Developing Covalent Protein Drugs via Proximity-Enabled Reactive Therapeutics.

Small molecule covalent drugs provide desirable therapeutic properties over noncovalent ones for treating challenging diseases. The potential of covalent protein drugs, however, remains unexplored due to protein's inability to bind targets covalently. We report a proximity-enabled reactive therapeutics (PERx) approach to generate covalent protein drugs. Through genetic code expansion, a latent bioreactive amino acid fluorosulfate-L-tyrosine (FSY) was incorporated into human programmed cell death protein-1 (PD-1). Only when PD-1 interacts with PD-L1 did the FSY react with a proximal histidine of PD-L1 selectively, enabling irreversible binding of PD-1 to only PD-L1 in vitro and in vivo. When administrated in immune-humanized mice, the covalent PD-1(FSY) exhibited strikingly more potent antitumor effect over the noncovalent wild-type PD-1, attaining therapeutic efficacy equivalent or superior to anti-PD-L1 antibody. PERx should provide a general platform technology for converting various interacting proteins into covalent binders, achieving specific covalent protein targeting for biological studies and therapeutic capability unattainable with conventional noncovalent protein drugs.

Carbon Nanotube Loading Strategies for Peptide Drugs: Insights from Molecular Dynamics Simulations.

Carbon nanotubes (CNTs) can be regarded as a potential platform for transmembrane drug delivery as many experimental works have demonstrated their capability to effectively transport bioactive molecules into living cells. Within this framework, the loading of a peptide drug onto either the interior or exterior of CNTs has gained considerable interest. This study aims to conduct a comprehensive comparison of these two loading methods. To this end, we performed molecular dynamics simulations and the umbrella sampling technique to investigate the interaction energy, conformational changes, and free energy changes of a model peptide drug containing α-helical structure interacting with the inner or outer walls of a 14.7-nm-long (20,20) CNT. Our finding reveals that, for a tube of such dimensions, it is thermodynamically more favorable for the peptide to be loaded onto the inner tube wall than the outer tube wall, primarily due to a larger free energy change for the former strategy. Conversely, unloading the drug from the tube interior poses greater challenges. Moreover, the tube's curvature plays an essential role in influencing the conformation of the adsorbed peptide. Despite the relatively weaker van der Waals interaction between the CNT exterior and the peptide, loading the peptide onto the exterior may induce significant conformational changes, particularly affecting the peptide's α-helix structure. In contrast, loading of the peptide on the CNT interior could maintain most of the α-helical content. CNTs do not typically attract specific peptide residues, with adsorbed groups primarily determined by the peptide's configurations and orientations. Finally, we offer a guideline for selecting an optimal loading strategy for CNT-based drug delivery.

Acceleration of the biodegradation of cationic polyacrylamide by the coupling effect of thermophilic microorganisms and high temperature in hyperthermophilic composting.

As a flocculant of sewage sludge, cationic polyacrylamide (CPAM) enters the environment with sludge and exists for a long time, posing serious threats to the environment. Due to the environmental friendliness and high efficiency in the process of organic solid waste treatment, hyperthermophilic composting (HTC) has received increasing attention. However, it is still unclear whether the HTC process can effectively remove CPAM from sludge. In this study, the effects of HTC and conventional thermophilic composting (CTC) on CPAM in sludge were compared and analyzed. At the end of HTC and CTC, the concentrations of CPAM were 278.96 mg kg-1 and 533.89 mg kg-1, respectively, and the removal rates were 72.17% and 46.61%, respectively. The coupling effect of thermophilic microorganisms and high temperature improved the efficiency of HTC and accelerated the biodegradation of CPAM. The diversity and composition of microbial community changed dramatically during HTC. Geobacillus, Thermobispora, Pseudomonas, Brevundimonas, and Bacillus were the dominant bacteria responsible for the high HTC efficiency. To our knowledge, this is the first study in which CPAM-containing sludge is treated using HTC. The ideal performance and the presence of key microorganisms revealed that HTC is feasible for the treatment of CPAM-containing sludge.

AMMVF-DTI: A Novel Model Predicting Drug-Target Interactions Based on Attention Mechanism and Multi-View Fusion.

Accurate identification of potential drug-target interactions (DTIs) is a crucial task in drug development and repositioning. Despite the remarkable progress achieved in recent years, improving the performance of DTI prediction still presents significant challenges. In this study, we propose a novel end-to-end deep learning model called AMMVF-DTI (attention mechanism and multi-view fusion), which leverages a multi-head self-attention mechanism to explore varying degrees of interaction between drugs and target proteins. More importantly, AMMVF-DTI extracts interactive features between drugs and proteins from both node-level and graph-level embeddings, enabling a more effective modeling of DTIs. This advantage is generally lacking in existing DTI prediction models. Consequently, when compared to many of the start-of-the-art methods, AMMVF-DTI demonstrated excellent performance on the human, C. elegans, and DrugBank baseline datasets, which can be attributed to its ability to incorporate interactive information and mine features from both local and global structures. The results from additional ablation experiments also confirmed the importance of each module in our AMMVF-DTI model. Finally, a case study is presented utilizing our model for COVID-19-related DTI prediction. We believe the AMMVF-DTI model can not only achieve reasonable accuracy in DTI prediction, but also provide insights into the understanding of potential interactions between drugs and targets.

Altered Storage and Function of von Willebrand Factor in Human Cardiac Microvascular Endothelial Cells Isolated from Recipient Transplant Hearts.

The assembly of von Willebrand factor (VWF) into ordered helical tubules within endothelial Weibel-Palade bodies (WPBs) is required for the efficient deployment of the protein at sites of vascular injury. VWF trafficking and storage are sensitive to cellular and environmental stresses that are associated with heart disease and heart failure. Altered storage of VWF manifests as a change in WPB morphology from a rod shape to a rounded shape and is associated with impaired VWF deployment during secretion. In this study, we examined the morphology, ultrastructure, molecular composition and kinetics of exocytosis of WPBs in cardiac microvascular endothelial cells isolated from explanted hearts of patients with a common form of heart failure, dilated cardiomyopathy (DCM; HCMECD), or from nominally healthy donors (controls; HCMECC). Using fluorescence microscopy, WPBs in HCMECC (n = 3 donors) showed the typical rod-shaped morphology containing VWF, P-selectin and tPA. In contrast, WPBs in primary cultures of HCMECD (n = 6 donors) were predominantly rounded in shape and lacked tissue plasminogen activator (t-PA). Ultrastructural analysis of HCMECD revealed a disordered arrangement of VWF tubules in nascent WPBs emerging from the trans-Golgi network. HCMECD WPBs still recruited Rab27A, Rab3B, Myosin-Rab Interacting Protein (MyRIP) and Synaptotagmin-like protein 4a (Slp4-a) and underwent regulated exocytosis with kinetics similar to that seen in HCMECc. However, secreted extracellular VWF strings from HCMECD were significantly shorter than for endothelial cells with rod-shaped WPBs, although VWF platelet binding was similar. Our observations suggest that VWF trafficking, storage and haemostatic potential are perturbed in HCMEC from DCM hearts.

Progression of type B intramural hematoma in patients with obstructive sleep apnea.

OBJECTIVE: In the present study, we estimated the influence of obstructive sleep apnea (OSA) on the progression of type B intramural hematoma (IMHB). METHODS: A total of 127 patients had undergone sleep evaluations and esophageal pressure measurements. The variables associated with aorta-related adverse events and mortality were summarized by logistic regression analysis and Cox proportional hazard models. A competing risk analysis of death was used to estimate aorta- and non-aorta-related mortality. RESULTS: The OSA group had a greater aorta-related adverse events rate (46% vs 4%; P < .001). The mean nighttime systolic pressure (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.11-1.38; P < .001) was associated with aorta-related adverse events during the acute phase. Thoracic endovascular aortic repair (hazard ratio [HR], 16.2; 95% CI, 7.68-34.22, P < .001) and mean morning systolic pressure (HR, 1.43; 95% CI, 1.22-1.68; P < .001) were associated with a higher rate of aorta-related adverse events. OSA (HR, 3.19; 95% CI, 2.57-12.15; P < .001) and mean morning systolic pressure (HR, 1.59; 95% CI, 1.27-2.01; P = .002) were significantly associated with aorta-related mortality. Competing risk analysis revealed significantly higher aorta-related mortality in the OSA group (11.8% vs 2.0%; P = .0412). A neutrophil/lymphocyte ratio >3.52 (specificity, 90.2%; sensitivity, 89.5%) and mean platelet volume/platelet ratio >0.049 (specificity, 98.0%; sensitivity, 98.7%) had diagnostic value for detecting OSA in patients with IMHB. CONCLUSIONS: The presence of OSA led to a higher aorta-related adverse event rate and mortality in patients with IMHB. The variables associated with these outcomes included thoracic endovascular aortic repair, mean morning and nighttime systolic pressure, and OSA. The neutrophil/lymphocyte ratio and platelet volume/platelet ratio are valuable for detecting OSA in patients with IMHB.

Outcomes of uncomplicated Type B intramural hematoma patients with Type 2 diabetes mellitus.

OBJECTIVES: We aimed to summarize the clinical presentations, therapeutic approaches, and outcomes of Type B intramural hematoma (IMHB) patients with and without Type 2 diabetes mellitus (DM). METHODS: Patients with uncomplicated IMHBs were included between January 2016 and January 2018 and divided into two groups according to whether or not they had DM. We also assessed the potential diagnostic value of serum matrix metalloproteinase-9 (MMP-9) level and the association of it with the disease progression of uncomplicated IMHB patients with and without DM. RESULTS: A total of 149 patients were included (DM group [n = 60] and non-DM group [n = 89]). Patients in the non-DM group underwent thoracic endovascular aortic repair treatment more frequently (12% vs 2%, p = .028) and had a higher reintervention rate during the follow-up (9 in 81 patients, 11% vs. 2%, p = .043). There were significant differences between the two groups regarding the aorta-related mortality rate during the acute phase (9% vs. 0%, p = .042) and the all-cause mortality rate (22% vs. 7%, p = .011). Ulcer-like projection (ULP) development (during the acute phase; hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.15-1.79, p = .005), C-reactive protein (CRP) levels (HR, 2.08; 95% CI, 1.91-3.91, p = .003), and MMP-9 levels (HR, 15.77; 95% CI, 6.48-21.62, p < .001) were associated with an elevated risk for aorta-related mortality. CONCLUSIONS: IMHBs with DM have a considerably better prognosis and serum MMP-9 level appear to be a potential biomarker to predict the disease progression. ULP development (during the acute phase) and CRP levels are also associated with an elevated risk for aorta-related mortality.

Magnetic monitoring of topsoil and street dust in Xinyang (China) and their environmental implications.

The magnetic measurement is an effective tool to identify the source of pollutants and diagnose the urban pollution. In this study, 132 group samples (that topsoil and street dust were sampled at the same location is regarded as a group) were collected from Xinyang, central eastern China. In addition, the background samples (19 topsoils under woodland around the outskirts) were also sampled. Herein, the aim was to investigate and compare the magnetic characteristics of both topsoil and street dust, and further to discuss the source and environmental implications using magnetic and diffuse reflection spectrum methods. The following points are highlighted: (1) the primary magnetic carrier of both materials was magnetite and that of the background sample were magnetite and maghemite. Furthermore, the ferrimagnetic mineral concentration and magnetic domain follow the order: street dust > topsoil > background sample. (2) The source of both materials was mainly from anthropogenic activities (e.g. industrial and traffic vehicles). The difference between them was the contribution related to natural sources (e.g. parent materials), which was negligible in street dust, and played a secondary role in topsoil. (3) Both materials showed that areas with a higher intensity of anthropogenic activities had higher pollution level, whereas areas with a lower anthropogenic intensity had lower pollution level.

Iodide-Mediated Rapid and Sensitive Surface Etching of Gold Nanostars for Biosensing.

Iodide-mediated surface etching can tailor the surface plasmon resonance of gold nanostars through etching of the high-energy facets of the nanoparticle protrusions in a rapid and sensitive way. By exploring the underlying mechanisms of this etching and the key parameters influencing it (such as iodide, oxygen, pH, and temperature), we show its potential in a sensitive biosensing system. Horseradish peroxidase-catalyzed oxidation of iodide enables control of the etching of gold nanostars to spherical gold nanoparticles, where the resulting spectral shift in the surface plasmon resonance yields a distinct color change of the solution. We further develop this enzyme-modulated surface etching of gold nanostars into a versatile platform for plasmonic immunoassays, where a high sensitivity is possible by signal amplification via magnetic beads and click chemistry.

Quercetin protects against diabetic encephalopathy via SIRT1/NLRP3 pathway in db/db mice.

Epidemiological studies have found that diabetes and cognitive dysfunction are closely related. Quercetin has been certified with the effect on improving diabetes mellitus (DM) and cognitive impairment. However, the effect and related mechanism of quercetin on diabetic encephalopathy (DE) are still ambiguous. In this study, we used the db/db mice (diabetic model) to discover whether quercetin could improve DE through the Sirtuin1/NLRP3 (NOD-, LRR- and pyrin domain-containing 3) pathway. Behavioural results (Morris water maze and new object recognition tests) showed that quercetin (70 mg/kg) improved the learning and memory. Furthermore, quercetin alleviated insulin resistance and the level of fasting blood glucose. Besides, Western blot analysis also showed that quercetin increased the protein expressions of nerve- and synapse-related protein, including postsynapticdensity 93 (PSD93), postsynapticdensity 95 (PSD95), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of db/db mice. Quercetin also increased the protein expression of SIRT1 and decreased the expression of NLRP3 inflammation-related proteins, including NLRP3, the adaptor protein ASC and cleaved Caspase-1, the pro-inflammatory cytokines IL-1ß and IL-18. In conclusion, the present results indicate that the SIRT1/NLRP3 pathway may be a crucial mechanism for the neuroprotective effect of quercetin against DE.

Sodium tanshinone IIA sulfonate protects against Aß-induced cell toxicity through regulating Aß process.

Sodium tanshinone IIA sulfonate (STS) has been reported to prevent Alzheimer's disease (AD). However, the mechanism is still unknown. In this study, two in vitro models, Aß-treated SH-SY5Y cells and SH-SY5Y human neuroblastoma cells transfected with APPsw (SH-SY5Y-APPsw cells), were employed to investigate the neuroprotective of STS. The results revealed that pretreatment with STS (1, 10 and 100 µmol/L) for 24 hours could protect against Aß (10 µmol/L)-induced cell toxicity in a dose-dependent manner in the SH-SY5Y cells. Sodium tanshinone IIA sulfonate decreased the concentrations of reactive oxygen species, malondialdehyde, NO and iNOS, while increased the activities of superoxide dismutase and glutathione peroxidase in the SH-SY5Y cells. Sodium tanshinone IIA sulfonate decreased the levels of inflammatory factors (IL-1ß, IL-6 and TNF-α) in the SH-SY5Y cells. In addition, Western blot results revealed that the expressions of neprilysin and insulin-degrading enzyme were up-regulated in the SH-SY5Y cells after STS treatment. Furthermore, ELISA and Western blot results showed that STS could decrease the levels of Aß. ELISA and qPCR results indicated that STS could increase α-secretase (ADAM10) activity and decrease ß-secretase (BACE1) activity. In conclusion, STS could protect against Aß-induced cell damage by modulating Aß degration and generation. Sodium tanshinone IIA sulfonate could be a promising candidate for AD treatment.

Void-free 3D Bioprinting for In-situ Endothelialization and Microfluidic Perfusion.

Two major challenges of 3D bioprinting are the retention of structural fidelity and efficient endothelialization for tissue vascularization. We address both of these issues by introducing a versatile 3D bioprinting strategy, in which a templating bioink is deposited layer-by-layer alongside a matrix bioink to establish void-free multimaterial structures. After crosslinking the matrix phase, the templating phase is sacrificed to create a well-defined 3D network of interconnected tubular channels. This void-free 3D printing (VF-3DP) approach circumvents the traditional concerns of structural collapse, deformation and oxygen inhibition, moreover, it can be readily used to print materials that are widely considered "unprintable". By pre-loading endothelial cells into the templating bioink, the inner surface of the channels can be efficiently cellularized with a confluent endothelial layer. This in-situ endothelialization method can be used to produce endothelium with a far greater uniformity than can be achieved using the conventional post-seeding approach. This VF-3DP approach can also be extended beyond tissue fabrication and towards customized hydrogel-based microfluidics and self-supported perfusable hydrogel constructs.

Void-free 3D Bioprinting for In-situ Endothelialization and Microfluidic Perfusion.

Two major challenges of 3D bioprinting are the retention of structural fidelity and efficient endothelialization for tissue vascularization. We address both of these issues by introducing a versatile 3D bioprinting strategy, in which a templating bioink is deposited layer-by-layer alongside a matrix bioink to establish void-free multimaterial structures. After crosslinking the matrix phase, the templating phase is sacrificed to create a well-defined 3D network of interconnected tubular channels. This void-free 3D printing (VF-3DP) approach circumvents the traditional concerns of structural collapse, deformation and oxygen inhibition, moreover, it can be readily used to print materials that are widely considered "unprintable". By pre-loading endothelial cells into the templating bioink, the inner surface of the channels can be efficiently cellularized with a confluent endothelial layer. This in-situ endothelialization method can be used to produce endothelium with a far greater uniformity than can be achieved using the conventional post-seeding approach. This VF-3DP approach can also be extended beyond tissue fabrication and towards customized hydrogel-based microfluidics and self-supported perfusable hydrogel constructs.

Outcomes of type A intramural hematoma: Influence of diabetes mellitus.

OBJECTIVES: We aimed to investigate whether uncomplicated type A intramural hematoma (IMHA) patients with type 2 diabetes mellitus (DM) who underwent a "wait-and-watch strategy" and tight glycemic control had similar clinical outcomes as patients without DM who received the same treatment strategy. METHODS: Between January 2010 and December 2016, uncomplicated IMHA patients with and without diabetes mellitus were included and were propensity score-matched to improve the balance between the two groups. Cox proportional hazard models were constructed to identify the specific factors associated with aorta-related mortality. The Fine-Gray model for the competing risk analysis was used to estimate the aorta-related and nonaorta-related mortality in different groups during the follow-up period. RESULTS: A total of 109 IMHA patients were included in this study, and 66 patients were included after matching. Patients without DM experienced significantly more aorta-related adverse events (51.6% vs 13.3%; P = .001) and reinterventions than patients in the DM group (29.0% vs 6.7%; P = .023). Cox regression analysis revealed that a higher matrix metalloproteinase-9 level (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.39-2.09; P < .001) and larger maximum aortic diameter (HR, 1.41; 95% CI, 1.11-1.80; P = .005) were associated with higher aorta-related mortality. The competing risk analysis revealed a significantly higher aorta-related mortality during the follow-up period in the no DM group than in the DM group (36.4%; 95% CI, 11.6%-82.3%; P = .0294). CONCLUSIONS: Uncomplicated IMHA patients with DM (receiving the "wait-and-watch strategy" and tight glycemic control) may have lower aorta-related mortality and rates of aorta-related adverse events and reinterventions than the no DM group.

The evolution of treatments for uncomplicated type B intramural hematoma patients.

OBJECTIVES: We aimed to investigate whether uncomplicated type B intramural hematoma (IMHB) patients with known evolution predictors could benefit from more aggressive therapy. METHODS: Retrospective analysis was performed in uncomplicated IMHB patients with evolution predictors between January 2001 and August 2018. Cox proportional hazard models were constructed to identify the specific factors associated with aorta-related mortality. RESULTS: A total of 226 uncomplicated acute IMHB patients with evolution predictors were included. The conventional therapy group included 187 patients, and the other 39 patients received the more aggressive therapy. Aorta-related mortality in the first year was higher in the conventional therapy group than in the more aggressive therapy group (15% vs 2.5%, P = .035), and more patients died after thoracic endovascular aortic repair (TEVAR) (13 of 27 patients, 48.1% vs 2.5%, P < .001). The more aggressive therapy group had a higher rate of hematoma resolution than the conventional therapy group (81.6% vs 62.2%, P = .024), a lower possibility of hematoma worsening (2.6% vs 17.0%, P = .021), and a lower reintervention rate (0% vs 11.9%, P = .028). Cox regression analysis revealed that a higher rate of focal intimal disruption (FID) development (hazard ratio [HR], 3.99; 95% confidence interval [CI], 1.16-11.46, P = .010), and a higher C-reactive protein (CRP) level (HR, 1.27; 95% CI, 1.16-1.40, P < .001) were associated with increased aorta-related mortality. CONCLUSIONS: More aggressive therapy for uncomplicated IMHB patients with evolution predictors during the acute phase may result in better clinical outcomes. A higher rate of FID development and a higher CRP level are associated with increased aorta-related mortality.

Chronic Dexamethasone exposure activates the TLR4-Mediated inflammation pathway and induces epithelial apoptosis in the goat colon.

Chronic stress has a profound effect on health in both animals and humans. Dexamethasone (Dex), a synthetic glucocorticoid, is used to induce chronic stress in many studies. The impact of chronic stress on epithelial cells of hindgut of ruminants is still unknown. In this study, we investigated the effect of chronic stress induced by long term injection of low dosage of Dex on the colonic epithelium of goats. The results showed that Dex exposure increased the number of TUNEL-positive cells, upregulated caspase-3 and caspase-8 enzyme activity, but decreased protein expression of cell proliferation markers proliferating cell nuclear antigen (PCNA) and Cyclin D2(CCND2). It also activated TLR-4 and NF-κB pathway and increased the transcription levels of vital inflammatory cytokines such as interleukin-10 (IL-10), interleukin-1ß (IL-1ß), and inducible nitric oxide synthase 2 (iNOS2). Chronic stress down-regulated the methylation level of total DNA, suggesting a mechanism for the transcriptional activation of genes, such as claudin-1, claudin-4, ZO-1, and cell cycle-related genes. Taken together, long-term injection of a low dosage of Dex caused damage to the colon epithelium accompanied with the inhibition of cell proliferation and the activation of cell apoptosis and inflammation. However, a general up-regulation of genes expression induced by Dex is due to a lower level of genomic DNA methylation.

All-Factor Analysis and Correlations on the Transmembrane Process for Arginine-Rich Cell-Penetrating Peptides.

Currently, arginine-rich cell-penetrating peptides (CPPs), due to their little cytotoxicity and high transmembrane efficiency, are considered as one of the important intracellular carriers. Although the mechanism of the transmembrane process for arginine-rich CPPs was proposed, the quantitative correlations and the key factors involved in this process still deserve further investigation. In this study, all-atom molecular dynamics and the umbrella sampling technique were employed to study the arginine-rich CPPs transmembrane process. In the adsorption process of CPPs from solution to the surface of the lipid bilayer, the adsorption free energy (ΔGA) is found to be linearly related to the interaction energy change (ΔEA): ΔGA = 0.0426ΔEA + 36.7, R2 = 0.92. In the CPPs transmembrane process, the transmembrane free energy barrier (ΔGB) is roughly correlated with the corresponding interaction energy change (ΔEB): ΔGB = 0.108ΔEB +135, R2 = 0.73. The multiple salt bridges of guanidinium-PO4 account for 65% of the overall interaction energy, so the increased negative charges of the lipid bilayer or more salt bridges would facilitate CPPs adsorption and transmembrane processes. Also, the increased negative charges of the lipid bilayer would reduce the amount of water to be carried into the pore and further reduce the ΔGB. The peptide backbone would not have a direct impact on transmembrane efficiency. The ΔGB is also found to be related to the length of the pore (L): ΔGB = 46.2L - 31.3, R2 = 0.92, which makes the transmembrane efficiency estimable. This work is expected to deliver an in-depth understanding and help the optimization of CPPs.

Certain aortic geometries and hemodynamics are associated with FID development and impact the evolution of uncomplicated type B intramural hematoma during the acute phase.

OBJECTIVES: It is difficult to predict the evolution of uncomplicated type B intramural hematoma (IMHB) with a focal intimal disruption (FID) in the acute phase. The aims of this study were to investigate the predictors of FIDs and summarize the risk factors for the evolution of uncomplicated IMHB in the acute phase. METHODS: Eighty-six patients with uncomplicated IMHB were included and were divided according to the development of an FID during the acute phase: the FID group (n = 32) and the no-FID group (n = 54). Geometric measurements and computed fluid dynamic calculations were based on a computed tomography scan performed on admission. Multivariate logistic regression analysis was used to estimate the predictors of FID development. RESULTS: Thirty-two (37%) patients developed an FID. Patients with an FID had higher C-reactive protein levels (18.6 ± 2.3 vs 8.1 ± 0.2 mg/dL, P < 0.001) and white blood cell counts (10.3 ± 2.1 vs 7.5 ± 1.7 109 /L, P < 0.001). The no-FID group had lower occurrences of disease progression (15% vs 64%, P < 0.001) and aorta-related mortality (6% vs 25%, P = 0.016). Multivariate logistic regression analysis indicated a significant risk for the occurrence of an FID with a larger maximum aortic diameter (OR, 1.35; 95% CI, 1.05-1.73, P = 0.020), thicker hematoma (OR, 2.20; 95% CI, 1.40-3.48, P = 0.001), and higher oscillatory shear index (per 0.01 unit, OR, 1.74; 95% CI, 1.21-2.49, P = 0.003). The aorta-related mortality during the acute phase was 25% (n = 8). CONCLUSIONS: Certain aortic conditions, including ta larger aortic diameter, thicker hematoma and higher oscillatory shear stress, are associated with the FID development and result in worse clinical outcomes.

Surface Dynamics and Ligand-Core Interactions of Quantum Sized Photoluminescent Gold Nanoclusters.

Quantum-sized metallic clusters protected by biological ligands represent a new class of luminescent materials; yet the understanding of structural information and photoluminescence origin of these ultrasmall clusters remains a challenge. Herein we systematically study the surface ligand dynamics and ligand-metal core interactions of peptide-protected gold nanoclusters (AuNCs) with combined experimental characterizations and theoretical molecular simulations. We show that the peptide sequence plays an important role in determining the surface peptide structuring, interfacial water dynamics and ligand-Au core interaction, which can be tailored by controlling peptide acetylation, constituent amino acid electron donating/withdrawing capacity, aromaticity/hydrophobicity and by adjusting environmental pH. Specifically, emission enhancement is achieved through increasing the electron density of surface ligands in proximity to the Au core, discouraging photoinduced quenching, and by reducing the amount of surface-bound water molecules. These findings provide key design principles for understanding the surface dynamics of peptide-protected nanoparticles and maximizing the photoluminescence of metallic clusters through the exploitation of biologically relevant ligand properties.

Chronic dexamethasone exposure retards growth without altering the digestive tract microbiota composition in goats.

BACKGROUND: Dexamethasone (Dex), an artificially synthetic cortisol substitute, is commonly used as an anti-inflammatory drug, and is also employed to mimic the stress state experimentally. It is well known that chronic stress disturbs the gut microbiota community and digestive functions. However, no relevant studies have been conducted in ruminants. RESULTS: In this study, a low dosage of Dex (0.2 mg/kg body weight, Dex group, n = 5) was consecutively injected intramuscularly for 21 days to simulate chronic stress in growing goats. Goats were injected with saline (0.2 mg/kg body weight) as the control group (Con, n = 5). Dex-treated goats showed a higher number of white blood cells and blood glucose levels (p < 0.01), but lower dry matter intake (DMI) and body weight (p < 0.01) than those of saline-injected goats. Plasma cortisol concentration decreased significantly in response to the Dex injection compared to the control (p < 0.05). The Dex treatment did not change most ruminal volatile fatty acid (VFAs) concentrations before the morning feeding after 1-21 days of treatment (p > 0.05); however, ruminal VFA concentrations decreased dramatically 2, 4, 6, and 8 h after the morning feeding on day 21 of the Dex injections. In this study, chronic Dex exposure did not alter the community structure of microbes or methanogenes in the rumen, caecum, or colonic digesta. Only Prevotella increased on days 7 and 14 of Dex treatment, but decreased on day 21, and Methanosphaera was the only genus of methanogene that decreased. CONCLUSIONS: Our results suggest that chronic Dex exposure retards growth by decreasing DMI, which may be mediated by higher levels of blood glucose and lower ruminal VFA production. Microbiota in the digestive tract was highly resistant to chronic Dex exposure.