Comprehensive analysis of brain injury parameters in a preclinical porcine model of acute liver failure.

Introduction: Acute liver failure (ALF) is defined as acute loss of liver function leading to hepatic encephalopathy associated with a high risk of patient death. Brain injury markers in serum and tissue can help detect and monitor ALF-associated brain injury. This study compares different brain injury parameters in plasma and tissue along with the progression of ALF. Method: ALF was induced by performing an 85% liver resection. Following the resection, animals were recovered and monitored for up to 48 h or until reaching the predefined endpoint of receiving standard medical therapy (SMT). Blood and serum samples were taken at Tbaseline, T24, and upon reaching the endpoint (Tend). Control animals were euthanized by exsanguination following plasma sampling. Postmortem brain tissue samples were collected from the frontal cortex (FCTx) and cerebellum (Cb) of all animals. Glial fibrillary acidic protein (GFAP) and tau protein and mRNA levels were quantified using ELISA and qRT-PCR in all plasma and brain samples. Plasma neurofilament light (NFL) was also measured using ELISA. Results: All ALF animals (n = 4) were euthanized upon showing signs of brain herniation. Evaluation of brain injury biomarkers revealed that GFAP was elevated in ALF animals at T24h and Tend, while Tau and NFL concentrations were unchanged. Moreover, plasma glial fibrillary acidic protein (GFAP) levels were negatively correlated with total protein and positively correlated with both aspartate transaminase (AST) and alkaline phosphatase (AP). Additionally, lower GFAP and tau RNA expressions were observed in the FCTx of the ALF group but not in the CB tissue. Conclusion: The current large animal study has identified a strong correlation between GFAP concentration in the blood and markers of ALF. Additionally, the protein and gene expression analyses in the FCTx revealed that this area appears to be susceptible, while the CB is protected from the detrimental impacts of ALF-associated brain swelling. These results warrant further studies to investigate the mechanisms behind this process.

Molecular Insights into the Enhanced Activity and/or Thermostability of PET Hydrolase by D186 Mutations.

PETase exhibits a high degradation activity for polyethylene terephthalate (PET) plastic under moderate temperatures. However, the effect of non-active site residues in the second shell of PETase on the catalytic performance remains unclear. Herein, we proposed a crystal structure- and sequence-based strategy to identify the key non-active site residue. D186 in the second shell of PETase was found to be capable of modulating the enzyme activity and stability. The most active PETaseD186N improved both the activity and thermostability with an increase in Tm by 8.89 °C. The PET degradation product concentrations were 1.86 and 3.69 times higher than those obtained with PETaseWT at 30 and 40 °C, respectively. The most stable PETaseD186V showed an increase in Tm of 12.91 °C over PETaseWT. Molecular dynamics (MD) simulations revealed that the D186 mutations could elevate the substrate binding free energy and change substrate binding mode, and/or rigidify the flexible Loop 10, and lock Loop 10 and Helix 6 by hydrogen bonding, leading to the enhanced activity and/or thermostability of PETase variants. This work unraveled the contribution of the key second-shell residue in PETase in influencing the enzyme activity and stability, which would benefit in the rational design of efficient and thermostable PETase.

Factors influencing deceased organ donation rates in OECD countries: a panel data analysis.

OBJECTIVES: This study aims to investigate factors with a significant influence on deceased organ donation rates in Organisation for Economic Co-operation and Development (OECD) countries and determine their relative importance. It seeks to provide the necessary data to facilitate the development of more efficient strategies for improving deceased organ donation rates. DESIGN: Retrospective study. SETTING: Publicly available secondary annual data. PARTICIPANTS: The study includes 36 OECD countries as panel members for data analysis. OUTCOME MEASURES: Multivariable panel data regression analysis was employed, encompassing data from 2010 to 2018 for all investigated variables in the included countries. RESULTS: The following variables had a significant influence on deceased organ donation rates: 'opt-in' system (ß=-4.734, p<0.001, ref: 'opt-out' system), only donation after brain death (DBD) donors allowed (ß=-4.049, p=0.002, ref: both DBD and donation after circulatory death (DCD) donors allowed), number of hospital beds per million population (pmp) (ß=0.002, p<0.001), total healthcare employment pmp (ß=-0.00012, p=0.012), World Giving Index (ß=0.124, p=0.008), total tax revenue as a percentage of gross domestic product (ß=0.312, p=0.009) and percentage of population aged ≥65 years (ß=0.801, p<0.001) as well as high education population in percentage (ß=0.118, p=0.017). CONCLUSIONS: Compared with the promotion of socioeconomic factors with a positive significant impact on deceased organ donation rates, the following policies have been shown to significantly increase rates of deceased organ donation, which could be further actively promoted: the adoption of an 'opt-out' system with presumed consent for deceased organ donation and the legal authorisation of both DBD and DCD for transplantation.

Acupuncture for response and complete pain relief time of acute renal colic: Secondary analysis of a randomized controlled trial.

Background: The integration of acupuncture with intramuscular injection of diclofenac sodium can expedite the onset of analgesia in treating acute renal colic caused by urolithiasis. However, it remains unclear whether acupuncture can accelerate pain relief constantly until complete remission. This study aimed to explore the extent to which acupuncture can expedite the onset time of response or complete pain relief in treating acute renal colic, and the predictive value of patient characteristics for treatment efficacy. Methods: This secondary analysis utilized data from a prior randomized controlled trial. Eighty patients with acute renal colic were randomly assigned 1:1 to the acupuncture group or the sham acupuncture group. After intramuscular injection of diclofenac sodium, acupuncture or sham acupuncture was delivered to patients. The outcomes included time to response (at least a 50 % reduction in pain) and complete pain relief. Between-group comparison under the 2 events was estimated by Kaplan-Meier methodology. Subgroup analysis was performed utilizing the Cox proportional hazards model. Results: The median response time and complete pain relief time in the acupuncture group were lower than those in the sham acupuncture group (5 vs 30 min, Log Rank P < 0.001; 20 min vs not observed, Log Rank P < 0.001, respectively). Hazard Ratios (HRs) for response across all subgroups favored the acupuncture group. All HRs for complete pain relief favored acupuncture, expect large stone and moderate pain at baseline. No interaction was found in either event. Conclusion: Acupuncture can accelerate the response time and complete pain relief time for patients with acute renal colic, with the efficacy universally. Trial registration: This study has been registered at Chinese Clinical Trial Registry: ChiCTR1900025202.

Recognition and detection technology for microplastic, its source and health effects.

Microplastic (MP) is ubiquitous in the environment which appeared as an immense intimidation to human and animal health. The plastic fragments significantly polluted the ocean, fresh water, food chain, and other food items. Inadequate maintenance, less knowledge of adverse influence along with inappropriate usage in addition throwing away of plastics items revolves present planet in to plastics planet. The present study aims to focus on the recognition and advance detection technologies for MPs and the adverse effects of micro- and nanoplastics on human health. MPs have rigorous adverse effect on human health that leads to condensed growth rates, lessened reproductive capability, ulcer, scrape, and oxidative nervous anxiety, in addition, also disturb circulatory and respiratory mechanism. The detection of MP particles has also placed emphasis on identification technologies such as scanning electron microscopy, Raman spectroscopy, optical detection, Fourier transform infrared spectroscopy, thermo-analytical techniques, flow cytometry, holography, and hyperspectral imaging. It suggests that further research should be explored to understand the source, distribution, and health impacts and evaluate numerous detection methodologies for the MPs along with purification techniques.

Increasing Donor-Acceptor Interactions and Particle Dispersibility of Covalent Triazine Frameworks for Higher Crystallinity and Enhanced Photocatalytic Activity.

Covalent triazine frameworks (CTFs) have recently emerged as an efficient class of photocatalysts due to their structural diversity and excellent stability. Nevertheless, the synthetic reactions of CTFs have usually suffered from poor reversibility, resulting in a low crystallinity of the materials. Here, we report the introduction of methoxy groups on the monomer 2,5-diphenylthiazolo[5,4-d]thiazole to reinforce interlayer π-π interactions of the resulting donor-acceptor type CTFs, which improved crystallinity, further increasing the visible light absorption range and allowing for efficient separation and transport of carriers. The morphology is strongly correlated to the wettability, which has a significant impact on the mass transfer capacity and photocatalytic activity in the photocatalytic reaction. To further improve crystallinity and photocatalytic activity, CTF-NWU-T3 photocatalysts in a bowl shape were prepared using a SiO2 template. The energy band structure, photocatalytic hydrogen evolution, and pollutant degradation efficiency of involved materials were investigated. The donor-acceptor type CTF-NWU-T3 with a bowl-shaped morphology, synthesized using the template method and the introduction of methoxy groups, exhibited an excellent photocatalytic hydrogen production rate of 32064 µmol·h-1·g-1. This study highlights the significance of improving donor-acceptor interactions and increasing the dispersibility of catalyst particles in dispersion to enhance the photocatalytic activity of heterogeneous photocatalysts.

Bis-tridentate Ir(III) Phosphors and Blue Hyperphosphorescence with Suppressed Efficiency Roll-Off at High Brightness.

Narrowband blue emitters are indispensable in achieving ultrahigh-definition OLED displays that satisfy the stringent BT 2020 standard. Hereby, a series of bis-tridentate Ir(III) complexes bearing electron-deficient imidazo[4,5-b]pyridin-2-ylidene carbene coordination fragments and 2,6-diaryloxy pyridine ancillary groups were designed and synthesized. They exhibited deep blue emission with quantum yields of up to 89% and a radiative lifetime of 0.71 µs in the DPEPO host matrix, indicating both the high efficiency and excellent energy transfer process from the host to dopant. The OLED based on Irtb1 showed an emission at 468 nm with a maximum external quantum efficiency (EQE) of 22.7%. Moreover, the hyper-OLED with Irtb1 as a sensitizer for transferring energy to terminal emitter v-DABNA exhibited a narrowband blue emission at 472 nm and full width at half-maximum (FWHM) of 24 nm, a maximum EQE of 23.5%, and EQEs of 19.7, 16.1, and 12.9% at a practical brightness of 100, 1000, and 5000 cd/m2, respectively.

Effects of dissolved organic matter, pH and nutrient on ciprofloxacin bioaccumulation and toxicity in duckweed.

Water pollution induced by antibiotics has garnered considerable concern, necessitating urgent and effective removal methods. This study focused on exploring ciprofloxacin (CIP) removal by duckweed and assessing CIP bioaccumulation and toxic effects within duckweed under varying dissolved organic matter categories, pH levels, and nutrient (nitrogen (N) and phosphorus (P)) levels. The results revealed the proficient and rapid elimination of CIP from water by duckweed, resulting in 86.17 % to 92.82 % removal efficiency at the end of the 7-day experiment. Across all exposure groups, varying degrees of CIP bioaccumulation in duckweed were evident, with uptake established as a primary pathway for CIP elimination within this plant. Additionally, five CIP metabolites were identified in duckweed tissues. Interestingly, the presence of humic acid (HA) and fulvic acid (FA) reduced CIP absorption by duckweed, with FA yielding a more pronounced impact. Optimal CIP removal was recorded at a pH of 7.5, while duckweed displayed heightened physiological stress induced by CIP at pH 8.5. Although the influence of N and P concentrations on CIP removal by duckweed was modest, excessive N and P levels intensified the physiological strain of CIP on duckweed.

Application of carboxymethyl cellulose sodium (CMCNa) in maize-wheat cropping system (MWCS) in coastal saline-alkali soil.

Sodium carboxymethyl cellulose (CMCNa) application has been a promising approach to improve soil quality. The purpose of this study was to explore the effects of CMC-Na on soil infiltration, evaporation, water-salt distribution, crop growth, water use efficiency and net profit (Net) in a coastal saline-alkali soil maize-wheat cropping system (MWCS). Five CMC-Na application amounts (0, 0.1, 0.2, 0.4 and 0.6 g kg-1) were designed for the soil column experiment indoor, and five CMC-Na application amounts were used in 2019-2020 field experiment (CK: 0, C10: 10 kg ha-1, C20: 10 kg ha-1, C30: 10 kg ha-1 and C50: 10 kg ha-1), No treatment will be applied in 2021. The results showed that (1) CMC-Na treatment reduced soil cumulative infiltration, infiltration rate, daily evaporation, and cumulative evaporation. (2) After the application of CMCNa, the average soil water storage (SWS) in the 0-60 cm soil layer increased, and soil salinity (SSC) decreased in most treatments. (3) In the 2019-2020, the maize aboveground biomass (B), yield (Y) and water use efficiency (WUE) were the highest under the C20 and C30 treatments, which were 15.24 and 15.32 t ha-1, 5.67 and 5.49 t ha-1 and 1.74 and 1.52 kg ha-1 mm-1, respectively, and the wheat under C30 treatment is the highest, which were 10.98 t ha-1, 5.27 t ha-1 and 1.78 kg ha-1 mm-1. (4) A dose of 25.5 kg ha-1 and 38.9 kg ha-1 was recommended as the most optimal CMC-Na application for maize and wheat in coastal saline alkali soil, respectively.

Study on the mechanism and response law of fracture movement on the super-high position hard-thick strata.

In this paper, a thick plate structural mechanical model was established for the hard-thick rock strata in the Ordos region, which was characterized by the occurrence of high-energy strong earthquakes caused by the fracture of hard-thick rock strata. Subsequently, based on Vlasov's theory, the evolution process of hard-thick rock strata was analyzed. And the paper validated the analysis results using high-energy mine earthquake and surface subsidence data. The following conclusions were drawn: (1) The hard-thick strata in the cretaceous system will not be broken during the advancing and mining process of the test panel of the Shilawusu coal mine. (2) When the test panel is mined to a distance of two panel widths, no fracture occurred in the lower part of the hard-thick strata, because no separated space was formed. (3) When the test panel was advanced to about 856 m, the hard-thick strata have fractured in a vertical direction. (4) No high-energy mine earthquake event has occurred during mining at test panel, and the amount of surface subsidence is approximately 200 mm. (5) In the mining at test panel, two high-energy mining earthquakes occurred at 837 m, 1153 m away from the initial position of the panel, respectively, and the maximum amount of surface subsidence increased to 1397 mm, which accords with the results of the first and periodic breaks calculated by theory. The research results of this paper are of guiding significance for the study of the breaking law of hard-thick strata under similar engineering geological conditions and disaster pre-control.

Biomimetic Surface Engineering to Modulate the Coffee-Ring Effect for Amyloid-ß Detection in Rat Brains.

Surface engineering of nanoparticles has been widely used in biosensing and assays, where sensitivity was mainly limited by plasmonic colour change or electrochemical responses. Here, we report a novel biomimetic sensing strategy involving protein-modified gold nanoparticles (AuNPs), where the modulation strategy was inspired by gastropods in inhibition of coffee-ring effects in their trail-followings. The so-called coffee-ring effect presents the molecular behaviour of AuNPs to a macroscopic ring through aggregation, and thus greatly improves sensitivity. The assay relies upon the different assembly patterns of AuNPs against analytes, resulting in the formation or suppression of coffee-ring effects by the different surface engineering of AuNPs by proteins and peptides. The mechanism of the coffee-ring formation process is examined through experimental characterizations and computational simulations. A practical coffee-ring effect assay is developed for a proof-of-concept target, amyloid ß (1-42), which is a typical biomarker of Alzheimer's disease. A novel quasi-titrimetric protocol is constructed for quantitative determination of the target molecule. The assay shows excellent selectivity and sensitivity for the amyloid ß monomer, with a low detection limit of 20 pM. Combined with a fluorescent staining technique, the assay is designed as a smart sensor for amyloid ß detection and fibrillation evaluation in rat cerebrospinal fluids, which is a potential point-of-care test for Alzheimer's disease. Connections between amyloid fibrillation and different courses of brain ischaemia are also studied, with improved sensitivity, lower sample volumes that are required, convenience for rapid detection, and point-of-care testing.

Surface functionalization affects the retention and bio-distribution of orally administered mesoporous silica nanoparticles in a colitis mouse model.

Besides the many advantages of oral drug administration, challenges like premature drug degradation and limited bioavailability in the gastro-intestinal tract (GIT) remain. A prolonged residence time in the GIT is beneficial for enhancing the therapeutic outcome when treating diseases associated with an increased intestinal clearance rate, like inflammatory bowel disease (IBD). In this study, we synthesized rod-shaped mesoporous silica nanoparticles (MSNs) functionalized with polyethylene glycol (PEG) or hyaluronic acid (HA) and investigated their bio-distribution upon oral administration in vivo. The negatively charged, non-toxic particles showed different accumulation behavior over time in healthy mice and in mice with dextran sulfate sodium (DSS)-induced intestinal inflammation. PEGylated particles were shown to accumulate in the lower intestinal tract of healthy animals, whereas inflammation promoted retention of HA-functionalized particles in this area. Overall systemic absorption was low. However, some particles were detected in organs of mice with DSS-induced colitis, especially in the case of MSN-PEG. The in vivo findings were connected to surface chemistry-related differences in particle adhesion on Caco-2/Raji and mucus-producing Caco-2/Raji/HT29 cell co-culture epithelial models in vitro. While the particle adhesion behavior in vivo was mirrored in the in vitro results, this was not the case for the resorption results, suggesting that the in vitro model does not fully reflect the erosion of the inflamed epithelial tissue. Overall, our study demonstrates the possibility to modulate accumulation and retention of MSNs in the GIT of mice with and without inflammation through surface functionalization, which has important implications for the formulation of nanoparticle-based delivery systems for oral delivery applications.

Cadmium-induced reproductive toxicity combined with a correlation to the oogenesis process and competing endogenous RNA networks based on a Caenorhabditis elegans model.

Accumulation of the heavy metal Cadmium (Cd) in the ovaries and placenta can affect the structure and function of these organs and induce female reproductive toxicity. This toxicity may be due to Cd's similarity to estrogen and its ability to disrupt endocrine systems. However, the exact molecular mechanism by which Cd causes reproductive toxicity at the transcriptome level remains poorly understood. Hence, this study aimed to observe Cd-induced reproductive damage at the gene level, scrutinize the repercussions of Cd exposure on oogenesis, and explicate the putative pathogenesis of Cd-induced oogenesis based on Caenorhabditis elegans (C. elegans) as an in vivo model. The results showed that Cd exposure significantly decreased the number of offspring and prolonged the reproductive span of C. elegans. Cd exposure also reduced the number of cells in mitosis and the pachytene and diakinesis stages of meiosis, thereby disrupting oogenesis. Combined with transcriptional sequencing and bioinformatics analysis, a total of 3167 DEmRNAs were identified. Regarding gene expression, cul-6, mum-2, and vang-1 were found to be related to Cd-induced reproductive toxicity, and their competing endogenous RNA networks were constructed. We observed that mutations of mom-2 and vang-1 in the Wnt pathway could induce susceptibility to Cd-caused meiosis injury. In conclusion, the results indicated that Cd could impair the oogenesis of C. elegans and the Wnt pathway might serve as a protective mechanism against Cd reproductive toxicity. These findings contribute to a better understanding of the damaging effects and molecular biological mechanisms of Cd on the human reproductive system.

ABPP-CoDEL: Activity-Based Proteome Profiling-Guided Discovery of Tyrosine-Targeting Covalent Inhibitors from DNA-Encoded Libraries.

DNA-encoded chemical library (DEL) has been extensively used for lead compound discovery for decades in academia and industry. Incorporating an electrophile warhead into DNA-encoded compounds recently permitted the discovery of covalent ligands that selectively react with a particular cysteine residue. However, noncysteine residues remain underexplored as modification sites of covalent DELs. Herein, we report the design and utility of tyrosine-targeting DELs of 67 million compounds. Proteome-wide reactivity analysis of tyrosine-reactive sulfonyl fluoride (SF) covalent probes suggested three enzymes (phosphoglycerate mutase 1, glutathione s-transferase 1, and dipeptidyl peptidase 3) as models of tyrosine-targetable proteins. Enrichment with SF-functionalized DELs led to the identification of a series of tyrosine-targeting covalent inhibitors of the model enzymes. In-depth mechanistic investigation revealed their novel modes of action and reactive ligand-accessible hotspots of the enzymes. Our strategy of combining activity-based proteome profiling and covalent DEL enrichment (ABPP-CoDEL), which generated selective covalent binders against a variety of target proteins, illustrates the potential use of this methodology in further covalent drug discovery.

Virus-like Silica Nanoparticles Improve Permeability of Macromolecules across the Blood-Brain Barrier In Vitro.

The presence of the blood-brain barrier (BBB) limits the delivery of therapies into the brain. There has been significant interest in overcoming the BBB for the effective delivery of therapies to the brain. Inorganic nanomaterials, especially silica nanoparticles with varying surface chemistry and surface topology, have been recently used as permeation enhancers for oral protein delivery. In this context, nanoparticles with varying sizes and surface chemistries have been employed to overcome this barrier; however, there is no report examining the effect of nanoscale roughness on BBB permeability. This paper reports the influence of nanoscale surface roughness on the integrity and permeability of the BBB in vitro, using smooth surface Stöber silica nanoparticles (60 nm) compared to rough surface virus-like silica nanoparticles (VSNP, 60 nm). Our findings reveal that VSNP (1 mg/mL) with virus-mimicking-topology spiky surface have a greater effect on transiently opening endothelial tight junctions of the BBB than the same dose of Stöber silica nanoparticles (1 mg/mL) by increasing the FITC-Dextran (70 kDa) permeability 1.9-fold and by decreasing the trans-endothelial electrical resistance (TEER) by 2.7-fold. This proof-of-concept research paves the way for future studies to develop next-generation tailored surface-modified silica nanoparticles, enabling safe and efficient macromolecule transport across the BBB.

Preparation of honokiol-loaded titanium dioxide nanotube drug delivery system and its effect on CAL-27 cells.

Background: Tongue cancer is the most common type of oral cancer, and patients have a poor prognosis and quality of life after conventional surgical treatment. Honokiol (HNK) is a kind of lignan extracted from Chinese herbal medicine Houpu, many domestic and international experiments have demonstrated its anti-tumor effect. Titanium dioxide nanotube (TNTs) is a kind of nanomaterial which can be used as drug carrier. The purpose of this study is to explore the effects of HNK-loaded TNTs delivery system (HNK-TNTs) on anti-tumor. Methods: TNTs were prepared by anodic oxidation method, and HNK was loaded onto TNTs by physical adsorption. The effect of HNK-TNTs on the proliferation, migration and apoptosis of CAL-27 cells were explored by CCK-8 experiment, scratch assay, live and dead staining and cellular immunofluorescence analysis. Results: The material characterization test results showed that we had successfully prepared HNK-TNTs. CCK-8 experiment, scratch assay showed that the proliferation and migration ability of CAL-27 cells were significantly weakened after treatment with HNK-TNTs, and their cell proliferation rates significantly decreased. Live/dead staining, cell immunofluorescence analysis showed that HNK-TNTs could promote CAL-27 cells apoptosis by increasing the expression levels of the apoptosis-related protein Bax and Fas. Conclusion: In this experiment, we had successfully prepared Honokiol-loaded titanium dioxide nanotube drug delivery system (HNK-TNTs) and compared the effects of single drug HNK and HNK-TNTs on the proliferation, apoptosis and migration of tongue cancer CAL-27 cells. This experiment showed that HNK-TNTs had greater anti-proliferative, apoptosis-promoting and migration-inhibiting effects than the HNK as a single drug.

Computation-Based Design of Salt Bridges in PETase for Enhanced Thermostability and Performance for PET Degradation.

Polyethylene terephthalate (PET) is one of the most widely used plastics, and the accumulation of PET poses a great threat to the environment. IsPETase can degrade PET rapidly at moderate temperatures, but its application is greatly limited by the low stability. Herein, molecular dynamics (MD) simulations combined with a sequence alignment strategy were adopted to introduce salt bridges into the flexible region of IsPETase to improve its thermal stability. In the designed variants, the Tm values of IsPETaseI168R/S188D and IsPETaseI168R/S188E were 7.4 and 8.7 °C higher than that of the wild type, respectively. The release of products degraded by IsPETaseI168R/S188E was 4.3 times that of the wild type. Tertiary structure characterization demonstrated that the structure of the variants IsPETaseI168R/S188D and IsPETaseI168R/S188E became more compact. Extensive MD simulations verified that a stable salt bridge was formed between the residue R168 and D186 in IsPETaseI168R/S188D , while in IsPETaseI168R/S188E an R168-D186-E188 salt bridge network was observed. These results confirmed that the proposed computation-based salt bridge design strategy could efficiently generate variants with enhanced thermal stability for the long-term degradation of PET, which would be helpful for the design of enzymes with improved stability.