Fc mimicked the changes of GLAST in COH retinas. In purified cultured Müller cells, EphA4-Fc treatment reduced GLAST expression at mRNA and protein levels, which was reversed by the tyrosine kinase inhibitor PP2 or transfection with ephrinA3-siRNA (Si-EFNA3), suggesting that EphA4/ephrinA3 reverse signaling mediated GLAST downregulation. EphA4/ephrinA3 reverse signaling-induced GLAST downregulation was mediated by inhibiting PI3K/Akt/NF-κB pathways since EphA4-Fc treatment of cultured Müller cells reduced the levels of p-Akt/Akt and NF-κB p65, which were reversed by transfecting Si-EFNA3. In Müller cells with ephrinA3 knockdown, the PI3K inhibitor LY294002 still decreased the protein levels of NF-κB p65 in the presence of EphA4-Fc, and the mRNA levels of GLAST were reduced by LY294002 and the NF-κB inhibitor SN50, respectively. Pre-injection of the PI3K/Akt pathway activator 740 Y-P reversed the GLAST downregulation in COH retinas. Western blot and TUNEL staining showed that transfecting of Si-EFNA3 reduced Müller cell gliosis and RGC apoptosis in COH retinas. Our results suggest that activated EphA4/ephrinA3 reverse signaling induces GLAST downregulation in Müller cells via inhibiting PI3K/Akt/NF-κB pathways, thus contributing to RGC damage in glaucoma.

L- and T-type Ca2+ channels dichotomously contribute to retinal ganglion cell injury in experimental glaucoma.

Retinal ganglion cell apoptotic death is the main pathological characteristic of glaucoma, which is the leading cause of irreversible blindness. Disruption of Ca2+ homeostasis plays an important role in glaucoma. Voltage-gated Ca2+ channel blockers have been shown to improve vision in patients with glaucoma. However, whether and how voltage-gated Ca2+ channels are involved in retinal ganglion cell apoptotic death are largely unknown. In this study, we found that total Ca2+ current densities in retinal ganglion cells were reduced in a rat model of chronic ocular hypertension experimental glaucoma, as determined by whole-cell patch-clamp electrophysiological recordings. Further analysis showed that L-type Ca2+ currents were downregulated while T-type Ca2+ currents were upregulated at the later stage of glaucoma. Western blot assay and immunofluorescence experiments confirmed that expression of the CaV1.2 subunit of L-type Ca2+ channels was reduced and expression of the CaV3.3 subunit of T-type Ca2+ channels was increased in retinas of the chronic ocular hypertension model. Soluble tumor necrosis factor-α, an important inflammatory factor, inhibited the L-type Ca2+ current of isolated retinal ganglion cells from control rats and enhanced the T-type Ca2+ current. These changes were blocked by the tumor necrosis factor-α inhibitor XPro1595, indicating that both types of Ca2+ currents may be mediated by soluble tumor necrosis factor-α. The intracellular mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and nuclear factor kappa-B signaling pathway mediate the effects of tumor necrosis factor-α. TUNEL assays revealed that mibefradil, a T-type calcium channel blocker, reduced the number of apoptotic retinal ganglion cells in the rat model of chronic ocular hypertension. These results suggest that T-type Ca2+ channels are involved in disrupted Ca2+ homeostasis and apoptosis of retinal ganglion cells in glaucoma, and application of T-type Ca2+ channel blockers, especially a specific CaV3.3 blocker, may be a potential strategy for the treatment of glaucoma.

FTA-GAN: A Computation-Efficient Accelerator for GANs With Fast Transformation Algorithm.

Nowadays, generative adversarial network (GAN) is making continuous breakthroughs in many machine learning tasks. The popular GANs usually involve computation-intensive deconvolution operations, leading to limited real-time applications. Prior works have brought several accelerators for deconvolution, but all of them suffer from severe problems, such as computation imbalance and large memory requirements. In this article, we first introduce a novel fast transformation algorithm (FTA) for deconvolution computation, which well solves the computation imbalance problem and removes the extra memory requirement for overlapped partial sums. Besides, it can reduce the computation complexity for various types of deconvolutions significantly. Based on FTA, we develop a fast computing core (FCC) and the corresponding computing array so that the deconvolution can be efficiently computed. We next optimize the dataflow and storage scheme to further reuse on-chip memory and improve the computation efficiency. Finally, we present a computation-efficient hardware architecture for GANs and validate it on several GAN benchmarks, such as deep convolutional GAN (DCGAN), energy-based GAN (EBGAN), and Wasserstein GAN (WGAN). The experimental results show that our design can reach 2211 GOPS under 185-MHz working frequency on Intel Stratix 10SX field-programmable gate array (FPGA) board with satisfactory visual results. In brief, the proposed design can achieve more than 2× hardware efficiency improvement over previous designs, and it can reduce the storage requirement drastically.

ETA: An Efficient Training Accelerator for DNNs Based on Hardware-Algorithm Co-Optimization.

Recently, the efficient training of deep neural networks (DNNs) on resource-constrained platforms has attracted increasing attention for protecting user privacy. However, it is still a severe challenge since the DNN training involves intensive computations and a large amount of data access. To deal with these issues, in this work, we implement an efficient training accelerator (ETA) on field-programmable gate array (FPGA) by adopting a hardware-algorithm co-optimization approach. A novel training scheme is proposed to effectively train DNNs using 8-bit precision with arbitrary batch sizes, in which a compact but powerful data format and a hardware-oriented normalization layer are introduced. Thus the computational complexity and memory accesses are significantly reduced. In the ETA, a reconfigurable processing element (PE) is designed to support various computational patterns during training while avoiding redundant calculations from nonunit-stride convolutional layers. With a flexible network-on-chip (NoC) and a hierarchical PE array, computational parallelism and data reuse can be fully exploited, and memory accesses are further reduced. In addition, a unified computing core is developed to execute auxiliary layers such as normalization and weight update (WU), which works in a time-multiplexed manner and consumes only a small amount of hardware resources. The experiments show that our training scheme achieves the state-of-the-art accuracy across multiple models, including CIFAR-VGG16, CIFAR-ResNet20, CIFAR-InceptionV3, ResNet18, and ResNet50. Evaluated on three networks (CIFAR-VGG16, CIFAR-ResNet20, and ResNet18), our ETA on Xilinx VC709 FPGA achieves 610.98, 658.64, and 811.24 GOPS in terms of throughput, respectively. Compared with the prior art, our design demonstrates a speedup of 3.65× and an energy efficiency improvement of 8.54× on CIFAR-ResNet20.

Detection of plasma interleukin-6, C-reactive protein, D-dimer and fibrinogen among 96 patients with pneumoconiosis / 预防医学

Objective@# To investigate the plasma levels of interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer (D-D) and fibrinogen (Fib) among patients with pneumoconiosis, so as to provide insights into the prevention of thrombosis among patients with pneumoconiosis.@*Methods@#Ninety-six male coal workers with stable-stage pneumoconiosis admitted to China Pingmei Shenma Group Occupational Disease Prevention and Control Hospital from February 2019 to February 2021 were included in the pneumoconiosis group, and 43 male healthy volunteers in the hospital during the same period were selected as the control group. The plasma D-D, Fib, IL-6 and CRP levels were detected from subjects in the two groups. The associations of plasma D-D and Fib levels with IL-6 and CRP levels were examined using Pearson correlation analysis among pneumoconiosis patients. @*Results@#Participants in the pneumoconiosis group and the control group had a mean age of (52.91±3.89) and (52.64±4.12) years, D-D of (1.28±0.91) and (0.44±0.11) mg/L, Fib of (4.41±0.98) and (2.88±0.61) g/L, IL-6 of (0.63±0.19) and (0.42±0.06) ng/L and CRP of (3.30±1.65) and (1.35±0.12) mg/L, respectively. Higher plasma D-D, Fib, IL-6 and CRP levels were detected in the pneumoconiosis group than in the control group (all P<0.05). The plasma D-D level correlated positively with IL-6 level among pneumoconiosis patients (r=0.347, P<0.001). @*Conclusion@#High plasma IL-6, CRP, D-D and Fib levels are detected among patients with pneumoconiosis, and the plasma D-D level correlates positively with IL-6 level among patients with pneumoconiosis.

A novel mutation located in the intermembrane space domain of AFG3L2 causes dominant optic atrophy through decreasing the stability of the encoded protein.

Dominant optic atrophy (DOA) is the most common hereditary optic neuropathy. Although DOA is caused by mutations in several genes, there are still many cases that have not been diagnosed or misdiagnosed. Herein, we present a large family of 11 patients with DOA. To identify potential pathogenic mutations, whole exome sequencing (WES) was performed on the proband, a 35-year-old woman. WES revealed a novel pathogenic mutation (c.524T>C, p.F175S) in the AFG3L2 intermembrane space domain, rather than in the ATPase domain, which is the hot mutation region associated with most of the previously reported DOA cases. Functional studies on skin fibroblasts generated from patients and HEK293T cells showed that the mutation may impair mitochondrial function and decrease the ability of AFG3L2 protein to enter the mitochondrial inner membrane. In addition, this novel mutation led to protein degradation and reduced the stability of the AFG3L2 protein, which appeared to be associated with the proteasome-ubiquitin pathway.

P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice.

Microglia are involved in the inflammatory response and retinal ganglion cell damage in glaucoma. Here, we investigated how microglia proliferate and migrate in a mouse model of chronic ocular hypertension (COH). In COH retinas, the microglial proliferation that occurred was inhibited by the P2X7 receptor (P2X7R) blocker BBG or P2X7R knockout, but not by the P2X4R blocker 5-BDBD. Treatment of primary cultured microglia with BzATP, a P2X7R agonist, mimicked the effects of cell proliferation and migration in COH retinas through the intracellular MEK/ERK signaling pathway. Transwell migration assays showed that the P2X4R agonist CTP induced microglial migration, which was completely blocked by 5-BDBD. In vivo and in vitro experiments demonstrated that ATP, released from activated Müller cells through connexin43 hemichannels, acted on P2X7R to induce microglial proliferation, and acted on P2X4R/P2X7R (mainly P2X4R) to induce microglial migration. Our results suggest that inhibiting the interaction of Müller cells and microglia may attenuate microglial proliferation and migration in glaucoma.

Long non-coding RNA FOXP4-AS1 facilitates the biological functions of hepatocellular carcinoma cells via downregulating ZC3H12D by mediating H3K27me3 through recruitment of EZH2.

BACKGROUND: Some studies have reported the effect of long non-coding RNA forkhead box P4 antisense RNA 1 (lncRNA FOXP4-AS1) on hepatocellular carcinoma (HCC). Here, we aimed to discuss the effects of FOXP4-AS1/enhancer of zeste homolog 2 (EZH2)/trimethylation of lysine 27 on histone H3 (H3K27me3)/zinc finger CCCH-type containing 12D (ZC3H12D) axis on HCC. METHODS: The expression of FOXP4-AS1, EZH2, and ZC3H12D, and abundance of H3K27me3 in HCC tissues and cells were tested. The relationship between FOXP4-AS1 expression and prognosis of HCC patients was analyzed. The biological functions of HCC cells were detected via loss- and gain-of-function assays. The tumor weight and volume in vivo were tested. The interaction between FOXP4-AS1 and EZH2 as well as that between EZH2 and H3K27me3 was verified. RESULTS: FOXP4-AS1 and EZH2 expression and H3K27me3 abundance were enhanced while ZC3H12D expression was depressed in HCC tissues and cells. Knockdown of FOXP4-AS1 suppressed biological functions of HCC cells as well as the weight and volume of HCC transplanted tumor. Depleting ZC3H12D reversed the effect of downregulated FOXP4-AS1 on HCC cells. FOXP4-AS1 suppressed ZC3H12D expression via mediating H3K27me3 by recruitment of EZH2. CONCLUSION: The key findings of the present study demonstrate that FOXP4-AS1 suppresses ZC3H12D expression via mediating H3K27me3 by recruitment of EZH2, thus promoting the progression of HCC.