Therapeutics of Charcot neuroarthropathy and pharmacological mechanisms: A bone metabolism perspective.

Charcot neuroarthropathy (CN) is a chronic, destructive, and painless damage of the skeletal system that affects the life quality of patients. CN, with an unclear mechanism, is characterized with invasive destruction of bones and a serious abnormality of bone metabolism. Unfortunately, development of an effective prevention and treatment strategy for CN is still a great challenge. Of note, recent studies providing an insight into the molecular mechanisms of bone metabolism and homeostasis have propelled development of novel CN therapeutic strategies. Therefore, this review aims to shed light on the pathogenesis, diagnosis, and treatment of CN. In particular, we highlight the eminent role of the osteoprotegerin (OPG)-receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) system in the development of CN. Furthermore, we summarize and discuss the diagnostic biomarkers of CN as well as the potential pharmacological mechanisms of current treatment regimens from the perspective of bone metabolism. We believe that this review will enhance the current state of knowledge on the diagnosis, prevention, and therapeutic efficacy of CN.

Intra-arterial tenecteplase is safe and may improve the first-pass recanalization for acute ischemic stroke with large-artery atherosclerosis: the BRETIS-TNK trial.

Background and purpose: The first-pass recanalization of endovascular treatment (EVT) is closely correlated with clinical outcome of patients with large vessel occlusion (LVO) stroke. The aim of the study was to explore whether intra-arterial tenecteplase (TNK) during the first pass of EVT can increase first-pass successful reperfusion and improve the neurological outcome in AIS-LVO patients. Materials and methods: The BRETIS-TNK trial (ClinicalTrials.gov Identifier: NCT04202458) was a prospective, single-arm, single center study. Twenty-six eligible AIS-LVO patients with large-artery atherosclerosis etiology were consecutively enrolled from December 2019 to November 2021. Intra-arterial TNK (4 mg) after microcatheter navigation through the clot was administered, followed by TNK (0.4 mg/min) given continuously for 20 min after the first retrieval attempt of EVT without confirmation of the reperfusion status by DSA. The 50 control patients comprised of a historical cohort before the BRETIS-TNK trial (from March 2015 to November 2019). Successful reperfusion was defined as modified Thrombolysis In Cerebral Infarction (mTICI) ≥2b. Results: The first-pass successful reperfusion rate was higher in the BRETIS-TNK vs. control group (53.8% vs. 36%, p = 0.14), and the difference became statistically significant after propensity score matching (53.8% vs. 23.1%, p = 0.03). There was no difference in symptomatic intracranial hemorrhage between the BRETIS-TNK and control groups (7.7% vs. 10.0%, p = 0.92). There was a trend toward higher proportion of functional independence at 90 days in the BRETIS-TNK comparing with the control group (50% vs. 32%, p = 0.11). Conclusion: This is the first study to report that intra-arterial TNK during the first pass of EVT seems safe and feasible in AIS-LVO patients.

LC-MS/MS-based multiplex antibacterial platform for therapeutic drug monitoring in intensive care unit patients.

Empirically prescribed standard dosing regimens of antibacterial agents may result in insufficient or excess plasma concentrations with persistently poor clinical outcomes, especially for patients in intensive care units (ICUs). Therapeutic drug monitoring (TDM) of antibacterial agents can guide dose adjustments to benefit patients. In this study, we developed a robust, sensitive, and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform for the quantification of 14 antibacterial and antifungal agents (beta-lactams piperacillin, cefoperazone, and meropenem; beta-lactamase inhibitors tazobactam and sulbactam; antifungal agents fluconazole, caspofungin, posaconazole, and voriconazole; and daptomycin, vancomycin, teicoplanin, linezolid, and tigecycline) that can be used for patients with severe infection. This assay requires only 100 µL of serum with rapid protein precipitation. Chromatographic analysis was performed using a Waters Acquity UPLC C8 column. Three stable isotope-labeled antibacterial agents and one analogue were used as internal standards. Calibration curves ranged from 0.1-100 µg/mL, 0.1-50 µg/mL, and 0.3-100 µg/mL for different drugs, and all correlation coefficients were greater than 0.9085. Intra- and inter-day imprecision and inaccuracy values were below 15%. After validation, this new method was successfully employed for TDM in routine practice.

A qualitative of stable symptomatology for patients with schizophrenia: do they have adequate post-discharge rehabilitative resources?

Many patients diagnosed with schizophrenia face obstacles to rehabilitation and discharge into the community, particularly with regard to the way resources are structured. Clarifying the difficulties will help health care providers address rehabilitation shortcomings. Semistructured in-depth interviews and participatory observations were conducted in various locations (family home, hospital ward, outpatient clinic, and on the street) with families, social workers, doctors, nursing staff, and patients with schizophrenia. These patients met the medical facility's hospital discharge standards and either had not been discharged or had been discharged within two weeks of meeting the discharge criteria. This study explores the complex and interdependent role of social differences in the rehabilitation of patients with schizophrenia after acute treatment. The study identified five topics related to structural difficulties in resources for the rehabilitation of patients diagnosed with schizophrenia: (1) the role of policy; (2) inadequate facilities and responsibilities; (3) rejecting communities; (4) difficult families; and (5) the threat of stigma. The rehabilitation of patients diagnosed with schizophrenia is a systemic problem. Systemic rehabilitation policies and integrated social support would be more conducive to the rehabilitation of patients. Perhaps cognitive remediation therapy or the Assertive Community Treatment (ACT) Model could benefit individuals with complex disorders.

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice.

Introduction: Increased neutrophil extracellular trap (NET) formation has been reported to be associated with cerebrovascular dysfunction and neurological deficits in traumatic brain injury (TBI). However, the biological function and underlying mechanisms of NETs in TBI-induced neuronal cell death are not yet fully understood. Methods: First, brain tissue and peripheral blood samples of TBI patients were collected, and NETs infiltration in TBI patients was detected by immunofluorescence staining and Western blot. Then, a controlled cortical impact device was used to model brain trauma in mice, and Anti-Ly6G, DNase, and CL-amidine were given to reduce the formation of neutrophilic or NETs in TBI mice to evaluate neuronal death and neurological function. Finally, the pathway changes of neuronal pyroptosis induced by NETs after TBI were investigated by administration of peptidylarginine deiminase 4 (a key enzyme of NET formation) adenovirus and inositol-requiring enzyme-1 alpha (IRE1α) inhibitors in TBI mice. Results: We detected that both peripheral circulating biomarkers of NETs and local NETs infiltration in the brain tissue were significantly increased and had positive correlations with worse intracranial pressure (ICP) and neurological dysfunction in TBI patients. Furthermore, the depletion of neutrophils effectively reduced the formation of NET in mice subjected to TBI. we found that degradation of NETs or inhibition of NET formation significantly inhibited nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 1 (NLRP1) inflammasome-mediated neuronal pyroptosis after TBI, whereas these inhibitory effects were abolished by cyclic GMP-AMP (cGAMP), an activator of stimulating Interferon genes (STING). Moreover, overexpression of PAD4 in the cortex by adenoviruses could aggravate NLRP1-mediated neuronal pyroptosis and neurological deficits after TBI, whereas these pro-pyroptotic effects were rescued in mice also receiving STING antagonists. Finally, IRE1α activation was significantly upregulated after TBI, and NET formation or STING activation was found to promote this process. Notably, IRE1α inhibitor administration significantly abrogated NETs-induced NLRP1 inflammasome-mediated neuronal pyroptosis in TBI mice. Discussion: Our findings indicated that NETs could contribute to TBI-induced neurological deficits and neuronal death by promoting NLRP1-mediated neuronal pyroptosis. Suppression of the STING/ IRE1α signaling pathway can ameliorate NETs-induced neuronal pyroptotic death after TBI.

Hsa_circ_0002496 promotes the growth, angiogenesis, and stemness of breast cancer cells via miR-433-3p/YWHAZ cascade.

BACKGROUND: Breast cancer (BC) has been studied more and more in modern medicine. Circ_0002496 has established a critical role in BC. MiR-433-3p can exert important activity in cancer. YWHAZ can participate in BC development, but the targeting relationship among the three variables and its influence on the related process of BC are not clear. METHODS: RT-qPCR was used to analyze circ_0002496, miR-433-3p, and YWHAZ expression. Immunoblotting was used to analyze YWHAZ, Bax, Bcl-2, and PI3K/AKT-related proteins. RNase R assay was used to verify the ring structure of circ_0002496. Cell phenotypes were tested by Cell Counting Kit 8, EdU, sphere formation, tube formation, and flow cytometry assays. RESULTS: Circ_0002496 was enhanced and MiR-433-3p was downregulated in BC, while the expression of YWHAZ was higher in BC. Circ_0002496 targeted miR-433-3p and miR-433-3p targeted YWHAZ in BC cells. Depletion of circ_0002496 influenced the BC process, but miR-433-3p inhibitor reversed the impact of si-circ_0002496 on the BC process. Re-expression of YWHAZ weakened the influence of miR-433-3p on the BC process. Depletion of circ_0002496 could astrict tumor growth in vivo. Moreover, the circ_0002496/miR-433-3p/YWHAZ axis mediated the activation of the PI3K/AKT signaling pathway. CONCLUSION: Circ_0002496 participated in the malignant procession of BC by miR-433-3p/YWHAZ regulation cascade.

The impact of Water Ecological Civilization City Pilot on urban green innovation: the case of China.

As an essential part of ecological civilization, water ecological civilization has significant influence on the green and sustainable development of cities. Under the background of China's Water Ecological Civilization City Pilot (WECCP), based on data from 275 cities in China from 2007 to 2019 by using the difference-in-differences (DID) model, we empirically analyzed the influence of the WECCP establishment on urban green innovation and explored the impact mechanism in depth using a mediating effect model, which aimed to verify whether the "Porter hypothesis" holds true in China. The result indicated that the WECCP had made a remarkable contribution to enhancing urban green innovation in the pilot cities. Further research found that the input mechanism played an important mediating role. In addition, the heterogeneity test indicated that cities in the central region, at low administrative levels, and in the first batch of pilots gained more from the policy establishment. This paper has theoretical implications for understanding the derived innovation benefits of the environmental policy, practical implications for identifying new drivers of urban innovation, and provides related experience for the country to further promote and expand water ecological civilization construction and useful policy inspiration for other developing countries to formulate ecological and environmental policies.

Knockdown of KDM5B Leads to DNA Damage and Cell Cycle Arrest in Granulosa Cells via MTF1.

KDM5B is essential for early embryo development, which is under the control of maternal factors in oocytes. Granulosa cells (GCs) play a critical role during oocyte mature. However, the role of KDM5B in GCs remains to be elucidated. In the current study, we found that KDM5B expressed highly in the ovaries and located in goat GCs. Using an RNA sequence, we identified 1353 differentially expressed genes in the KDM5B knockdown GCs, which were mainly enriched in cell cycle, cell division, DNA replication and the cellular oxidative phosphorylation regulation pathway. Moreover, we reported a decrease in the percentage of proliferated cells but an increase in the percentage of apoptotic cells in the KDM5B knockdown GCs. In addition, in the KDM5B knockdown GCs, the percentage of GCs blocked at the S phase was increased compared to the NC group, suggesting a critical role of KDM5B in the cell cycle. Moreover, in the KDM5B knockdown GCs, the reactive oxygen species level, the mitochondrial depolarization ratio, and the expression of intracellular phosphorylated histone H2AX (γH2AX) increased, suggesting that knockdown of KDM5B leads to DNA damage, primarily in the form of DNA double-strand breaks (DSBs). Interestingly, we found a down-regulation of MTF1 in the KDM5B knockdown GCs, and the level of cell proliferation, as well as the cell cycle block in the S phase, was improved. In contrast, in the group with both KDM5B knockdown and MTF1 overexpression, the level of ROS, the expression of γH2AX and the number of DNA DSB sites decreased. Taken together, our results suggest that KDM5B inhibits DNA damage and promotes the cell cycle in GCs, which might occur through the up-regulation of MTF1.

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy.

The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.

Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal.

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitor (OP) expansion, hematopoietic stem cell dislocation, and CD41- granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41- GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in the hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores the efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy.

Research on spatial and temporal differences of carbon emissions and influencing factors in eight economic regions of China based on LMDI model.

With the gradual increase of international willingness to reach the carbon peak and carbon neutrality, this paper decomposes the influencing factors of China's carbon emission changes from 2008 to 2019 using the Logarithmic Mean Divisia Index model (LMDI), and analyzes the contribution amount and rate of each influencing factor. The results found that: for the whole country, the cumulative growth of carbon emissions during the study period is about 416,484.47 (104 tons), among which the economic growth effect plays a major role in promoting, with a cumulative contribution rate of 284.16%; The increase in regulation intensity and the optimization of industrial structure, however, suppress carbon emissions well, with a cumulative contribution rate of about - 199.21% and - 64.75%, respectively, during the study period. For economic regions, the cumulative influence direction of each driver is the same as that of the whole country, while the population size effect in the northeast economic region and the regulation input effect in the eastern coastal economic region act in the opposite direction from other economic regions, and the carbon emission reduction direction of the energy intensity effect varies from one economic region to another. Accordingly, this paper proposes policy recommendations to enhance regulatory intensity, optimize industrial and energy consumption structure, implement localized emission reduction strategies, and promote synergistic emission reduction in economic zones.

Comparison of magnetic susceptibility probes relevantly used in soil contamination applications.

Magnetic susceptibility (MS) technology can achieve the efficient rough measurement, mapping, and pollution assessment of soil heavy metal concentrations in topsoil due to atmospheric dust contamination. However, previous studies of commonly used MS field probes (MS2D, MS2F, and MS2K) have not dealt with the range of magnetic signal detection and the attenuation characteristics of the signal with respect to distance. In this study, the vertical and horizontal measurement ranges of the MS2D, MS2F, and MS2K probes were explored through laboratory and field experiments, and the intensity of their magnetic signals was further compared and analyzed in the field. The results showed that the magnetic signal intensity of the three probes decreased exponentially with distance. The penetration depths of the MS2D, MS2F, and MS2K probes were 8.5, 2.4, and 3.0 cm, respectively, and the horizontal detection boundary lengths of their magnetic signals were 32, 8, and 6.8 cm, respectively. In the field surface soil MS detection, the magnetic measurement signals of the MS2F and MS2K probes showed a weak linear correlation with the MS2D probe (R2 of 0.43 and 0.50, respectively), while the MS2F and MS2K probes had a significantly better correlation (R2 = 0.68) with each other. In general, the MS2D probe and MS2K probe correlation had a slope close to unity, meaning MS2K probes had good mutual substitution. Furthermore, results of this study improve the effectiveness of the MS evaluation of heavy metal pollution in urban topsoil.

Low diastolic blood pressure and adverse outcomes in inpatients with acute exacerbation of chronic obstructive pulmonary disease: A multicenter cohort study.

BACKGROUND: Although intensively studied in patients with cardiovascular diseases (CVDs), the prognostic value of diastolic blood pressure (DBP) has little been elucidated in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). This study aimed to reveal the prognostic value of DBP in AECOPD patients. METHODS: Inpatients with AECOPD were prospectively enrolled from 10 medical centers in China between September 2017 and July 2021. DBP was measured on admission. The primary outcome was all-cause in-hospital mortality; invasive mechanical ventilation and intensive care unit (ICU) admission were secondary outcomes. Least absolute shrinkage and selection operator (LASSO) and multivariable Cox regressions were used to identify independent prognostic factors and calculate the hazard ratio (HR) and 95% confidence interval (CI) for adverse outcomes. RESULTS: Among 13,633 included patients with AECOPD, 197 (1.45%) died during their hospital stay. Multivariable Cox regression analysis showed that low DBP on admission (<70 mmHg) was associated with increased risk of in-hospital mortality (HR = 2.16, 95% CI: 1.53-3.05, Z = 4.37, P <0.01), invasive mechanical ventilation (HR = 1.65, 95% CI: 1.32-2.05, Z = 19.67, P <0.01), and ICU admission (HR = 1.45, 95% CI: 1.24-1.69, Z = 22.08, P <0.01) in the overall cohort. Similar findings were observed in subgroups with or without CVDs, except for invasive mechanical ventilation in the subgroup with CVDs. When DBP was further categorized in 5-mmHg increments from <50 mmHg to ≥100 mmHg, and 75 to <80 mmHg was taken as reference, HRs for in-hospital mortality increased almost linearly with decreased DBP in the overall cohort and subgroups of patients with CVDs; higher DBP was not associated with the risk of in-hospital mortality. CONCLUSION: Low on-admission DBP, particularly <70 mmHg, was associated with an increased risk of adverse outcomes among inpatients with AECOPD, with or without CVDs, which may serve as a convenient predictor of poor prognosis in these patients. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trail Registry, No. ChiCTR2100044625.

Sustainable Operation and Maintenance Modeling and Application of Building Infrastructures Combined with Digital Twin Framework.

Sustainable management is a challenging task for large building infrastructures due to the uncertainties associated with daily events as well as the vast yet isolated functionalities. To improve the situation, a sustainable digital twin (DT) model of operation and maintenance for building infrastructures, termed SDTOM-BI, is proposed in this paper. The proposed approach is able to identify critical factors during the in-service phase and achieve sustainable operation and maintenance for building infrastructures: (1) by expanding the traditional 'factor-energy consumption' to three parts of 'factor-event-energy consumption', which enables the model to backtrack the energy consumption-related factors based on the relevance of the impact of random events; (2) by combining with the Bayesian network (BN) and random forest (RF) in order to make the correlation between factors and results more clear and forecasts more accurate. Finally, the application is illustrated and verified by the application in a real-world gymnasium.

Characterization and stability evaluation of Ca2+ cross-linked soybean protein isolate/chitosan/sodium alginate ternary complex coacervate phase.

To improve the stability of the soybean protein isolate/chitosan/sodium alginate ternary complex coacervate phase against environmental pH and ionic strength, the complex ternary phase cross-linked by Ca2+ was characterized and evaluated. The viscoelastic properties, thermal properties, microstructure, and texture profile were characterized using rheology, differentia scanning calorimetry as well as thermmogravimetric analysis, scanning electron microscopy as well as transmission electron microscopy, and texture profile analysis, respectively. Compared with the uncross-linked ternary complex coacervate, the complex in situ cross-linked with 1.0 % Ca2+ for 1 h still retains its typical solid characteristics, and has a more compact network structure and better stability. Our research results also showed that prolonging the cross-linking time (from 3 h to 5 h) and increasing the concentration of the cross-linking agent (from 1.5 % to 2.0 %) did not further improve the rheological, thermodynamic and textural properties of the complex coacervate. The ternary complex coacervate phase cross-linked in situ under 1.5 % concentration of Ca2+ for 3 h showed significantly improved stability at low pH 1.5-3.0, which indicats that the ternary complex coacervate phase cross-linked in situ by Ca2+ can be used as a potential delivery platform for the effective delivery of biomolecules under physiological conditions.

Facile modification of nanochitin in aqueous media for stabilizing tea tree oil based Pickering emulsion with prolonged antibacterial performance.

Nanochitins have been explored for preparing Pickering Emulsions, however its application is restricted by its simplex disperse nature. It was hypothesized that zwitterionic nanochitins should be capable of stabilizing oil/water (O/W) interfaces in wider pH range. Furthermore, the control of their size, disperse nature and self-assembly performance suggest the formulation of tunable emulsions. Zwitterionic nanochitins were prepared via Schiff base reaction. A systematic study was performed analyzing the disperse nature, fibril morphology, surface characteristic of modified nanochitins. Oil-in-Water Pickering Emulsions stabilized by modified nanochitins were formulated and emulsion stability was analyzed as function of concentration, pH and self-assembly property and further applied for prolonged antibacterial applications. Comparing freshly prepared nanochitins, neutral/alkaline stably dispersed nanochitins can be prepared while maintaining fibril characteristics such as fibril size, crystallinity, thermal stability and so on. Better suspension stability of modified nanochitins under alkaline conditon together with the self assembly performance resulting from amino groups and carboxyl groups benefit the enhanced emulsion stability under nanochitins concentreation of 0.2 %. Encapsulation of tea tree oil in Pickering Emulsions prolongs the diffusion rate oil in the aqueous environment, thus resulting prolongs its antibacterial performance against E. coli and B. subtilis.

Analysis and subcellular distribution of organophosphate esters (OPEs) in rice tissues.

Recent studies have identified the ability of plants to uptake and translocate organophosphate esters (OPEs) within cells. In response to the increasing interest in OPEs and their occurrence in paddy fields and rice, the current study aimed to present an effective and sensitive GC-MS based methodology for quantitative determination of 11 OPEs with octanol-water coefficients ranging from 1.6 to 10. Rice was sonicated with hexane and dichloromethane, and fractionated on two columns: one consisting of neutral alumina, and neutral silica, and the other consisting of graphitized carbon black. Method precision was validated using spiked rice (n = 30) and procedural blanks (n = 9). The mean recovery of matrix spikes for all target OPEs were within 78-110% with relative standard deviation lower than 25%, with a few exceptions. This method was applied to process the wild rice (O. sativa) in which tri-n-propyl phosphate was the dominant targeted OPE. The recoveries of surrogate standards were 81 ± 17% for d12- tris(2-chloroethyl) phosphate and 95 ± 8.8% for 13C12- triphenyl phosphate. The developed method was further used to examine the recoveries of target OPEs in the subcellular structure of rice tissues, including cell wall, cell organelles, cell water-soluble fractions, and cell residue. Recoveries of most target OPEs were in the range of 50-150%; however, ion enhancement was observed for four OPEs in root and shoot tissues. Hydrophobic OPEs accumulated in the cell wall, cell residue, and cell organelles while chlorinated OPEs mainly distributed in the cell water-soluble fraction. These results provide new insight for the ecological risk assessment of OPEs in an important food staple.

The longitudinal and regional analysis of bleomycin-induced pulmonary fibrosis in mice by microcomputed tomography.

Introduction: Microcomputed tomography (micro-CT) is powerful for assessment of the progression of lung fibrosis in animal model, but current whole lung analysis (WLA) methods are time-consuming. Here, a longitudinal and regional analysis (LRA) method was developed to assess fibrosis easily and quickly by micro-CT. Method: Firstly, we investigated the distribution pattern of lesions in BLM-induced pulmonary fibrosis mice. Then, the VOIs for LRA were selected based on the anatomical locations and we compared the robustness, accuracy, repeatability, analysis time of LRA to WLA. Additionally, LRA was applied to assess different stages of pulmonary fibrosis, and was validated with conventional endpoint measurements (such as lung hydroxyproline and histopathology). Results: The lesions of fibrosis in 66 bleomycin (BLM)-induced pulmonary fibrosis mice were mostly in the middle and upper parts of lungs. By applying LRA, the percentages of high-density voxels in selected volumes of interest (VOIs) were well correlated with that in WLA both at Day 7 and Day 21 after bleomycin induction (R2 = 0.8784 and 0.8464, respectively). The relative standard deviation (RSD) of the percentage of high-density voxels in the VOIs was lower than that of WLA (P < 0.05). The cost time of LRA was shorter than that of WLA (P < 0.05) and the accuracy of LRA was further confirmed by the histological analysis and biochemical quantification of hydroxyproline. Conclusion: LRA is probably an easier and more time-saving method to assess fibrosis formation and evaluate treatment efficacy.

Development of a modularized aptamer targeting the nuclear T-cell suppressor PAC1.

Aptamers associated with cancer targeting therapy are commonly focused on cell membrane proteins; however, the study of intracellular, particularly, nuclear proteins is limited. The nuclear phosphatase PAC1 has been reported to be a potential T cell-related immunotherapeutic target. Here, we identified an aptamer, designated as PA5, with high affinity and specificity for PAC1 through the systematic evolution of ligands by exponential enrichment (SELEX) procedure. We then developed a dual-module aptamer PAC1-AS consisting of a cell-internalizing module and a targeting module, which can recognize PAC1 in the nucleus under physiological conditions. This modularized aptamer raises the possibility of manipulating endosomes and provides insights into the exploration and development of an efficient cancer immunotherapy approach.