In Situ Electrochemical Rapid Induction of Highly Active γ-NiOOH Species for Industrial Anion Exchange Membrane Water Electrolyzer.

Limited by the strong oxidation environment and sluggish reconstruction process in oxygen evolution reaction (OER), designing rapid self-reconstruction with high activity and stability electrocatalysts is crucial to promoting anion exchange membrane (AEM) water electrolyzer. Herein, trace Fe/S-modified Ni oxyhydroxide (Fe/S-NiOOH/NF) nanowires are constructed via a simple in situ electrochemical oxidation strategy based on precipitation-dissolution equilibrium. In situ characterization techniques reveal that the successful introduction of Fe and S leads to lattice disorder and boosts favorable hydroxyl capture, accelerating the formation of highly active γ-NiOOH. The Density Functional Theory (DFT) calculations have also verified that the incorporation of Fe and S optimizes the electrons redistribution and the d-band center, decreasing the energy barrier of the rate-determining step (*O→*OOH). Benefited from the unique electronic structure and intermediate adsorption, the Fe/S-NiOOH/NF catalyst only requires the overpotential of 345 mV to reach the industrial current density of 1000 mA cm-2 for 120 h. Meanwhile, assembled AEM water electrolyzer (Fe/S-NiOOH//Pt/C-60 °C) can deliver 1000 mA cm-2 at a cell voltage of 2.24 V, operating at the average energy efficiency of 71% for 100 h. In summary, this work presents a rapid self-reconstruction strategy for high-performance AEM electrocatalysts for future hydrogen economy.

Effects of CYP3A4*22 and POR*28 variations on the pharmacokinetics of tacrolimus in renal transplant recipients: a meta-analysis of 18 observational studies.

PURPOSE: This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus. METHODS: Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0/Dose). RESULTS: The study included 2931 renal transplant recipients from 18 publications. Weight-adjusted daily dose of CYP3A4*1/*1 carriers was 0.04 (WMD = 0.04, 95% CI: 0.02 to 0.06), 0.03 (WMD = 0.03, 95% CI: 0.02 to 0.05), 0.02 (WMD = 0.02, 95% CI: 0.01 to 0.03), or 0.02 mg/kg/day (WMD = 0.02, 95% CI: 0.00 to 0.04) higher than CYP3A4*22 carriers in Caucasians at 1 month, 3 months, 6 months, or 12 months post-transplantation. Conversely, C0/Dose was lower for CYP3A4*1/*1 carriers at 3 days (SMD = -0.35, 95% CI: -0.65 to -0.06), 1 month (SMD = -0.67, 95% CI: -1.16 to -0.18), 3 months (SMD = -0.60, 95% CI: -0.89 to -0.31), 6 months (SMD = -0.76, 95% CI: -1.49 to -0.04), or 12 months post-transplantation (SMD = -0.69, 95% CI: -1.37 to 0.00). Furthermore, C0/Dose of POR*1/*1 carriers was 22.64 (WMD = 22.64, 95% CI: 2.54 to 42.74) or 19.41 (ng/ml)/(mg/kg/day) (WMD = 19.41, 95% CI: 9.58 to 29.24) higher than POR*28 carriers in CYP3A5 expressers at 3 days or 7 days post-transplantation, and higher in Asians at 6 months post-transplantation (SMD = 0.96, 95% CI: 0.50 to 1.43). CONCLUSIONS: CYP3A4*22 variant in Caucasians restrains the metabolism of tacrolimus, while POR*28 variant in CYP3A5 expressers enhances the metabolism of tacrolimus for renal transplant recipients. However, further well-designed prospective studies are necessary to substantiate these conclusions given some limitations.

Ubiquitous Gait Analysis through Footstep-Induced Floor Vibrations.

Quantitative analysis of human gait is critical for the early discovery, progressive tracking, and rehabilitation of neurological and musculoskeletal disorders, such as Parkinson's disease, stroke, and cerebral palsy. Gait analysis typically involves estimating gait characteristics, such as spatiotemporal gait parameters and gait health indicators (e.g., step time, length, symmetry, and balance). Traditional methods of gait analysis involve the use of cameras, wearables, and force plates but are limited in operational requirements when applied in daily life, such as direct line-of-sight, carrying devices, and dense deployment. This paper introduces a novel approach for gait analysis by passively sensing floor vibrations generated by human footsteps using vibration sensors mounted on the floor surface. Our approach is low-cost, non-intrusive, and perceived as privacy-friendly, making it suitable for continuous gait health monitoring in daily life. Our algorithm estimates various gait parameters that are used as standard metrics in medical practices, including temporal parameters (step time, stride time, stance time, swing time, double-support time, and single-support time), spatial parameters (step length, width, angle, and stride length), and extracts gait health indicators (cadence/walking speed, left-right symmetry, gait balance, and initial contact types). The main challenge we addressed in this paper is the effect of different floor types on the resultant vibrations. We develop floor-adaptive algorithms to extract features that are generalizable to various practical settings, including homes, hospitals, and eldercare facilities. We evaluate our approach through real-world walking experiments with 20 adults with 12,231 labeled gait cycles across concrete and wooden floors. Our results show 90.5% (RMSE 0.08s), 71.3% (RMSE 0.38m), and 92.3% (RMSPE 7.7%) accuracy in estimating temporal, spatial parameters, and gait health indicators, respectively.

[Liver impairment status toward workers exposed to vinyl chloride under different techniques].

OBJECTIVE: To analyse potential differences towards liver impairment status on vinyl chloride monomer(VCM) exposed population from technique under acetylene hydrochlorination to the one of ethylene oxychlorination respectively and to explore the possible reasons, which will pave the way for occupational health promotion in terms of hazard reduction. METHODS: a cross-sectional study was initiated between June and September in 2022 towards 2 groups of VCM exposed population from the facility of acetylene hydrochlorination(n=78) and the one of ethylene oxychlorination(n=69) in a PVC petrochemical complex enterprise(abbreviation of H) in Tianjin City. The demographic information concerning age, gender, messages on occupational history, field investigation were inquired through questionnaire interview. Then, venous blood(4 mL/person) and urine(10-50 mL/person) were collected during the physical exam phase and indices of 8-hydroxy-2 deoxyguanosine(8-OHdG) in blood and thiodiglycolic acid(TDGA) in urine were detected through ELISA and solid phase extraction-ion chromatography respectively. RESULTS: The 2 groups of population were matched well in terms of average age distribution and gender composition ratio, with significant differences on population composition ratio were found on variables of working years, alcohol consumption and daily sleeping duration(P<0.01 or P<0.05). It was found that the average content of TDGA in acetylene hydrochlorination group was(0.81±0.05)mg/L while the content in ethylene oxychlorination group reached to(0.83±0.06)mg/L, noteworthy differences were only found among 6 posts in the acetylene hydrochlorination group and 5 others in the ethylene oxychlorination group after classification for specific posts, however, the average concentration of 8-OHdG in acetylene hydrochlorination group(122(78.3, 168.8) µg/m~3) was different from the one in ethylene oxychlorination group(101.7(79.6, 149.7) µg/m~3)(Z=6.82, P<0.05). Moreover, a series of positive correlations in moderate intensity between 8-OHdG concentration and TDGA content were observed among posts of polymerization cleaners(r=0.53), aggregation operators(r=0.47), maintenance repairers(r=0.45), sampling operators(r=0.41) in acetylene hydrochlorination group(P<0.05) and posts of cracking reactants(r=0.64), DCS operators(r=0.51), oxychlorination operators(r=0.50) and chemical loaders(r=0.44) in ethylene oxychlorination group(P<0.05). Liver function indices such as content on ALT(χ~2=15.41, P<0.01), AST(χ~2=9.95, P<0.01) and ALP(χ~2=3.79, P<0.01) were different in the 2 groups population with statistical significance, then proportions on population composition ratio that exceeded normal ranges of indices on ALT, AST, AST/ALT ratio, ALP and Alb/Glb ratio were higher in acetylene hydrochlorination group than ones in ethylene oxychlorination group with great significance(P<0.05), so as to the abnormalities in liver B altrosonography test between groups(χ~2=17.33, P<0.01). Binary logistic regression model indicated that 8-OHdG concentration in blood that exceed 90 µg/m~3, TDGA content in urine that exceed 0.60 mg/L, working years that were over 10a, alcohol consumption, sleeping duration less than 6 h per day and male workers were potential risky factors for liver impairment(P<0.05). CONCLUSION: The degree on liver impairment status was higher in acetylene hydrochlorination group than ones in in ethylene oxychlorination group under the same PVC factory, which might be associated with the oxidative stress injury induced from the combination of higher VCM concentration at workplaces, longer cumulative exposure time, longer working years, alcohol consumption habits and sleep shortage caused by shift work patterns.

[Improvement of protective facilities in vinyl chloride units on liver injury status of occupational exposed group].

OBJECTIVE: To comprehensively evaluate the effectiveness of improvement of protective facilities in a vinyl chloride monomer(VCM) on promotion toward health status of occupational exposed group and safety production at poly-vinyl chloride(PVC) by comparing the liver function indicators and inspection result before and after the improvement, and to analyze the possible influential factors. METHODS: The information collection concerning facilities improvement in 2013 and 2016, identification toward critical controlling points, data or detection result from occupational on-site survey and physical examination were originated in July 2020, and 227 VCM exposed workers and 179 others without chemical reagents exposure history from production factory with calcium carbide process in Tianjin City were selected as objects. The effectiveness toward improvement of protective facilities in critical controlling points that occupational exposed workers usually involve in were evaluated through comparison toward VCM concentration result, thiodiglycolic acid(TDGA) content in urine, indicators on liver function and biochemistry and liver ultrasound. At the mean time, both binary Logistic regression analysis was used to screen the possible factors that contributed to abnormal symptoms and single dependent variable general linear regression model was used to find out the mutual interaction among influential factors. RESULTS: Prior to improvement on protective facilities, the C_(TWA)of VCM exposed by all 8 positions in G had exceeded 1 to 2 folds of occupational exposure limit(OEL=10 mg/m~3) and the position of synthetic operator and field sampling man were ones exposed to 1, 2-DCE with the range from 50% to 1 OEL, others hazard factors were found to meet relative OELs. Next, the content of TDGA in urine of exposed group was found to correlate strongly to the average concentration of VCM(r=0.79, P<0.05), and result of TDGA content, alanine aminotransferase(ALT), γ-glutamyl transpeptidase(GGT) and abnormal rate toward liver ultrasound test in exposed group were much higher than ones in control group with significant differences(P<0.05 or P<0.001). By contrast, after the improvement, the exposure level toward all identified hazard factors were declined to meet OEL levels with significant differences in TDGA content, and result of ALT, GGT and abnormal rates toward symptoms in liver ultrasound test such as liver calcification with thickened liver echo, peripheral fibrosis of the liver, multiple hepatic cysts were markedly lower than ones before improvement and still were higher than ones in control group(P<0.05 or P<0.001). Further, parameters of gender, length of employment, weekly contact time, VCM exposed level, TDGA content were all important contributing factors to abnormal symptoms in liver ultrasound test before and after improvement on protective facilities(P<0.05 or P<0.001), in which a significant interaction effect between gender and length of employment(F=4.028, P=0.044), weekly contact time and TDGA content(F=2.183, P=0.046) in urine were found in contribution analysis to abnormal symptoms in liver ultrasound test(P<0.05). CONCLUSION: The improvement measure carried out in VCM facilities by this PVC production factories with calcium carbide process effectively reduced the ambient concentration of hazard factors mainly led by VCM, but workers might still be at risk of liver injury even under VCM exposure at relative lower level, which may referred to factors of long weekly contact time, long length of employment and high fat diet.

[Risk assessment of noise-induced hearing loss among workers in railway transportation equipment manufacturing enterprises].

OBJECTIVE: To analyze the noise exposure and hearing loss of workers in railway transportation equipment manufacturing enterprises, and to assess the risk of hearing loss caused by noise. METHODS: From 2018 to 2020, an investigation was carried out on 3 railway transportation equipment manufacturing enterprises in Hubei Province and Hunan Province. A total of 840 noise-exposed workers were selected, the individual noise exposure level(L_(Aeq·8 h)) and hearing loss level were measured, the cumulative noise exposure(CNE) was calculated, and the relationship between hearing loss and technological process, working time and CNE were analyzed. ISO1999:2013 was used to calculate the change of hearing threshold and the risk of noise-induced hearing loss after 40 years old. RESULTS: The median age of workers was 32 years old, and the median working age for noise exposure was 10 years. The distribution of positions is mainly welding, machining, assembly and painting.79.5%(120/151) of the individual noise exposure doses exceeded 85 dB(A), and the average L_(Aeq.8 h) was 89.9(A). There were significant differences in the proportion of hearing loss among workers in different process units(χ~2= 29.597, P<0.001), and the proportion of hearing loss in the preparation and steel structure units was higher. The proportion of hearing loss showed an upward trend with the increase of working years(χ~2=164.462, P<0.001), and the high-frequency combined speech-frequency hearing loss(26.7%) increased significantly after working for more than 20 years. With the increase of CNE, the proportion of high-frequency hearing loss and the proportion of high-frequency combined speech-frequency hearing loss increased accordingly(χ~2=192.544, P<0.001). The proportion of high frequency combined speech frequency hearing loss increased significantly in the group with CNE greater than 105 dB(A)·years. It is predicted that the risk of hearing loss caused by noise in assemblers appears earliest and the risk is the greatest. The risk of high noise-induced frequency hearing loss of assemblers was 3.6%-8.6% at the age of 40, 20.2% at the age of 50, 22.0% at the age of 60. The risk of high-frequency combined speech-frequency hearing loss of assemblers was 1.2%-6.2% at the age of 50 and 8.6% at the age of 60. CONCLUSION: The noise hazard is serious and widely distributed in railway transportation equipment manufacturing enterprises, and the proportion of hearing loss increases with the increase of working time and CNE. Although ISO1999:2013 predicts that there may be an underestimation of noise-induced hearing loss in workers, it can be used as an early warning of hearing loss to identify the potential risk of hearing loss in the population.

[Occupational risk assessment levels before and after improvement on fueling devices in ammoniation facilities from 2 nuclear plants].

OBJECTIVE: To evaluate and compare possible changes of individual health risk levels for ammonia exposed positions from ammoniation facilities in 2 nuclear power plants(X and Y) through occupational risk assessment models(OHRA) before and after devices improvement. METHODS: This study tried to understand the improvement of fueling devices in ammoniation facilities, to identify the ammonia exposed positions and their working content, to collect information on protective measures and personal protective equipment situation through on-sites survey and detailed records of work days. Next, detection on C_(STE) of ammonia at different worksites and C_(TWA) of 10 involved positions were conducted, fresh air requirement and ventilation air changing rates were calculated through wind speed detection or collected directly. Finally, a semi-quantitative comprehensive index model and a quantitative non-carcinogenic model from standard GBZ/T 298-2017 were utilized to assess risk levels before and after improvement. RESULTS: After devices improvement, a series of innovations were observed, followed by:(1) ammonia steal tanks in stacking storage were replaced by metal pressure sealing tanks for reduction of exposure frequency and long time storage. (2) manual filling pattern was totally substituted by automatic filling devices with new installed ventilation systems and alarming apparatus. (3) increasing ventilation effect by doors opening when ammonia was filling. In this regard, conentration levels(C_(STE)) referred to positions of chemical analysis engineers, chemical sampling engineers, nuclear maintenance workers at 3# unit from X, and regular island operators at 1#unit, patrolling operators at 2# unit from Y were declined to qualified levels after improvement from unqualified levels before that, and significant difference of C_(STE )detected before and after improvement were found statistically(Z=10.856, P<0.001). C_(TWA )were all within the qualified ranges before and after improvement for relatively short cumulative exposure time. Moreover, the ventilation air changing rates from related indoor sectors were increased to 13.0 to 30.9 times/h after improvement which indicated a statistical difference as compared to quantitative ranges before started(Z=11.670, P<0.001). Further, a relative negative correlation was observed between C_(STE )and ventilation air changing rates(r=-0.39, P<0.05) while no correlation between them was spotted after improvement(r=-0.051, P>0.05). In addition, most positions like chemical analysis engineers and others changed their risk levels to a lower one from that they used to be after improvement with an observed significant difference(Z=1.345, P<0.05), by contrast, risk levels of positions like nuclear maintenance workers at 3#unit or patrolling operators at 4#unit increased a level or remained the same before and after improvement might be result ed from enhancement of cumulative exposure time. No significant difference among position risk levels under the quantitative non-carcinogenic model was observed(Z=0.447, P>0.05). CONCLUSION: The measure of devices improvement indeed decreased the ambient ammonia concentrations at workplaces of ammoniation facilities in X and Y and changed individual risk levels for most involved positions. The semi-quantitative comprehensive index model was more appropriated for self-contrast risk assessment application than quantitative non-carcinogenic model did, especially when improvement occurred.

[Occupational health risk assessment of silicosis caused by silica dust exposure in non-ferrous metal mines in 7 provinces from 2019 to 2020].

OBJECTIVE: To explore the occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mining enterprises. METHODS: Using typical sampling method, 44 non-ferrous metal mining enterprises were selected in seven provinces.37 non-ferrous metal mining enterprises were included, and most of them were underground enterprises(97.30%). Enterprises basic information and silica dust exposure data of key positions were collected by using on-site hygiene investigation and detecting method. Finally, the International Council on Mining and Metals'(ICMM) risk rating table method and occupational hazard risk index method(INDEX) were used to analyze the occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mines from total and respirable dust views, respectively. Meanwhile, the square weighted Kappa test was performed to analyze the consistency between two risk assessment method. RESULTS: Medium enterprises(64.69%(40.38%, 73.41%)), silver mining enterprises(84.69%(63.38%, 86.06%)) and antimony mining enterprises(72.22%) had relatively higher silica dust exposure rates. On-site hygiene detecting result showed that:(1) M(P25, P75) of free silica content was 21.18%(17.03%, 30.47%). (2) 1.60(0.86, 2.46)mg/m~3 for total dust concentration, 64.47% total dust concentration samples exceeding Chinese permissible concentration-time weighted average(PC-TWA), 0.68(0.30, 1.18) mg/m~3 for respiratory dust concentration, 50.00% respirable dust concentration samples exceeding Chinese PC-TWA. (3) Medium-sized enterprises, as well as rock drillers and crushers, had higher levels of silica dust exposure. Occupational health risk assessment result showed that:(1) The overall occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mining enterprises was medium:(1) In term of total dust, ICMM risk rating table method and INDEX method indicated high and medium risks, respectively(S_(weighted) were 3.52 and 2.79). (2) In term of respirable dust, both ICMM risk rating table and INDEX method indicated medium risks(S_(weighted) were 2.78 and 2.35). (2) Medium-sized enterprises risk level was higher than other two production scales enterprises. ICMM risk rating table method and the INDEX method consistency analyses showed that these two risk assessment method had strong consistencies in terms of total dust or respirable dust(both Kappa values ≥ 0.600). CONCLUSION: The overall occupational health risk level of silicosis caused by silica dust exposure in non-ferrous metal mining enterprises was medium, and the risk levels of medium production-scale mining enterprises, rock driller and crusher were higher.

[Role of PTEN in FAK and α-SMA protein levels changes in human embryonic lung fibroblasts induced by silica].

OBJECTIVE: To investigate the roles of phosphatase and tensin homolog deleted on chromosome 10(PTEN) in focal adhesion kinase(FAK) and α-smooth muscle actin(α-SMA) protein levels changes in human embryonic lung fibroblasts(HELFs) induced by silica. METHODS: The HELF cells were cultured in low serum medium containing 0, 25, 50, 100 and 200 µg/cm~2 silica for 24 hours, and the cell counting kit-8(CCK8) experiment was used to determine the appropriate dose of silica for stimulation. Meanwhile, the effect of different doses of silica on the morphology of HELFs was observed under inverted microscope. 50 µg/cm~2 silica solution was used to culture HELFs for 0, 1, 2, 4, 8, 12 and 24 hours(h), and the control group were used as the control group. In addition, Western blot was used to detect HELFs PTEN, p-PTEN, FAK, p-FAK and α-SMA protein levels at each culture time. Besides, HELFs were cultured with 2×10~(-3) mol/L PTEN inhibitor(VO-Ohpic) and/or silica for 24 h, including HELFs group, HELFs plus silica group, and HELFs plus silica plus VO-Ohpic group, and the FAK, p-FAK and α-SMA in each group were also detected by Western blot. RESULTS: With the increase of silica dose, HELFs viability firstly increased and then decreased, and the cell viability of 50 µg/cm~2 group(144. 91±5. 10) was significantly higher than that of 0 µg/cm~2 group(101. 23±6. 57)(P<0. 05). Compared with the control group of silica treated HELFs, the expression levels of PTEN and p-PTEN at 12 h and 24 h were significantly decreased(PTEN: 0. 44±0. 08 at 12 h, 0. 25±0. 02 at 24 h; p-PTEN: 0. 09±0. 01 at 12 h, 0. 01±0. 00 at 24 h; all P values<0. 05); whereas, FAK at 12 h(0. 92±0. 05) and 24 h(0. 89±0. 01), and p-FAK(0. 77±0. 02) and α-SMA at 24 h(1. 32±0. 01) were significantly increased(all P values<0. 05). The expression levels of FAK(0. 25±0. 03), p-FAK(0. 40±0. 02) and α-SMA(0. 36±0. 01) of HELFs plus silica plus VO-Ohpic group were significantly higher than those of HELFs plus silica group(P<0. 05). CONCLUSION: While silica induces HELFs FAK, p-FAK, and α-SMA increase, PTEN may downregulate FAK, p-FAK and α-SMA expression levels.

[Effect of ERK/JNK cell signaling pathway in carbon black induced cytokine IL-6 and IL-8 expression changes].

OBJECTIVE: To investigate the roles of extracellular signal-regulated kinase(ERK)/c-Jun amino-terminal kinase(JNK) signaling pathway on the expression of interleukin-6(IL-6) and interleukin-8(IL-8) in human embryonic lung fibroblasts(HELF) induced by carbon black. METHODS: HELFs were cultured in RPMI-1640 medium containing 0, 15, 30, 60, 120 or 240 µg/mL carbon black for 24 h, and the appropriate dose of carbon black was determined by MTT assay result HELFs were divided into three groups: HELFs, HELFs transfected with ERK dominant negative mutant plasmid(DN-ERK) and HELFs transfected with JNK dominant negative mutant plasmid(DN-JNK). 100 µg/mL carbon black was used to treat HELFs(CB), DN-ERK HELFs(CB-DN-ERK), DN-JNK HELFs(CB-DN-JNK), and HELFs without any black carbon treatment were considered as control group. At 16 h after carbon black treatment, scanning electron microscope(SEM) was used to observe HELFs morphology and whether there were carbon black particless. At 0, 1, 2, 4, 8, 12, 24 and 36 h, the enzyme linked immunosorbent assay(ELISA) was used to detect CB and control groups HELFs IL-6 and IL-8 expression levels, whereas CB-DN-ERK and CB-DN-JNK HELFs were detected only at 24 h. RESULTS: SEM result showed no carbon black particles were observed in CB group HELFs, whereas their surface projections were increased. The CB group HELFs IL-6 expression levels at 2 h(44. 86±3. 65 ng/L) and 4 h(76. 52±3. 15 ng/L) were significantly lower than those of the control group(96. 78±2. 82 and 147. 32±3. 26 ng/L)(P<0. 05), whereas the IL-6 expression levels were significantly higher than those of the control group(105. 54±6. 10, 101. 27±5. 84 and 97. 15±5. 12 ng/L) at 16 h(202. 64±7. 20 ng/L), 24 h(200. 38±6. 20 ng/L) and 36 h(183. 54±4. 54 ng/L)(P<0. 001). At 24 h(136. 75±3. 81 ng/L) and 36 h(149. 12±2. 74 ng/L), the CB group IL-8 expression levels were significantly higher than those of the control group(75. 16±2. 84 and 73. 44±2. 15 ng/L)(P<0. 001). Compared with CB group HELFs, CB-DN-ERK and CB-DN-JNK groups HELFs had significantly lower IL-6 and IL-8 expression levels(P<0. 05). CONCLUSION: While carbon black induced HELFs IL-6 and IL-8 expression levels changes, ERK and JNK may upregulate IL-6 and IL-8 expression levels.

A Dual Targeting Dendrimer-Mediated siRNA Delivery System for Effective Gene Silencing in Cancer Therapy.

Small interfering RNA (siRNA) is emerging as a novel therapeutic for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing an RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to deliver siRNA effectively, while the aim of the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing, and more potent anticancer activity compared to nontargeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further developed to provide RNAi-based personalized medicine against cancer. Our study also gives new perspectives on the use of nanotechnology based on self-assembling dendrimers in various biomedical applications.

Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway.

Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient-derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues. Secreted AGR2 was defined to enhance VEGFR2 activity as evidenced by physical interaction of purified recombinant human AGR2 (rhAGR2) with rhVEGFA through the formation of a disulfide bond. Mutant or deleted thioredoxin motif in rhAGR2 was also unable to bind to rhVEGFA that led to the significant abolishment in the vessel formation, but partially affecting the aggressive process, implicating alternative mechanisms are required for AGR2-conferring metastasis. Cytosolic AGR2 contributed to cell metastasis ascribed to its stabilizing effect on p65 protein, which subsequently activated the NF-κB and facilitated epithelial to mesenchymal transition (EMT). Importantly, GSH and cabozantinib, but not bevacizumab, effectively blocked the pro-angiogenic effect of rhAGR2 in vitro and in vivo, providing evidence that secreted AGR2 acts as a predictive biomarker for selection of angiogenesis-targeting therapeutic drugs based on its levels in the circular system.

[Occupational health risk assessment of pure methanol fuel].

OBJECTIVE: To assess the occupational health risk of pure methanol fuel( M100) during the methanol fuel pilot stage. METHODS: The subjects are workers who are exposed to M100 in pilot areas for methanol vehicles, southwest of China. Use field investigation and detection to get the information of production technology, exposure level of methanol and prevention measures and facilities. Use Singapore Occupational Exposure to Harmful Chemicals Semi-Quantitative Method to assess the health risk of the methanol. Use "Classification of occupational hazards at workplace " to classify the occupational hazard of methanol. RESULTS: The main occupational hazard factor existing during the use procedure of M100 is methanol. The concentration of methanol in M100 filling station, methanol automobile repair shop and methanol automobile driver 's cab( up to47. 90 mg/m~3) and main methanol exposure post( up to 10. 25 mg/m~3) are accord with occupational exposure limit. According to the methanol occupational health riskassessment result, the risk of filling worker( R = 2. 4), methanol loade( R = 2. 0) r and maintenance worker( R = 2. 0) are low, and the risk of the driver( R = 1. 4) is negligible risk, which are basically identical with the occupational hazard classification result. CONCLUSION: Under the current production process and protection level, the occupational health risks of M100 can be controlled at low level. The chronic health effects and occupational exposure limit of methanol should be further studied.

Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro.

AIM: Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. METHODS: A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. RESULTS: Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 µmol/L, respectively. JA (1.5 µmol/L) and JB (5 µmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. CONCLUSION: Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest.

Preparation and Characterization of Lanthanum-Incorporated Hydroxyapatite Coatings on Titanium Substrates.

Titanium (Ti) has been widely used in clinical applications for its excellent biocompatibility and mechanical properties. However, the bioinertness of the surface of Ti has motivated researchers to improve the physicochemical and biological properties of the implants through various surface modifications, such as coatings. For this purpose, we prepared a novel bioactive material, a lanthanum-incorporated hydroxyapatite (La-HA) coating, using a dip-coating technique with a La-HA sol along with post-heat treatment. The XRD, FTIR and EDX results presented in this paper confirmed that lanthanum was successfully incorporated into the structure of HA. The La-HA coating was composed of rod-like particles which densely compacted together without microcracks. The results of the interfacial shear strength test indicated that the incorporation of lanthanum increased the bonding strength of the HA coating. The mass loss ratios under acidic conditions (pH=5.5) suggested that the La-HA coatings have better acid resistance. The cytocompatibility of the La-HA coating was also revealed by the relative activity of alkaline phosphatase, cellular morphology and cell proliferation assay in vitro. The present study suggested that La-HA coated on Ti has promising potential for applications in the development of a new type of bioactive coating for metal implants.

LncRNA CA12-AS1 targets miR-133a to promote LPS-induced inflammatory response in bovine mammary epithelial cells.

Bovine mastitis seriously affects milk production and quality and causes huge economic losses in the dairy industry. Recent studies have shown that long non-coding RNAs (lncRNAs) may regulate bovine mastitis. In this study, the expression of lncRNA CA12-AS1 was significantly upregulated in LPS-induced bovine mammary epithelial cells (bMECs) but negatively correlated with the expression of miR-133a, suggesting that it may be related to the inflammatory response in bMECs. Dual luciferase reporter gene assay revealed that miR-133a is a downstream target gene of lncRNA CA12-AS1. Furthermore, lncRNA CA12-AS1 silencing negatively regulated the expression of miR-133a inhibited the secretion of inflammatory factors (IL-6, IL-8 and IL-1ß) and decreased the mRNA expression levels of nuclear factor kappa B (NF-κB) (p65/p50) and apoptosis-related genes (BAX, caspase3 and caspase9). LncRNA CA12-AS1 silencing also promoted the mRNA expression levels of the Tight junction (TJ) signaling pathway-related genes (Claudin-1, Occludin and ZO-1), apoptotic gene BCL2, proliferation-related genes (CDK2, CDK4 and PCNA) and the viability of bMECs. However, overexpression of lncRNA CA12-AS1 reversed the above effects. These results revealed that lncRNA CA12-AS1 is a pro-inflammatory regulator, and its silencing can alleviate bovine mastitis by targeting miR-133a, providing a novel strategy for molecular therapy of cow mastitis.

In-home Gait Abnormality Detection through Footstep-Induced Floor Vibration Sensing and Person-Invariant Contrastive Learning.

Detecting gait abnormalities is crucial for assessing fall risks and early identification of neuromusculoskeletal disorders such as Parkinson's and stroke. Traditional assessments in gait clinics are infrequent and pose barriers, particularly for disadvantaged populations. Previous efforts have explored sensor-based approaches for in-home gait assessments, yet they face limitations such as visual obstructions (cameras), limited coverage (pressure mats), and the need for device carrying (wearables and insoles). To overcome these limitations, we introduce an in-home gait abnormality detection system using footstep-induced floor vibrations, enabling low-cost, non-intrusive, device-free gait health monitoring. The main research challenge is the high uncertainty in floor vibrations due to gait variations among people, making it challenging to develop a generalizable model for new patients. To address this, we analyze time-frequency-domain features of floor vibration data during specific gait phases and develop a feature transformation method through contrastive learning to address the between-people gait variation challenge. Our method transforms the features from vibrations to an embedding space where samples from different people stay close to each other (robust to people variation) while normal and abnormal gait samples are far apart (sensitive to gait abnormality). After that, gait abnormalities are detected by a downstream classifier after feature transformation. We evaluated our approach through a real-world walking experiment with 21 participants and achieved an 85% to 95% mean accuracy in detecting various gait abnormalities. This novel method overcomes prior limitations in in-home gait assessments, offering accessible gait abnormality detection without the need for intrusive devices or labels for new patients.

Association of IL-8 and CXCR2 with AST/ALT Ratio in Liver Abnormalities Screening during Oxidative Stress Injury Caused by VCM.

Liver impairment caused by VCM has been linked to irreversible damage such as fibrosis, necrosis, hepatocellular carcinoma, and liver angiosarcoma. However, the ability to detect abnormalities during initial phase have not been achieved so far. Thus, this study aimed to investigate the effect of interleukin 8 (IL-8) and C-X-C chemokines 2 (CXCR2) on screening for a VCM-exposed group (n = 227) from a PVC manufacturing factory compared to a control group (n = 110) in Tianjin City in 2020 with influence factors evaluation. Ambient concentrations of VCM and health archives from 2012 to 2018 were collected for establishing the dose-effect trend. A cross-sectional survey in 2020 was performed to measure TDGA, IL-8, CXCR2, 8-OHdG, SOD, GPX, CAT, MDA, and ROS levels. Results indicated a continuous increased incidence on liver abnormalities despite a fluctuated downward trend in cumulative time-weighted average (CTWA) VCM concentrations over the years. ALT, AST, and AST/ALT ratio all contributed to liver abnormalities that contained fatty liver, liver calcification, and liver cysts, IL-8 and CXCR2 correlated with each other strongly and showed significant associations with oxidative stress markers, even AST/ALT ratio. IL-8 (>1547 µg/m3) or CXCR2 (<139 µg/m3) influenced the AST/ALT ratio through reciprocal interactions under oxidative stress injury, CXCR2 (>222 µg/m3), working years of 21 to 30 (a) and 11 to 20 (a), TDGA (>1.52 mg/L), alcohol consumption, smoking habit, and a less sleeping duration of <4 h per day would also be potential factors affecting the AST/ALT ratio. In conclusion (1) even with decreased VCM concentrations in PVC manufacturing factories liver abnormalities that contained fatty liver, liver calcification, and liver cysts could still occur due to oxidative stress injury with involvement of IL-8 and CXCR2. The status of protective measure and appropriate mask types also play a role; (2) the AST/ALT ratio could be a specific indicator for detecting abnormalities when combined with liver B ultrasonography results before impairment altered from bad to worse; and (3) factors such as definite medication history, fully broken protective facilities, alcohol consumption, less sleeping duration, inappropriate mask types, and longer working years could also influence AST/ALT ratio alterations through complex interactions.

Autonomous artificial intelligence for diabetic eye disease increases access and health equity in underserved populations.

Diabetic eye disease (DED) is a leading cause of blindness in the world. Annual DED testing is recommended for adults with diabetes, but adherence to this guideline has historically been low. In 2020, Johns Hopkins Medicine (JHM) began deploying autonomous AI for DED testing. In this study, we aimed to determine whether autonomous AI implementation was associated with increased adherence to annual DED testing, and how this differed across patient populations. JHM primary care sites were categorized as "non-AI" (no autonomous AI deployment) or "AI-switched" (autonomous AI deployment by 2021). We conducted a propensity score weighting analysis to compare change in adherence rates from 2019 to 2021 between non-AI and AI-switched sites. Our study included all adult patients with diabetes (>17,000) managed within JHM and has three major findings. First, AI-switched sites experienced a 7.6 percentage point greater increase in DED testing than non-AI sites from 2019 to 2021 (p < 0.001). Second, the adherence rate for Black/African Americans increased by 12.2 percentage points within AI-switched sites but decreased by 0.6% points within non-AI sites (p < 0.001), suggesting that autonomous AI deployment improved access to retinal evaluation for historically disadvantaged populations. Third, autonomous AI is associated with improved health equity, e.g. the adherence rate gap between Asian Americans and Black/African Americans shrank from 15.6% in 2019 to 3.5% in 2021. In summary, our results from real-world deployment in a large integrated healthcare system suggest that autonomous AI is associated with improvement in overall DED testing adherence, patient access, and health equity.

Autonomous Artificial Intelligence Increases Access and Health Equity in Underserved Populations with Diabetes.

Diabetic eye disease (DED) is a leading cause of blindness in the world. Early detection and treatment of DED have been shown to be both sight-saving and cost-effective. As such, annual testing for DED is recommended for adults with diabetes and is a Healthcare Effectiveness Data and Information Set (HEDIS) measure. However, adherence to this guideline has historically been low, and access to this sight-saving intervention has particularly been limited for specific populations, such as Black or African American patients. In 2018, the US Food and Drug Agency (FDA) De Novo cleared autonomous artificial intelligence (AI) for diagnosing DED in a primary care setting. In 2020, Johns Hopkins Medicine (JHM), an integrated healthcare system with over 30 primary care sites, began deploying autonomous AI for DED testing in some of its primary care clinics. In this retrospective study, we aimed to determine whether autonomous AI implementation was associated with increased adherence to annual DED testing, and whether this was different for specific populations. JHM primary care sites were categorized as "non-AI" sites (sites with no autonomous AI deployment over the study period and where patients are referred to eyecare for DED testing) or "AI-switched" sites (sites that did not have autonomous AI testing in 2019 but did by 2021). We conducted a difference-in-difference analysis using a logistic regression model to compare change in adherence rates from 2019 to 2021 between non-AI and AI-switched sites. Our study included all adult patients with diabetes managed within our health system (17,674 patients for the 2019 cohort and 17,590 patients for the 2021 cohort) and has three major findings. First, after controlling for a wide range of potential confounders, our regression analysis demonstrated that the odds ratio of adherence at AI-switched sites was 36% higher than that of non-AI sites, suggesting that there was a higher increase in DED testing between 2019 and 2021 at AI-switched sites than at non-AI sites. Second, our data suggested autonomous AI improved access for historically disadvantaged populations. The adherence rate for Black/African Americans increased by 11.9% within AI-switched sites whereas it decreased by 1.2% within non-AI sites over the same time frame. Third, the data suggest that autonomous AI improved health equity by closing care gaps. For example, in 2019, a large adherence rate gap existed between Asian Americans and Black/African Americans (61.1% vs. 45.5%). This 15.6% gap shrank to 3.5% by 2021. In summary, our real-world deployment results in a large integrated healthcare system suggest that autonomous AI improves adherence to a HEDIS measure, patient access, and health equity for patients with diabetes - particularly in historically disadvantaged patient groups. While our findings are encouraging, they will need to be replicated and validated in a prospective manner across more diverse settings.