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Yue-Jiao Lan,1,2 Napoleon Bellua Sam,3 Ming-Han Cheng,1 Hai-Feng Pan,4,5 Jian Gao1 1Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 3Department of Medical Research and Innovation, School of Medicine, University for Development Studies, Tamale, Ghana; 4Department of Epidemiology & Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 5Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, People’s Republic of ChinaCorrespondence: Jian GaoPediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200120, People’s Republic of ChinaEmail gaojian@scmc.com.cn; gaojianayfy@163.comHai-Feng PanDepartment of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of ChinaEmail panhaifeng@ahmu.edu.cnAbstract: Progranulin (PGRN), a secretory glycoprotein consisting of 593 amino acid residues, is a key actor and regulator of multiple system functions such as innate immune response and inflammation, as well as tissue regeneration. Recently, there is emerging evidence that PGRN is protective in the development of a variety of immune-mediated diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) by regulating signaling pathways known to be critical for immunology, particularly the tumor necrosis factor alpha/TNF receptor (TNF-α/TNFR) signaling pathway. Whereas, the role of PGRN in psoriasis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is controversial. This review summarizes the immunological functions of PGRN and its role in the pathogenesis of several immune-mediated diseases, in order to provide new ideas for developing therapeutic strategies for these diseases.Keywords: PGRN, TNF-α, TNFR, immune-mediated diseases, therapeutic

Background: Capsular contracture is one of the most severe complications following breast augmentation surgery. It has been reported that botulinum toxin Type A (BTX-A) can inhibit capsular contracture, but the exact mechanisms remain unclear. Therefore, this study aims to explore the potential mechanisms behind BTX-A's inhibition of capsular contracture by observing its effects on the biological behavior of fibroblasts and its impact on the TGF-β/Smad signaling pathway., Methods: In vitro experiments involved culturing fibroblasts on PDMS surfaces, subsequently treating them with various concentrations of BTX-A. Fibroblast proliferation activity was assessed using the CCK-8 assay, while the migration and cytoskeletal morphology of the fibroblasts were meticulously examined. ELISA was utilized to quantify the expression of fibrosis-related cytokines. Gene and protein expressions related to the TGF-β/Smad pathway were analyzed through real-time PCR and Western blotting techniques., Results: BTX-A moderately enhanced the early proliferation and migration of fibroblasts on the surface of PDMS silicone sheets and reduced the synthesis of collagen types I and III. Furthermore, under the influence of BTX-A, the expression of TGF-βR2 and α-SMA in the TGF-β/Smad pathway was significantly inhibited., Conclusions: This study demonstrates that BTX-A can inhibit fibroblast differentiation by downregulating the expression of TGF-βR2, thereby suppressing the TGF-β/Smad pathway. This suggests a possible mechanism through which BTX-A mitigates capsular contracture., No Level Assigned: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Multivalent ligands hold promise for enhancing avidity and selectivity to simultaneously target multimeric proteins, as well as potentially modulating receptor signaling in pharmaceutical applications. Essential for these manipulations are nanosized scaffolds that precisely control ligand display patterns, which can be achieved by using polyproline oligo-helix macrocyclic nanoscaffolds via selective binding to protein oligomers and cell surface receptors. This work focuses on synthesis and structural characterization of different-sized polyproline tri-helix macrocyclic (PP3M) scaffolds. Through combined analysis of circular dichroism (CD), small- and wide-angle X-ray scattering (SWAXS), electron spin resonance (ESR) spectroscopy, and molecular modeling, a non-coplanar tri-helix loop structure with partially crossover helix ends is elucidated. This structural model aligns well with scanning tunneling microscopy (STM) imaging. The present work enhances the precision of nanoscale organic synthesis, offering prospects for controlled ligand positioning on scaffolds. This advancement paves the way for further applications in nanomedicine through selective protein interaction, manipulation of cell surface receptor functions, and developments of more complex polyproline-based nanostructures., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The transmembrane BAX inhibitor-1-containing motif 6 (TMBIM6) is suggested to modulate apoptosis by regulating calcium homeostasis in the endoplasmic reticulum (ER). However, the precise molecular mechanism underlying this calcium regulation remains poorly understood. To shed light on this issue, we investigated all negatively charged residues in BsYetJ, a bacterial homolog of TMBIM6, using mutagenesis and fluorescence-based functional assays. We reconstituted BsYetJ in membrane vesicles with a lipid composition similar to that of the ER. Our results show that the charged residues E49 and R205 work together as a major gate, regulating calcium conductance in these ER-like lipid vesicles. However, these residues become largely inactive when reconstituted in other lipid environments. In addition, we found that D195 acts as a minor filter compared to the E49-R205 dyad. Our study uncovers a previously unknown function of BsYetJ/TMBIM6 in the calcium-dependent inactivation of BsYetJ, providing a framework for the development of a lipid-dependent mechanistic model of BsYetJ that will facilitate our understanding of calcium-dependent apoptosis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yun-Wei Chiang reports financial support was provided by National Science and Technology Council of Taiwan. Yun-Wei Chiang reports financial support was provided by Ministry of Education of Taiwan., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Pulmonary fibrosis (PF) is a chronic interstitial lung disease with no effective therapies. Galectin-3 (Gal-3), a marker of oxidative stress, plays a key role in the pathogenesis of PF. Fibroblast-myofibroblast differentiation (FMD) is an important source of fibrotic cells in PF. Previous studies showed that melatonin (MT) exerted anti-fibrotic effect in many diseases including PF through its antioxidant activity. In the present study we investigated the relationships among Gal-3, NRF2, ROS in FMD and their regulation by MT. We established an in vitro model of FMD in TGF-β1-treated human fetal lung fibroblast1 (HFL1) cells and a PF mouse model via bleomycin (BLM) intratracheal instillation. We found that Gal-3 expression was significantly increased both in vitro and in vivo. Knockdown of Gal-3 in HFL1 cells markedly attenuated TGF-β1-induced FMD process and ROS accumulation. In TGF-β1-treated HFL1 cells, pretreatment with NRF2-specific inhibitor ML385 (5 μM) significantly increased the levels of Gal-3, α-SMA and ROS, suggesting that the expression of Gal-3 was regulated by NRF2. Treatment with NRF2-activator MT (250 μM) blocked α-SMA and ROS accumulation accompanied by reduced Gal-3 expression. In BLM-induced PF model, administration of MT (5 mg·kg -1 ·d -1 , ip for 14 or 28 days) significantly attenuated the progression of lung fibrosis through up-regulating NRF2 and down-regulating Gal-3 expression in lung tissues. These results suggest that Gal-3 regulates TGF-β1-induced pro-fibrogenic responses and ROS production in FMD, and MT activates NRF2 to block FMD process by down-regulating Gal-3 expression. This study provides a useful clue for a clinical strategy to prevent PF. Graphic abstract of the mechanisms. MT attenuated BLM-induced PF via activating NRF2 and inhibiting Gal-3 expression., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The host-material interface is critical in determining the successful integration of medical devices into human tissue. The surface topography can regulate the fibrous capsule formation around implants through macrophage polarization, but the exact mechanism remains unclear. In this study, four types of microgrooves (10 or 50 µm in groove depths and 50 or 200 µm in groove widths) were fabricated on polydimethylsiloxane (PDMS) using lithography. The microgroove surfaces were characterized using the laser scanning confocal microscopy and fourier transform infrared spectroscopy. The effect of surface topography on macrophage phenotypes and conditioned medium (CM) collected from macrophages on human foreskin fibroblast 1 (HFF-1) were investigated. The result revealed that a deeper and narrower microgroove structure means a rougher surface. Macrophages tended to adhere and aggregate on group 50-50 surface (groove depths and widths of 50 µm). THP-1 cell polarized toward both inflammatory M1 and anti-inflammatory M2 macrophages on the surface of each group. Meanwhile, CM from macrophages culture on PDMS differentially up-regulated the proliferation, migration and fibrosis of HFF-1. Among them, the group 50-50 had the strongest promoting effect. In vivo, the inflammatory response and fibrotic capsule around the implants were observed at 1 week and 4 weeks. As time passed, the inflammatory response decreased, while the capsule thickness continued to increase. The rough material surface was more inclined to develop a severe fibrotic encapsulation. In conclusion, this finding further suggested a potential immunomodulatory effect of macrophages in mediating the fibrotic response to implants and facilitated the design of biomaterial interfaces for improving tissue integration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Within the scope of the FANTOM6 consortium, we perform a large-scale knockdown of 200 long non-coding RNAs (lncRNAs) in human induced pluripotent stem cells (iPSCs) and systematically characterize their roles in self-renewal and pluripotency. We find 36 lncRNAs (18%) exhibiting cell growth inhibition. From the knockdown of 123 lncRNAs with transcriptome profiling, 36 lncRNAs (29.3%) show molecular phenotypes. Integrating the molecular phenotypes with chromatin-interaction assays further reveals cis- and trans-interacting partners as potential primary targets. Additionally, cell-type enrichment analysis identifies lncRNAs associated with pluripotency, while the knockdown of LINC02595, CATG00000090305.1, and RP11-148B6.2 modulates colony formation of iPSCs. We compare our results with previously published fibroblasts phenotyping data and find that 2.9% of the lncRNAs exhibit a consistent cell growth phenotype, whereas we observe 58.3% agreement in molecular phenotypes. This highlights that molecular phenotyping is more comprehensive in revealing affected pathways., Competing Interests: Declaration of interests The authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Nanodiscs are broadly used for characterization of membrane proteins as they are generally assumed to provide a near-native environment. In fact, it is an open question whether the physical properties of lipids in nanodiscs and membrane vesicles of the same lipid composition are identical. Here, we investigate the properties of lipids (1,2-dipalmitoyl- sn -glycero-3-phosphocholine, 1,2-dilauroyl- sn -glycero-3-phosphocholine, and their mixtures) in two different sample types, nanodiscs and multilamellar vesicles, by means of spin-label electron spin resonance techniques. Our results provide a quantitative description of lipid dynamics and ordering, elucidating the molecular details of how lipids in the two sample types behave differently in response to temperature and lipid composition. We show that the properties of lipids are altered in nanodiscs such that the dissimilarity of the fluid and gel lipid phases is reduced, and the first-order phase transitions are largely abolished in nanodiscs. We unveil that the ensemble of lipids in the middle of a nanodisc bilayer, as probed by the end-chain spin-label 16-PC, is promoted to a state close to a miscibility critical point, thereby rendering the phase transitions continuous. Critical phenomena have recently been proposed to explain features of the heterogeneity in native cell membranes. Our results lay the groundwork for how to establish a near-native environment in nanodiscs with simple organization of lipid components.

Maintaining glutamate homeostasis through astrocyte-enriched glutamate transporter 1 (GLT-1) is critical for neuronal survival, but it is often disrupted after brain injury. Hericium erinaceus (HE), an edible mushroom, was reported to be anti-inflammatory and neuroprotective against brain ischemia, but its effect on glutamate homeostasis was unknown. Here we investigated the neuroprotective effect of erinacine A (EA), an active component of HE, with special focus on the GLT-1 function in the in vitro and in vivo cerebral ischemia mouse models. By using oxygen-glucose deprivation (OGD) to challenge mouse glia-neuron (GN) mixed culture as the in vitro model, we found that EA treatment significantly improved neuronal/astroglial survival and attenuated OGD-induced proinflammatory NFκB and AKT signaling activations. Notably, EA attenuated OGD-induced GLT-1 downregulation, and a selective GLT-1 inhibitor WAY-213613 reversed these EA-mediated neuroprotection. EA also ameliorated glutamate excitotoxicity effectively. In a transient hypoxia-ischemia (tHI) brain injury mouse model, we examined an EA treatment strategy by performing a pre-tHI daily oral gavage of EA (oEA) for 7 days followed by a post-tHI intranasal injection of EA (nEA) for 3 days, and found that this treatment significantly protected sensorimotor cortex and improved the post-tHI forepaw grip strength. Western blotting results further revealed that EA treatment also preserved astrocyte-enriched glutamate and aspartate transporter (GLAST) as well as a GLT-1 function-associated potassium channel Kir4.1 in the cerebral cortex and striatum after tHI. These results suggest that EA is effective for preserving GLT-1 and glutamate clearance machinery to protect against excitotoxicity after ischemic brain injury., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze the mediating effect of work-occupation fit between occupational stress and anxiety symptoms in medical staff. Methods: Convenience sampling method was adopted to select participants of one general hospital and three specialized hospitals as respondents for a questionnaire survey in Henan Province from October 2020 to January 2021. A total of 2050 medical staff were investigated, and 1988 valid questionnaires were collected, and the effective rate of the questionnaire was 97.0% (1988/2050) . The "Depression-Anxiety-Stress Scale" and "Worker-Occupation Fit Inventory" were used to evaluate the occupational stress, anxiety symptoms and worker-occupation fit level of medical staff, and the mediation effect of work-occupation fit on the relationship between occupational stress and anxiety symptoms was analyzed using a mediating effect model. Results: The average age of the 1988 medical staff was (32.7±7.8) years old, the positive detection rates of occupational stress and anxiety symptoms were 42.5% (845/1988) and 56.7% (1127/1988) , respectively. Anxiety symptoms of medical staff were positively correlated with occupational stress, negatively correlated with worker-occupation fit ( r =0.831, -0.364, P <0.001) , work-occupation fit was negatively correlated with occupational stress ( r =-0.259, P <0.001) . The results of the mediation effect analysis showed that occupational stress had a direct effect on anxiety symptoms ( β =0.677, BCa 95% CI : 0.648-0.707) , and worker-occupation fit ( β =0.047, BCa 95% CI : 0.039-0.056) , characteristic fit ( β =0.089, BCa 95% CI : 0.074-0.104) , need-supply fit ( β =0.075, BCa 95% CI : 0.062-0.089) , and ability-demand fit ( β =0.035, BCa 95% CI : 0.026-0.044) mediated the association between occupational stress and anxiety symptoms in medical staff, with the mediating effect as a percentage of 6.5%, 12.3%, 10.3%, and 4.8%, respectively. Conclusion: Worker-occupation fit has a mediating effect between occupational stress and anxiety symptoms in medical staff, but mainly direct effect.

The human brain is a complex, three-dimensional structure. To better recapitulate brain complexity, recent efforts have focused on the development of human-specific midbrain organoids. Human iPSC-derived midbrain organoids consist of differentiated and functional neurons, which contain active synapses, as well as astrocytes and oligodendrocytes. However, the absence of microglia, with their ability to remodel neuronal networks and phagocytose apoptotic cells and debris, represents a major disadvantage for the current midbrain organoid systems. Additionally, neuroinflammation-related disease modeling is not possible in the absence of microglia. So far, no studies about the effects of human iPSC-derived microglia on midbrain organoid neural cells have been published. Here we describe an approach to derive microglia from human iPSCs and integrate them into iPSC-derived midbrain organoids. Using single nuclear RNA Sequencing, we provide a detailed characterization of microglia in midbrain organoids as well as the influence of their presence on the other cells of the organoids. Furthermore, we describe the effects that microglia have on cell death and oxidative stress-related gene expression. Finally, we show that microglia in midbrain organoids affect synaptic remodeling and increase neuronal excitability. Altogether, we show a more suitable system to further investigate brain development, as well as neurodegenerative diseases and neuroinflammation., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Objective: To explore safety and accuracy of four-point acupotomy for the treatment of tarsal tunnel syndrome regarding release of ankle tunnel flexor retinaculum to provide an anatomical basis of clinical treatment., Methods: Twenty-nine adult specimens (15 males and 14 females) fixed with 10% formalin, aged from 47 to 98 years old with an average age of (81.10±11.14) years old, 29 on the right side and 29 on the left side, which were selected for the study from September 2020 to October 2020. Simulate the operation of loosening flexor retinaculumt with a needle knife on the human specimen, and place the specimen on the frog position of lower limbs with medial malleolus upward to determine the center of medial malleolus. Choose 4 different positions near the flexor retinaculum to insert the needle so that the needle body was perpendicular to skin and cutting edge direction was perpendicular to the running direction of the flexor retinaculum. The needle knife penetrates the skin and explores slowly. When the flexor retinaculum was reached, the needle tip may touch the tough tissue. At this time, the cutting is loosened for 4 times. After acupotomy release operation was completed, make a lateral incision on the skin surface along acupotomy direction, open the area of the exposed flexor retinaculum, dissecting layer by layer, observe and record the needle knife and its surrounding anatomical structure. The length of acupotomy cutting marks of flexor retinaculum was measured by electronic vernier caliper. The safety and accuracy of acupotomy loosening of ankle canal flexor retinaculum were evaluated by observing the number and degree of ankle canal contents such as tendons and nerves injured by needle knife. The safety is to count the number of cases of acupotomy injury to the contents of the ankle canal, and to calculate the injury rate, that is, the number of injury cases/total cases × 100%. The effective release was defined as the release length L ≥ W/2(W is the width of the flexor retinaculum, defined as 20 mm)., Results: For safety, there were no acupotomy injuries to nerves or blood vessels in 58 cases, 26 cases injuried to posterior tibial tendon which 17 of these tendon injury cases, the tendon was penetrated and severely injured, and flexor digitorum longus tendon was injured in 12 cases. Among these cases, tendon was penetrated and severely injured in 4 cases, and total injury rate was 32.14%. No nerve and vessel injury on c3 and c4 point. For accuracy, 58 specimens were successfully released. The length Lc of releasing trace for acupotomy was (10.40±1.36) cm, and length range 6.38 to 12.88 cm. Among all cases, the length of releasing trace was ≥10 mm in 37 cases. The overall success rate of release was 100.00%. Layered structure of ankle tube flexor retinaculumt:fiber diaphragm from flexor retinaculum divides contents of ankle tube into different chambers inward, and fiber diaphragm meets here to synthesize a complete flexor retinaculum at the midpoint of the line between the medial malleolus tip and calcaneal tubercle(above the neurovascular course)., Conclusion: Four-point needle-knife method of releasing flexor retinaculum for the treatment of tarsal tunnel syndrome is performed at the attachment of the two ends of flexor retinaculum;the tendon, but not the nerves and blood vessels, is easily damaged. It is safe to insert needle on the side of calcaneus. The extent of release is relatively complete, but due to the "layered" structure of the flexor retinaculum, classic surgical technique could only release one layer of flexor retinaculum when a needle is inserted at the edge of the bone and cannot achieve complete release of the full thickness of the flexor. Therefore, it remains to be determined whether the desired effect can be achieved clinically.

Objective: To analyze the literature of related research reports on occupational hearing loss (ONIHL) , study the characteristics of the subject and determine the research hotspots. Methods: In December 2020, PubMed database was searched by bibliometrics for ONIHL published in PubMed database from January 1971 to December 2020. Bicomb 2.03 software was used to extract the subject. The publication year, publication country, source magazine and subject words were summarized and analyzed. Results: A total of 1 473 papers were included in this study, and the number of papers was 66 from 1971 to 1980, and 628 from 2011 to 2020, an increase of nearly 10 times. The top three countries were the United States, China and Germany, with 31.5% (464/1473) , 11.5% (171/1473) and 6.2% (91/1473) ; The cross-sectional study was the most applied type; The top five words for 2011-2020: Mental Illness, polymorphism, cardiovascular disease, high frequency hearing impairment and standards and regulations. Conclusion: Susceptibility Genes, Psychological Disorders, Cardiovascular Diseases and Risk Assessment are hot areas in ONIHL at present. Researchers should focus on major fields and grasp future trends as a whole.

Objective: To explore the influential factors of job stress suffered by workers in railway stations, the level of job stress of were measured and subjective comfort of employees targeting to working environment were reported. Methods: In March 2019, a cluster sampling study was designed to collect the personal characteristics, job characteristics and subjective comfort degree of working environment of 432 employees in Chongqing railway stations. Meanwhile, job stress was assessed using the effort-reward imbalance scale. Chi-square test was used to compare the difference of occupational stress detection rate among different stratified factors such as occupational characteristics. Logistic regression was applied to analyze the influential factors of occupational stress. Results: The detection rate of job stress of workers in the railway stations was 31.02% (134/432) . The detection rate of job stress was higher among the divorced workers in railway stations, those earning less than 5, 000 yuan per month, those with 10-20 years' length of service, those who worked as a conductor and other workers including baggageman, station master on duty and assistant engineer (χ(2)=9.61, 14.76, 23.28, 11.06, P =0.008, 0.002, 0.000, 0.011) . The detection rate of job stress was higher among those whose working environment subjective feelings were uncomfortable, the differences were statistically significant ( P <0.001) . The results showed that the occupational stress of the staff in the railway stations was influenced by their subjective feeling of air quality, noise and Space Layout ( P <0.05) . The risk factors of occupational stress were air quality, noise and uncomfortable space layout ( OR =0.571, 0.068, 0.441, P =0.051, 0.054, 0.007) . Conductor, other (Bellboy, Duty Station Master, assistant engineer) were the risk factors of occupational stress ( OR =1.884, 2.703, P =0.065, 0.019) . The employees of station A and station B were the risk factors of occupational stress ( OR =4.681, 1.811, P =0.002, 0.067) . Conclusion: The higher detection rate of job stress of workers in the railway stations is correlated with the subjective comfort degree of the working environment of the workers.

Double electron-electron resonance (DEER) is a powerful technique for studying protein conformations. To preserve the room-temperature ensemble, proteins are usually shock-frozen in liquid nitrogen prior to DEER measurements. The use of cryoprotectant additives is, therefore, necessary to ensure the formation of a vitrified state. Here, we present a simple modification of the freezing process using a flexible fused silica microcapillary, which increases the freezing rates and thus enables DEER measurement without the use of cryoprotectants. The Bid protein, which is highly sensitive to cryoprotectant additives, is used as a model. We show that DEER with the simple modification can successfully reveal the cold denaturation of Bid, which was not possible with the conventional DEER preparations. The DEER result reveals the nature of Bid folding. Our method advances DEER for capturing the chemically and thermally induced conformational changes of a protein in a cryoprotectant-free medium.

Purpose: To evaluate the feasibility of in-vivo imaging of the retina and choroid using spectral domain optical coherence tomography (OCT) in guinea pigs. Methods: The study included 19 pigmented guinea pigs (age: 3-4 weeks) which underwent sonographic axial length measurements and OCT imaging. At study end, the animals were sacrificed and histomorphometric examinations of the retina and choroid were performed. We assessed the reproducibility of the OCT measurements and compared in-vivo measurements to histomorphometric data. Results: The mean thickness of the retina and choroid near the optic nerve head was 175.6 ± 25.8 and 63.4 ± 16.5 μm, respectively, and mean Bruch's membrane opening (BMO) diameter was 831 ± 121 μm. The intra-observer comparison of measurements of retinal thickness (intraclass correlation coefficient (ICC) = 0.92, 95% CI: 0.86-0.96; P < 0.001), choroidal thickness (ICC = 0.92, 95% CI: 0.86-0.96; P < 0.001), and BMO diameter (ICC = 0.92, 95% CI: 0.86-0.96; P < 0.001) showed a high correlation. A high agreement was present also for the inter-observer reproducibility of the measurements of retinal thickness (Pearson correlation coefficient ( R ) = 0.98; P < 0.001), choroidal thickness ( R = 0.96; P < 0.001), and BMO diameter ( R = 0.98; P < 0.001). The Bland-Altman plots showed that 2.6% (1/38), 5.3% (2/38), and 7.9% (3/38) of the measurement points of retinal thickness, choroidal thickness and BMO diameter, respectively, were located outside of the 95% limits of agreement. The OCT-based thickness measurements of retina and choroid were significantly higher than those measured by histomorphometry (both P -values <0.01). Conclusion: OCT-based in-vivo morphometric imaging of the retina and choroid in guinea pigs is feasible with an acceptable intra-observer repeatability and inter-observer reproducibility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dong, Li, Jiang, Lan, Shao, Jonas and Wei.)

Objective: To investigate the long-term efficacy and safety of alternating double balloon occlusion combined with intra-aneurysm injection of human fibrin binder in the endovascular repair of ruptured abdominal aortic aneurysm (rAAA). Methods: The clinical data of 28 patients with rAAA admitted to Department of Vascular Surgery, the Fourth Affiliated Hospital of Guangxi Medical University from January 2015 to December 2019 were retrospectively analyzed. There were 23 males and 5 females, aged (62±5) years (range: 46 to 88 years).The maximum diameter of the tumors was (65.2±10.5) mm (range: 47.3 to 100.5 mm), all of which were subrenal rAAA. The intraoperative EVAR for abdominal aortic aneurysm was successfully performed under the emergency green channel procedure, and this surgery was assisted used the double balloon occlusion technique in aorta of inferior renal and superior renalcombined with intraoperative human fibrin binder injection technique. Observation indexes included: patients with preoperative preparation, operation time, hospitalization days, surgical treatment success rate and the incidence of postoperative complications, and aortic stent form during the follow-up period, the incidence of leakage, branch stents patency rate and infection rates. Results: The preoperative preparation time of 28 patients was (45.5±8.5) minutes (range:20 to 100 minutes). The operation time was (100.0±15.5) minutes (range:85 to 210 minutes), the ICU stay time was (7±2) days(range:1 to 17 days). The length of hospitalization was (13.5±2.5) days(range:5 to 43 days). The success rate of surgical treatment was 92.9% (26/28). Two patients died, 1 case died of postoperative multifocal lacunar cerebral infarction and massive gastrointestinal hemorrhage, and another elderly patient (84 years old) died of massive abdominal fluid due to preoperative abdominal aortic aneurysm rupture, postoperative complicated with significant abdominal compartment syndrome, and secondary multiple organ failure. Balloon occlusion of the upper renal aorta took (13±2)minutes (range:12 to 30 minutes). The intraoperative injection of fibrin adhesive was (14±2) ml(range:6 to 28 ml) in 22 cases. The incidence of major postoperative complications was 57.1% (16/28). Among the 26 patients who survived the surgery, 69.2% (18/26) completed the 3-year follow-up, and the follow-up time was (30±3) months(range:13 to 36 months). During the follow-up, the aortic stent was in good shape without obvious displacement. The incidence of leakage within 6 months after the operation was 10.7% (3/28), and there was no internal leakage in the patients who were followed up for 36 months after the operation. The patency rate of renal artery and iliac artery branch stents was 16/18. The incidence of stent infection was 7.7% (2/26), 1 case occurred at 1 month and another case at 6 months, respectively. All patients recovered after prolonged intensive anti-infection therapy. Conclusions: Under the standard emergency treatment process, the double balloon alternating occlusion technique combined with the intra-aneurysm injection of human fibrin adhesive technique can assist the successful completion of the endovascular repair of rAAA, effectively improve the success rate of treatment for patients, and reduce the incidence of postoperative leakage and serious complications. The mid-term and long-term results of EVAR for rAAA are good, safe and reliable.

Pulmonary fibrosis (PF) is a progressive and devastating lung disease of unknown etiology, excessive fibroblast proliferation serves as a key event to promote PF. Transcription factor forkhead box M1 (FOXM1) is not only a well-known proto-oncogene, but also an essential driver of cell proliferation. Recently, 5'-AMP-activated protein kinase (AMPK) is reported to reduce the incidence of PF. However, it remains elusive whether have an underlying relationship between AMPK and FOXM1 in fibroblast proliferation-mediated PF. Here, the progression of lung fibroblast proliferation and the expression levels of AMPK and FOXM1 were observed by intratracheally instilled of bleomycin (BLM) and intraperitoneal injection of metformin in C57BL/6 J mice. Meanwhile, human fetal lung fibroblast1 (HFL1) cells were respectively treated with AMPK activator metformin or AMPK inhibitor Compound C, or FOXM1 depletion by transfected small interfering RNA (siRNA) to unveil roles of AMPK, FOXM1 and the link between them on platelet-derived growth factor (PDGF)-induced fibroblast proliferation. Our results demonstrated that AMPK activated by metformin could down-regulate FOXM1 and alleviate BLM-induced mouse PF model. In vitro, activation of AMPK attenuated PDGF-induced fibroblast proliferation accompanied by the down-regulation of FOXM1. In contrast, inhibition of AMPK enhanced PDGF-induced fibroblast proliferation along with activating FOXM1. These findings suggest that AMPK can ameliorate the progression of fibroblast proliferation during PF via suppressing the expression of FOXM1 and provide new insight into seek PF treatment approaches., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Fibroblast-myofibroblast differentiation (FMD) is a critical cellular phenotype during the occurrence and deterioration of pulmonary fibrosis (PF). FMD can increase with an elevated level of reactive oxygen species (ROS) on fibroblasts under oxidative stress. Thioredoxin-interacting protein (TXNIP) is an α-arrestin family protein that regulates the level of intracellular ROS. Nuclear factor erythroid 2-related factor 2 (Nrf2) can protect against FMD in PF. However, the relationship between Nrf2 and TXNIP in FMD remains elusive. Therefore, we established TGF-β1-induced FMD in vitro and bleomycin (BLM)-induced mouse PF model in vivo to explore whether the activation of Nrf2 can inhibit TXNIP-mediated FMD in PF. Dimethyl itaconate (DMI) was selected to activate Nrf2. Our results showed that TXNIP was elevated and FMD was aggravated in mice lung tissues after BLM administration compared with the saline group. Inversely, Nrf2 decreased TXNIP expression and alleviated FMD in PF. In vitro, TXNIP overexpression enhanced FMD and increased the level of ROS. In contrast, TXNIP deficiency by small interfering RNA (siRNA) attenuated TGF-β1-induced FMD and reduced ROS. An increase in ROS by H 2 O 2 can upregulate TXNIP expression. Moreover, Nrf2 also inhibited TGF-β1-induced FMD and the increase of ROS, with reducing expression of TXNIP, and the inhibitory effect was better than TXNIP siRNA. These results suggest that activation of Nrf2 by DMI can protect against PF via inhibiting TXNIP expression. Our study may provide new therapeutic targets and treatment approaches for PF., (© 2021 Wiley Periodicals LLC.)

This paper summarizes the basic principles and models of early warning for infectious disease outbreaks, introduces the early warning systems for infectious disease based on different data sources and their applications, and discusses the application potential of big data and their analysing techniques, which have been studied and used in the prevention and control of COVID-19 pandemic, including internet inquiry, social media, mobile positioning, in the early warning of infectious diseases in order to provide reference for the establishment of an intelligent early warning mechanism and platform for infectious diseases based on multi-source big data.

This study aimed to develop an automated computer-based algorithm to estimate axial length and subfoveal choroidal thickness (SFCT) based on color fundus photographs. In the population-based Beijing Eye Study 2011, we took fundus photographs and measured SFCT by optical coherence tomography (OCT) and axial length by optical low-coherence reflectometry. Using 6394 color fundus images taken from 3468 participants, we trained and evaluated a deep-learning-based algorithm for estimation of axial length and SFCT. The algorithm had a mean absolute error (MAE) for estimating axial length and SFCT of 0.56 mm [95% confidence interval (CI): 0.53,0.61] and 49.20 μm (95% CI: 45.83,52.54), respectively. Estimated values and measured data showed coefficients of determination of r 2 = 0.59 (95% CI: 0.50,0.65) for axial length and r 2 = 0.62 (95% CI: 0.57,0.67) for SFCT. Bland-Altman plots revealed a mean difference in axial length and SFCT of -0.16 mm (95% CI: -1.60,1.27 mm) and of -4.40 μm (95% CI, -131.8,122.9 μm), respectively. For the estimation of axial length, heat map analysis showed that signals predominantly from overall of the macular region, the foveal region, and the extrafoveal region were used in the eyes with an axial length of < 22 mm, 22-26 mm, and > 26 mm, respectively. For the estimation of SFCT, the convolutional neural network (CNN) used mostly the central part of the macular region, the fovea or perifovea, independently of the SFCT. Our study shows that deep-learning-based algorithms may be helpful in estimating axial length and SFCT based on conventional color fundus images. They may be a further step in the semiautomatic assessment of the eye., Competing Interests: XYH, JHX, and CXL were employed by the company Beijing Eaglevision Technology Co., Ltd., China The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2021 Dong, Hu, Yan, Zhang, Zhou, Shao, Wang, Xu, Lan, Li, Xiong, Liu, Ge, Jonas and Wei.)

BCL-2, a key protein in inhibiting apoptosis, has a 65-residue-long highly flexible loop domain (FLD) located on the opposite side of its ligand-binding groove. In vivo phosphorylation of the FLD enhances the affinity of BCL-2 for pro-apoptotic ligands, and consequently anti-apoptotic activity. However, it remains unknown as to how the faraway, unstructured FLD modulates the affinity. Here we investigate the protein-ligand interactions by fluorescence techniques and monitor protein dynamics by DEER and NMR spectroscopy tools. We show that phosphomimetic mutations on the FLD lead to a reduction in structural flexibility, hence promoting ligand access to the groove. The bound pro-apoptotic ligands can be displaced by the BCL-2-selective inhibitor ABT-199 efficiently, and thus released to trigger apoptosis. We show that changes in structural flexibility on an unstructured loop can activate an allosteric protein that is otherwise structurally inactive.

This paper reviews the limitations of current infectious disease surveillance and early warning system in China, analyzes the concepts and countermeasures of the establishment of an intelligent early warning platform of infectious diseases based on multi-point trigger mechanism and multi-channel surveillance mechanism and proposes the realization routes for the purpose of facilitating capacity building and improvement of surveillance and early warning of infectious diseases in China.

Objective: To explore the relationship between the worker-occupation fit and occupational stress in nurses. Methods: Convenience sampling method was used to collect 1 463 nurses from one general hospital and three specialized hospitals from July to October 2019. Depression-anxiety-stress scale (DASS-21) was used to assess the level of occupational stress. Pearson correlation and multivariate logistic regression model were used to analyze the relationship between the worker-occupation fit and occupational stress. Results: The average age of 1 463 nurses was (31.8±7.2) years, and 92.3% ( n =1 350) of nurses were female. 47.2% ( n =690) of nurses had occupational stress and the mean score of worker-occupation fit was (34.4±6.1). The worker-occupation fit and occupational stress had a significant negative correlation ( r =-0.472, P <0.001). The moderate and high level of the worker-occupation fit, characteristic fit, need supply fit, and demand ability fit had protective effects on occupational stress based on the outcome of multivariate logistic regression model [ OR (95% CI ) were 0.40 (0.28-0.59), 0.16 (0.10-0.24); 0.32 (0.22-0.47), 0.18 (0.11-0.20); 0.33 (0.21-0.52), 0.18 (0.11-0.30); 0.59 (0.37-0.9), 0.54 (0.38-0.78), respectively]. Conclusion: The worker-occupation fit and different types of fit, including characteristic fit, need supply fit, and demand ability fit, could be associated with the occupational stress.

To examine the influence of epidermal growth factor (EGF) and its receptor (EGFR) on axial ocular elongation, we intraocularly injected an EGF antibody and an EGFR antibody into young guinea pigs with lens-induced axial elongation (myopization). Mean axial elongation was reduced in the eyes injected with the EGF/EGFR-antibody compared with the contralateral control eyes injected with PBS (phosphate-buffered solution) (0.43 ± 0.13 mm vs 0.53 ± 0.13 mm; P < .001). The intereye difference in axial length increased (P = .005) as the doses of the EGF antibody and EGFR antibody increased. As a corollary, the thickness of the retina at the posterior pole was dose-dependently increased in the injected eyes compared to the contralateral control eyes. Immunohistochemical staining for EGF and the relative mRNA expression of EGF and EGFR were the highest in eyes not injected with the EGF antibody or EGFR antibody and decreased (P < .05) as the dose of EGF antibody or EGFR antibody increased. In an in vitro study, EGF had a stimulating effect and the EGF antibody had an inhibitory effect on the proliferation and migration of RPE cells. The findings showed that the intravitreal application of an EGF antibody and EGFR antibody is associated with a dose-dependent reduction in lens-induced axial elongation in young guinea pigs. The EGFR family may play a role in axial elongation of the eye and in the development of myopia., (© 2020 Federation of American Societies for Experimental Biology.)

Background: Intraocular pressure (IOP) is an important physiological measure of the eye and is associated with some ocular disorders. We aimed to assess the influence of topical beta blocker-induced IOP reduction on lens-induced axial elongation in young guinea pigs., Methods: The experimental study included 20 pigmented guinea pigs (age: 2-3 weeks). Myopia was induced in the right eyes for 5 weeks with - 10 diopter lenses. The right eyes additionally received either one drop of carteolol 2% (study group, n = 10) or one drop of artificial tears daily (control group, n = 10), while the contralateral eyes of all animals remained untouched. The outcome parameter was axial elongation during the follow-up period. The mean of all IOP measurements taken during the study was referred to as mean IOP., Results: Greater axial elongation was associated with a shorter axial length at baseline (P < 0.001; standardized regression coefficient beta: - 0.54) and lens-induced myopization (P < 0.001; beta: 0.55). In the multivariable model, axial elongation was not significantly correlated with the IOP at study end (P = 0.59), the mean IOP during the study period (P = 0.12), the mean of all IOP measurements (P = 0.17), the difference between the IOP at study end and baseline IOP (P = 0.38), the difference between the mean IOP during the study period and the baseline IOP (P = 0.11), or the application of carteolol eye drops versus artificial tears eye drops (P = 0.07). The univariate analysis of the relationships between axial elongation and the IOP parameters yielded similar results. The inter-eye difference between the right eye and the left eye in axial elongation was significantly associated with the inter-eye difference in baseline axial length (P = 0.001; beta:-0.67) but not significantly correlated with the inter-eye difference in any of the IOP-related parameters (all P > 0.25)., Conclusions: In young guinea pigs with or without lens-induced axial elongation, neither the physiological IOP nor the IOP reduced by carteolol, a topical beta-blocker, was associated with the magnitude of axial elongation. These results suggest that IOP, regardless of whether it is influenced by carteolol, does not play a major role in axial elongation in young guinea pigs.

The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings., (Copyright © 2020 Eura, Matsui, Luginbühl, Matsubayashi, Nanaura, Shiota, Kinugawa, Iguchi, Kiriyama, Zheng, Kouno, Lan, Kongpracha, Wiriyasermkul, Sakaguchi, Nagata, Komeda, Morikawa, Kitayoshi, Jong, Kobashigawa, Nakanishi, Hasegawa, Saito, Shiromizu, Nishimura, Kasai, Takeda, Kobayashi, Inagaki, Tanaka, Makinodan, Kishimoto, Kuniyasu, Nagamori, Muotri, Shin, Sugie and Mori.)

The relationship between colorectal cancer and asbestos exposure has not been fully clarified. This study aimed to determine the associations between asbestos exposure and colorectal cancer. We performed a meta-analysis to quantitatively evaluate this association. A fixed effects model was used to summarize the relative risks across studies. Sources of heterogeneity were explored through subgroup analyses and meta-regression. We analyzed the dose-effect relationship using lung cancer standardized mortality ratio (SMR) and the risk of mesothelioma as a percent (%) as exposure surrogates. A total of 47 cohort studies were included. We identified 28 incidence cohort studies from 17 separate papers and extracted colorectal cancer standardized incidence ratio (SIR). Cancer mortality data were extracted from 19 separate cohorts among 13 papers. The overall colorectal cancer SMR for synthesis cohort was 1.07 (95% CI 1.02-1.12). Statistically significant excesses were observed in exposure to mixed asbestos (SMR/SIR=1.07), exposure to production (SMR/SIR=1.11), among asbestos cement workers (SMR/SIR=1.18) and asbestos textile workers (SMR/SIR=1.11). Additionally, we determined that the SMR for lung cancer increased with increased exposure to asbestos, as did the risk for colorectal cancer. This study confirms that colorectal cancer has a positive weak associations with asbestos exposure.

Background: BAX activation is a crucial step for commitment to apoptosis. Several activators, such as BimBH3-based therapeutic peptides and cleaved Bid (cBid) protein, can trigger BAX-mediated apoptosis, but it is unclear whether they proceed through the same pathway., Methods: Here we utilize PEGylation-based approach, which is shown to efficiently shield individual binding grooves in BAX from activators, to investigate and reveal that the activators take different routes to induce BAX-mediated apoptosis. Various spectroscopic/biochemical tools, including electron spin resonance, circular dichroism, fluorescence recovery after photobleaching, and label-transfer assay, were employed to reveal details in the processes., Results: We observe a key mutant BAX 164-PEG that acts differently in response to cBid and BimBH3 stimuli. While BimBH3 directly interacts with the trigger groove (TG) to induce the conformational changes in BAX that includes the release of α9 from the canonical groove (CG) and oligomerization, cBid engages with CG and works with mitochondrial lipids to fully activate BAX., Conclusion: PEGylation-based approach is proven useful to shield individual binding grooves of BAX from apoptotic stimuli. Groove engagement in CG of BAX is required for a full cBid-induced BAX activation. This study has identified differences in the pathways involved during the initiation of BAX activation by full-length cBid protein versus synthetic BimBH3-based peptides., General Significance: Our finding is potentially valuable for therapeutic application as the pore-forming activity of 164-PEG is independent from the cBid-mediated apoptotic pathways, but can be administrated by the synthetic short peptides., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: We aimed to investigate the effect of different pulse numbers of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the motor cortex on cortical excitability in healthy participants., Methods: Fifteen healthy participants received 600 and 1200 pulses of 5-Hz rTMS on separate days in a random order. Stimulation (duration, 2 seconds and interval, 1 seconds) was delivered over the left primary motor cortex for the hand, at 90% of resting motor threshold (rMT). The rMT and motor evoked potential (MEP) were measured before stimulation, and at 0 and 30 minutes after rTMS., Results: No significant differences were observed between the two conditions for MEP (P = .919) or rMT (P = .266). Compared with baseline, MEP was increased significantly at 0 (P < .001) and 30 minutes (P < .001) after stimulation. After stimulation, rMT was decreased at 0 minute for the 600 and 1200 pulse conditions (P < .001), but had recovered by 30 minutes (P = .073)., Conclusion: Subthreshold 5-Hz rTMS increased motor cortex excitability in healthy humans. However, the number of pulses may exhibit a ceiling effect in that beyond a certain point, that is, increasing the number of pulses may exhibit no further increase in cortical excitability., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Objective: To analyze the hearing self-protection behavior patterns and internal factors of workers exposured to occupational noise in an aircraft manufacturing industry based on health belief model, so as to provide reference for further health promotion programs and intervention measures. Methods: A total of 1600 front-line workers were selected from 10 units of an aircraft manufacturing enterprise by cluster sampling method. The basic and occupational information of employees were collected, and a self-reported questionnaire was designed according to the health belief model to acquire the hearing self-protection behaviors of workers. Results: There were significant differences in the perceived severity, perceived benefit, perceived impairment, self-efficacy and behavioral incentive scores of different hearing self-protection behaviors among the noise-causing workers ( P <0.05). There were significant differences in the distribution of hearing self-protection behaviors among different genders, ages, education levels, length of service, initial noise exposure time and cumulative noise reception time ( P <0.05). The perceived benefits, perceived barriers, behavioral incentives, self-efficacy scores, and educational attainment of the noise-causing workers were all related to the type of hearing self-protection behavior ( P <0.05) . Conclusion: The educational level and health belief model can predict the hearing self-protection behavior patterns of front-line workers to some extent, more attention should be paid to the monitoring of the well-educated employees.

Recent research indicates that learning a second language (L2) results in both functional and structural brain changes. However, few studies have examined whether structural brain changes vary as a function of the context in which L2 learning takes place. The current study examines changes in cortical thickness (CT) and gray matter volume (GMV) in response to short-term L2 vocabulary learning. In particular, we compared structural changes for learning with paired picture-word (PW) association versus learning within virtual environments (VE) and non-trained controls. Both L2 training groups learned the same 90 Mandarin Chinese nouns across 7 training sessions over approximately 20 days. Our results show (a) CT and GMV increased in regions implicated in a language control network for both L2 training groups, and (b) participants in different learning contexts may rely on different structures within this language control network. In particular, CT in the right IFG was associated with L2 training performance for the PW group, whereas CT in the right IPL showed a positive correlation with L2 training performance for the VE group. Our findings indicate that short-term L2 training leads to changes in brain structure, which vary based on L2 learning contexts and individual differences in cognitive ability., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the regulatory effect of miR-29c on the trans-differentiation of pulmonary fibroblasts into myofibroblasts induced by silica dust. Methods: Fibroblasts obtained from SD rat lung tissue and pulmonary macrophages (NR8383) were co-cultured to establish the silicosis cell model in vitro. And real time-quantitative polymerase chain reaction (RT-qPCR) and Western Blot assays were performed to detect the altered expression level of miR-29c and α-smooth muscle actin (α-SMA) . After that, the in vitro cell model was transfected with corresponding viruses to establish miR-29c overexpression and inhibition cell models, and the mRNA and protein expression levels of α-SMA were detected simultaneously. Results: Compared with control group, the expression level of miR-29c in the silicosis cell model in vitro was down-regulated significantly after 12 or 18 h exposed to SiO(2), and both of the mRNA and protein expression levels of α-SMA were up-regulated instead ( P <0.05) . When transfected with corresponding viruses, the mRNA and protein expression levels of α-SMA in the pulmonary fibroblasts were significantly up-regulated in miR-29c inhibition group and down-regulated in miR-29c overexpression group ( P <0.05) . Conclusion: Based on the findings, it could be safely infered that the development of pulmonary fibrosis could be impeded by inhibiting transdifferentiation process of pulmonary fibroblasts into myofibroblasts regulated by miR-29c, miR-29c could be an potential therapeutic target to lung fibrosis induced by silica.

BCL-2-associated X (BAX) protein acts as a gatekeeper in regulating mitochondria-dependent apoptosis. Under cellular stress, BAX becomes activated and transforms into a lethal oligomer that causes mitochondrial outer membrane permeabilization (MOMP). Previous studies have identified several structural features of the membrane-associated BAX oligomer; they include the formation of the BH3-in-groove dimer, the collapse of the helical hairpin α5-α6, and the membrane insertion of α9 helix. However, it remains unclear as to the role of lipid environment in determining the conformation and the pore-forming activity of the BAX oligomers. Here we study molecular details of the membrane-associated BAX in various lipid environments using fluorescence and ESR techniques. We identify the inactive versus active forms of membrane-associated BAX, only the latter of which can induce stable and large membrane pores that are sufficient in size to pass apoptogenic factors. We reveal that the presence of CL is crucial to promoting the association between BAX dimers, hence the active oligomers. Without the presence of CL, BAX dimers assemble into an inactive oligomer that lacks the ability to form stable pores in the membrane. This study suggests an important role of CL in determining the formation of active BAX oligomers., (Copyright © 2018 Elsevier B.V. All rights reserved.)

For the practical application of Bacillus licheniformis γ-glutamyltranspeptidase (BlGGT), we illustrated a simple and efficient approach to fabricate a biocatalytic system by immobilizing the enzyme onto graphene oxide (GO) nanosheets via both non-covalent (GO-BlGGT) and covalent (GO/GA-BlGGT) bonds. The enzyme-loading capacity for the prepared GO/GA nanomaterial was 3.47 mg/mg support, corresponding to 68.7% recovery of the initial activity. Native and enzyme-bound layered GOs were characterized by X-ray diffraction, followed by Raman and Fouier transform infrared spectroscopy, elemental analysis and thermogram analysis. As compared to the free form of BlGGT, the immobilized enzymes exhibited significantly higher activity, possibly due to the beneficial effect of the layered GO carrier. The kinetic behaviors of GO-BlGGT and GO/GA-BlGGT were mostly consistent with those of free enzyme. The covalently immobilized enzyme had a comparable stability respective to free enzyme during a storage period of 30 days and could be recycled nine times with 45.3% retention of the initial activity. Besides, the biocatalytic synthesis of γ-l-glutamyl-phenylalanine and γ-l-glutamyl-leucine by immobilized enzymes resulted in the product yield of more than 31%. Taken together, these results suggest that the facile strategy is an economical means of depositing bioactive enzymes upon GO nanosheets for BlGGT-mediated biocatalysis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To assess psychological acceptance and occupational stress of medical staff, analyze the relationship among personality, psychological acceptance and occupational stress and discuss the direct or indirect effects of personality to occupational stress. Methods: Eysenck Personality Questionnaire (EPQ-RSC) , Acceptance and Action Questionnaire-II (AAQ-Ⅱ) and Revised Occupational Stress Inventory (OSI-R) were administered to 749 medical staff. Results: The level of occupational stress of medical staff was high, the score of PSY was 26.8±7.13 and the score of PHS was 24.3±6.50. Personality and psychological acceptance can predict occupational stress. Psychological acceptance was a protective factor of occupational stress. Medical staff with personality of introversion, neuroticism and psychoticism suffered higher occupational stress. Personality have both direct and indirect effects on occupational stress. Neuroticism have the strongest effect on occupational stress with effect size of 0.496 (psychological stress) and 0.431 (physical strain) . Conclusion: Medical staff have heavier occupational stress. There is a significant correlation between personality and occupational stress. Measures depending on personality should be taken to deal with this situation.

Objective: To evaluate the quality of Pneumoconiosis Network Direct Report in Sichuan Province in 2006-2016. Methods: download all the pneumoconiosis report cards from the Network Direct Report system. Screen out cards based on the diagnosis time that is between January 1st 2006 and December 31st 2016. Using R 3.4.0 software to analysis the number of missing or repeated cards, time-logical error rates, timeliness, reporting year, reporting intervals to evaluate the quality of Pneumoconiosis Network Direct Report and location distribution. Results: there are 38 855 pieces of Pneumoconiosis report card in total in 2006-2016. 352 pieces of cards were reported twice. 224 cards were missing. 229 cards have time-logical error. The rate of timely reporting for 2006-2016 years was 66.41% (2 5453/38 326) , 67.14% (24 658/36 726) for new cases, 58.87% (783/1 330) for promoting cases and 4.44% (12/270) for deaths. 87.38% (33 490/38 326) patients was reported in the same year. 10 days was needed to finish one report, confirming-filling cost much more time than filling-report (9.865/49.019) . Conclusion: the records of pneumoconiosis report cards are much more complete, logical errors are less, and the timeliness was a little bit higher than the average level in China. But it also should be improved. The death cases are difficult to report. It takes longer to diagnose and fill in cards. Improving the timeliness rate can significantly improve the quality of network direct reporting.

Objective: To evaluate occupational stress and perceptions of the work experience among the nurses, and to analyze the effects of recovery experiences on the adjustment of the relationship of stress and perceptions of the work experience. Methods: A questionnaire survey was conducted among nurses from 7 third hospitals in a city through sampling. A self-designed questionnaire, "Job Content Questionnaire (JCQ) " , "Recovery Experience Questionnaire (REQ-C) " and "Quality of working life (QWL7-32) " were completed by the subjects. Establishment of recovery experience types by sample cluster analysis, combined with regression analysis in the regulation of perceptions of the work experience of recovery experiences'types. Results: There have differences instatus and score of perceptions of the work experience among nurses with different tension level ( P <0.05) . The Perceptions of Work Experience scores of nurses with different types of recovery experience are different with the tension level, and the type of recovery experience has an independent moderating effect on the relationship between tension and perceptions of work experience. Conclusion: The moderating effects of different types of recovery experiences on perceptions of work experience are different.

Objective: To discuss the feasibility, effect and safety of lower abdominal aorta balloon occlusion technique by ultrasound guiding during caesarean section in patients with pernicious placenta previa. Methods: The clinical data of 40 patients with pernicious placenta previa complicated with placenta accreta from January 2015 to August 2017 in Liuzhou workers hospital were analyzed retrospectively. The study group included 20 cases, which were operated in the way of cesarean section combined lower abdominal aorta balloon occlusion technique by ultrasound guiding, while the control group also included 20 cases, which were operated in the way of the conventional cesarean section without balloon occlusion technique. The bleeding amount, blood transfusion volume, operative total time, hysterectomy and complications of the two groups were compared. Results: The bleeding amount and blood transfusion volume in study group were(850±100)ml and (400±50)ml, which were lower than that of the control group[(2 500±230)ml and (1 500±100)ml], the difference was statistically significant( t =35.624, 16.523, all P <0.05). In addition, the hysterectomy rate in study group was 5%, which was lower than that in the control group(30%), the difference was statistically significant(χ 2 =8.672, P <0.05). And the total time of operation was (2.0±0.5)h in the study group, which was shorter than that in the control group[(3.5±0.4)h]. The difference was statistically significant( t =11.362, P <0.05). No postoperative complications took place in the study group.The blood pressure, heart rate and blood oxygen fluctuated significantly, and the postoperative renal function was significantly reduced in the control group. Conclusions: The lower abdominal aorta balloon occlusion technique by ultrasound guiding during a caesarean section in patients with pernicious placenta previa can effectively control the bleeding during operation, and preserve reproductive function to the utmost degree.Therefore, the technique is safe, feasible, convenient and cheaper, and worthy of being widely applied in clinic.

Hippocampal function is important for learning and memory, and dysfunction of the hippocampus has been linked to the pathophysiology of neuropsychiatric diseases such as schizophrenia. Neuregulin1 (NRG1) and ErbB4, two susceptibility genes for schizophrenia, reportedly modulate long-term potentiation (LTP) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, little is known regarding the contribution of hippocampal NRG1/ErbB4 signaling to learning and memory function. Here, quantitative real-time PCR and Western blotting were used to assess the mRNA and protein levels of NRG1 and ErbB4. Pharmacological and genetic approaches were used to manipulate NRG1/ErbB4 signaling, following which learning and memory behaviors were evaluated using the Morris water maze, Y-maze test, and the novel object recognition test. Spatial learning was found to reduce hippocampal NRG1 and ErbB4 expression. The blockade of NRG1/ErbB4 signaling in hippocampal CA1, either by neutralizing endogenous NRG1 or inhibiting/ablating ErbB4 receptor activity, enhanced hippocampus-dependent spatial learning, spatial working memory, and novel object recognition memory. Accordingly, administration of exogenous NRG1 impaired those functions. More importantly, the specific ablation of ErbB4 in parvalbumin interneurons also improved learning and memory performance. The manipulation of NRG1/ErbB4 signaling in the present study revealed that NRG1/ErbB4 activity in the hippocampus is critical for learning and memory. These findings might provide novel insights on the pathophysiological mechanisms of schizophrenia and a new target for the treatment of Alzheimer's disease, which is characterized by a progressive decline in cognitive function.

Many psychiatric diseases such as post-traumatic stress disorder (PTSD) are characterized by abnormal processing of emotional stimuli particularly fear. The medial prefrontal cortex (mPFC) is critically involved in fear expression. However, the molecular mechanisms underlying this process are largely unknown. Neuregulin-1 (NRG1) reportedly regulates pyramidal neuronal activity via ErbB4 receptors, which are abundant in parvalbumin (PV)-expressing interneurons in the PFC. In this study, we aimed to determine how NRG1/ErbB4 signaling in the mPFC modulates fear expression and found that tone-cued fear conditioning increased NRG1 expression in the mPFC. Tone-cued fear conditioning was inhibited following neutralization of endogenous NRG1 and specific inhibition or genetic ablation of ErbB4 in the prelimbic (PL) cortex but not in the infralimbic cortex. Furthermore, ErbB4 deletion specifically in PV neurons impaired tone-cued fear conditioning. Notably, overexpression of ErbB4 in the PL cortex is sufficient to reverse impaired fear conditioning in PV-Cre;ErbB4 -/- mice. Together, these findings identify a previously unknown signaling pathway in the PL cortex that regulates fear expression. As both NRG1 and ErbB4 are risk genes for schizophrenia, our study may shed new light on the pathophysiology of this disorder and help to improve treatments for psychiatric disorders such as PTSD.

Objective: To examine the relationship between recovery experience, occupational stress, and physiological health of nurses in a municipal grade A tertiary hospital. Methods: A total of 296 in-service nurses from 7 municipal grade A tertiary hospitals were selected from October 2015 to February 2016. Individual characteristics of the subjects were collected using a self-made questionnaire. The recovery experience, occupational stress, and physiological health of the subjects were assessed based on the physiological health dimensions in the Chinese version of Recovery Experience Questionnaire (REQ-C) , Job Content Questionnaire (JCQ) , and Quality of Work Life (QWL7-32) . Results: The mean recovery experience score of nurses from the municipal grade A tertiary hospital was 45.04±7.72, and 51.35% of the nurses had satisfactory recovery experience. Occupational stress was identified in 81.76% of the nurses. Based on the four categories of occupational stress, 65 nurses were identified with high-strain jobs (21.95%) , 56 with relaxed (low-strain) jobs (18.92%) , 49 with passive jobs (16.55%) , and 126 with active jobs (42.57%) . In addition, the mean physiological health score of the nurses was 21.20±4.24. Physiological health was negatively correlated with occupational stress ( r =-0.173, P <0.05) , but positively correlated with recovery experience ( r =0.198, P <0.01) . Recovery experience was negatively correlated with occupational stress ( r =-0.116, P <0.05) . Job demand was the major contributor to occupational stress, where subjects with high-demand active jobs had the poorest recovery experience ( F =2.610, P <0.05) and physiological health ( F =8.166, P <0.01) . Conclusion: Job demand has a great impact on the occupational stress of nurses, where increased job demand can lead to stronger stress response, reduced recovery experience, and poorer physiological health.

While activation of BAX is required for initiating mitochondria-mediated apoptosis, the underlying mechanisms remain unsettled. We studied conformations of BAX protein using pressure- and temperature-resolved ESR techniques and obtained the thermodynamic properties of the conformations. We show that inactive BAX is structurally heterogeneous and exists in equilibrium between two major populations of the conformations, UM and UM', of which the former is thermodynamically favored at room temperature. An increase in the population of UM', induced by either pressure or point mutations of BAX, renders BAX susceptible to oligomerization, which leads to cell death. This study uncovers the biological significance of BAX conformations and shows that the pro-apoptotic activity of BAX can be triggered by altering the equilibrium between the two states. It suggests that therapeutic intervention may focus on shifting the balance in the conformational heterogeneity.

Objective: To evaluate the current status of job burnout and qual ity of work life (QWL) in workers for offshore oil platforms, and to analyze the relationship of job stress with job burnout and QWL and the direct and indirect effects of job stress on QWL. Methods: Cluster random sampling was used to select 382 work-ers for 8 oil platforms of China National Offshore Oil Corporation in October 2015. A self - designed questionnaire was used to collect the individual characteristics of subjects. The Quality of Work Life Scale (QWL7 - 32) , Occupa-tional Stress Inventory - Revised Edition (OSI - R) , and Maslach Burnout Inventory - General Survey (MBI - GS) were used to investigate the QWL, job stress, and job burnout of subjects. Results: Among all the workers for offshore oil platforms, 87.2% had mild job burnout. The total QWL score was 116.01 ± 16.73; 8.3% of the workers had poor QWL, and 68.5% had moderate QWL. QWL was reduced with heavier task, vaguer task, and increasing mental stress and physical stress ( P <0.05) , and increased with more social support ( P <0.05) . Job stress had di-rect and indirect effects on QWL; stress reaction had the most effect on QWL (total effect size - 0.509) , followed by social support (total effect size 0.444) . Conclusion: Most workers for offshore oil platforms have mild job burn-out and moderate QWL. Job stress is associated with job burnout and QWL, and stress reaction and social support have relatively high influence on QWL.

Objectives: To investigate the polymorphisms in interleukin 17A IL-17A) and interleukin 17F ( IL-17F ) and their relationship with pulmonary inflammation risk of dust exposed workers., Methods: A case-control study among 193 subjects, including 67 subjects in case group and 126 in control group was conducted. PCR-RFLP was applied to genotype IL-17A (G-197A) and IL-17F (7488T/C). Logistic regression analysis was used to determine the effects of IL-17A (G-197A) and IL-17F (7488T/C) on the lung inflammation risk in dust exposed workers., Results: The genotypes analysis showed that the proportions of IL-17A (G-197A) A/A, A/G and G/G were 42 (21.76%), 95 (49.22%), 56 (29.02%) in 193 cases, respectively, and the IL-17F (7488T/C) T/T, T/C and C/C genotypes were 128 (66.32%), 54 (28.98%), 11 (5.70%), respectively. The frequency distribution of each genotype was consistent with the Hardy-Weinberg equilibrium fixed law. The ratio of IL-17A (G-197A) A/A in the case group was lower than that of control group ( P <0.05), while the G/G and A/G genotypes were higher than that of control group ( P <0.05). Furthermore, the genotypes of IL-17A (G-197A) A/G ( OR =5.03, P <0.01) and G/G( OR =3.35, P <0.05) were associated with an increased risk of lung inflammation in workers exposed to dust. The frequency distribution difference of IL-17F (7488T/C) T/T, T/C and C/C genotypes in the cases and control group was unobvious ( P >0.05)., Conclusions: Under the same dust concentration, the dust exposed workers carrying IL-17A (G-197A) A/G, G/G genotypes are more susceptible to pulmonary inflammation in the southwest of China.

Background and Objectives: To investigate the effect of overweight status on the 6-month survival rate in patients with extrahepatic hepatocellular carcinoma (HCC)., Methods and Study Design: We retrospectively analyzed the records of 51 patients with hepatocellular carcinoma and extrahepatic metastases between 2007 and 2010 before treatment. The associations among overweight status (body mass index [BMI] >24 kg/m2), demographic variables, and survival outcome were analyzed by univariate and multivariate analysis., Results: BMI>24 kg/m2 was significantly associated with the 6-month survival rate (p=0.042). Gender (p=0.149), Child Pugh classification (p=0.149), Okuda staging (p=0.093), and albumin concentration >3.5 mg/dL (p=0.082) showed marginal survival benefits in univariate analysis. Multivariate analysis confirmed that BMI >24 kg/m2 was an independent prognostic factor for the 6-month survival rate (p=0.03)., Conclusions: BMI >24 kg/m2 was associated with an improved 6-month survival rate in patients with extrahepatic metastatic hepatocellular carcinoma.