Membrane Disruption-Enhanced Photodynamic Therapy against Gram-Negative Bacteria by a Peptide-Photosensitizer Conjugate.

Photodynamic therapy (PDT) emerges as a promising strategy for combating bacteria with minimal drug resistance. However, a significant hurdle lies in the ineffectiveness of most photosensitizers against Gram-negative bacteria, primarily attributable to their characteristic impermeable outer membrane (OM) barrier. To tackle this obstacle, we herein report an amphipathic peptide-photosensitizer conjugate (PPC) with intrinsic outer membrane disruption capability to enhance PDT efficiency against Gram-negative bacteria. PPC is constructed by conjugating a hydrophilic ultrashort cationic peptide to a hydrophobic photosensitizer. PPC could efficiently bind to the OM of Gram-negative bacteria through electrostatic adsorption, and subsequently disrupt the structural integrity of the OM. Mechanistic investigations revealed that PPC triggers membrane disruption by binding to both lipopolysaccharide (LPS) and phospholipid leaflet in the OM, enabling effective penetration of PPC into the Gram-negative bacteria interior. Upon light irradiation, PPC inside bacteria generates singlet oxygen not only to effectively decrease the survival of Gram-negative bacteria P. aeruginosa and E. coli to nearly zero in vitro, but also successfully cure the full-thickness skin infection and bacterial keratitis (BK) induced by P. aeruginosa in animal models. Thus, this study provides a broad-spectrum antibacterial phototherapeutic design strategy by the synergistic action of membrane disruption and PDT to combat Gram-negative bacteria.

A ratiometric near-infrared fluorescence/photoacoustic dual-modal probe with strong donor dithienopyrrole for in vivo nitric oxide detection.

Integrating the imaging techniques of near-infrared fluorescence (NIRF) and photoacoustic (PA) can make up for each other and provide more useful medical information. Ratiometric imaging activated by disease-associated biomarkers can further augment imaging specificity. However, very few studies have employed the NIRF/PA dual-modal ratiometric imaging to improve the accuracy and specificity of disease diagnosis to date. In this paper, we present the synthesis of a nitric oxide (NO)-activated ratiometric NIRF/PA dual-modal nanoprobe RAPNP for in vivo NO imaging. The ratiometric imaging function was achieved jointly by a NO/acidity-responsive molecule DTP-BTDA and a nonresponsive fluorophore DTP-BBTD. In these fluorophores, the dithienopyrrole (DTP) moiety had strong electron-donating ability and imparted strong intramolecular charge transfer and relatively long emission wavelengths. The BTDA moiety in DTP-BTDA could be rapidly oxidized by NO under weak acidic environments, achieving the NIRF and PA signal activation. By using RAPNP as a contrast agent, we achieved the ratiometric detection of the endogenous NO in inflammatory bowel disease by NIRF/PA dual-modal imaging. This work provides the first case of the NIRF/PA dual-signal ratiometric probe for the real-time detection of NO in vivo.

Effects of iRGD conjugation density on the in vitro and in vivo properties of cylindrical polymer brushes.

iRGD can significantly improve the tumor accumulation and tumor penetration of nanomaterials. However, it still remains unclear how far iRGD can enhance the properties of nanomaterials when its conjugation density is maximized. Herein, we synthesized three types of cylindrical polymer brushes (CPBs) with 0%, 50% and 100% of side chains terminated by iRGD, which were named CPBs-1, CPBs-2 and CPBs-3, respectively, and studied the effects of iRGD density on their cellular uptake, and tumor targeting ability and tumor permeability. It was demonstrated that compared with the iRGD-free CPBs-1, the cellular uptake of CPBs-3 was enhanced 5 times and their tumor accumulation was enhanced twice. The penetration depth of CPBs-3 in three-dimensional multicellular spheroids was larger than 100 µm. Our results provide useful information for the design of active tumor targeting nanomaterials as therapeutics or contrast agents.

Semiconductor Polymer with Strong NIR-II Absorption for Photoacoustic Imaging and Photothermal Therapy.

Semiconductor polymers have several featured advantages, such as easily tunable optical properties, high light harvesting, good photostability, etc. However, semiconductor polymers with desirable NIR-II absorbance for the applications of both NIR-II photoacoustic (PA) imaging and photothermal therapy (PTT) are still lacking. Herein, we synthesized a donor-acceptor (D-A) type semiconductor polymer PTPTQ with thiophene (TP) as the electron donor and thiadiazoloquinoxaline (TQ) as the acceptor. PTPTQ had a brushlike topological structure with two poly(ethylene glycol) (PEG) chains (2000 Da) in each repeating unit. Such an intriguing structure endowed it with high hydrophilicity, good biocompatibility, and prominent passive tumor targeting ability. PTPTQ exhibited strong absorption in 600-1800 nm and good photostability. Its photothermal conversion efficiency was determined to be about 41.36%, which rendered it excellent properties in NIR-II PA imaging and PTT. By using PTPTQ as a PTT agent, the mouse tumor models can be eradicated. Taken together, the overall properties of PTPTQ make it promising as a tumor theranostic agent.

Advances in the Development of Biomarkers for Poststroke Epilepsy.

Stroke is the main cause of acquired epilepsy in elderly people. Poststroke epilepsy (PSE) not only affects functional recovery after stroke but also brings considerable social consequences. While some factors such as cortical involvement, hemorrhagic transformation, and stroke severity are associated with increased seizure risk, so far that remains controversial. In recent years, there are an increasing number of studies on potential biomarkers of PSE as tools for diagnosing and predicting epileptic seizures. Biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glutamate, and S100 calcium-binding protein B (S100B) in blood are associated with the occurrence of PSE. This review is aimed at summarizing the progress on potential biomarkers of PSE.

Associated Factors and Prognostic Implications of Non-convulsive Status Epilepticus in Ischemic Stroke Patients With Impaired Consciousness.

Background and Purpose: Non-convulsive status epilepticus (NCSE) is common in patients with disorders of consciousness and can cause secondary brain injury. Our study aimed to explore the determinants and prognostic significance of NCSE in stroke patients with impaired consciousness. Method: Consecutive ischemic stroke patients with impaired consciousness who were admitted to a neuro intensive care unit were enrolled for this study. Univariate and multivariable logistic regression were used to identify factors associated with NCSE and their correlation with prognosis. Results: Among the 80 patients studied, 20 (25%) died during hospitalization, and 51 (63.75%) had unfavorable outcomes at the 3-month follow-up. A total of 31 patients (38.75%) developed NCSE during 24-h electroencephalogram (EEG) monitoring. Logistic regression revealed that NCSE was significantly associated with an increased risk of death during hospital stay and adverse outcomes at the 3-month follow-up. Patients with stroke involving the cerebral cortex or those who had a severely depressed level of consciousness were more prone to epileptogenesis after stroke. Conclusion: Our results suggest that NCSE is a common complication of ischemic stroke, and is associated with both in-hospital mortality and dependency at the 3-month follow-up. Long-term video EEG monitoring of stroke patients is, therefore required, especially for those with severe consciousness disorders (stupor or coma) or cortical injury.

Highly Efficient, Environmentally Friendly Lignin-Based Flame Retardant Used in Epoxy Resin.

We prepared novel flame retardants with concurrent excellent smoke-suppression properties based on lignin biomass modified by functional groups containing N and P. Each lignin-based flame retardant (Lig) was quantitatively added to a fixed amount of epoxy resin (EP), to make a Lig/EP composite. The best flame retardancy was achieved by a Lig-F/EP composite with elevated P content, achieving a V-0 rating of the UL-94 test and exhibiting excellent smoke suppression, with substantial reduction of total heat release and smoke production (by 46.6 and 53%, respectively). In this work, we characterized the flame retardants and the retardant/EP composites, evaluated their performances, and proposed the mechanisms of flame retardancy and smoke suppression. The charring layer of the combustion residual was analyzed using SEM and Raman spectroscopy to support the proposed mechanisms. Our work provides a feasible method for lignin modification and applications of new lignin-based flame retardants.

MicroRNA-188 regulates age-related switch between osteoblast and adipocyte differentiation.

Bone marrow mesenchymal stem cells (BMSCs) exhibit an age-dependent reduction in osteogenesis that is accompanied by an increased propensity toward adipocyte differentiation. This switch increases adipocyte numbers and decreases the number of osteoblasts, contributing to age-related bone loss. Here, we found that the level of microRNA-188 (miR-188) is markedly higher in BMSCs from aged compared with young mice and humans. Compared with control mice, animals lacking miR-188 showed a substantial reduction of age-associated bone loss and fat accumulation in bone marrow. Conversely, mice with transgenic overexpression of miR-188 in osterix+ osteoprogenitors had greater age-associated bone loss and fat accumulation in bone marrow relative to WT mice. Moreover, using an aptamer delivery system, we found that BMSC-specific overexpression of miR-188 in mice reduced bone formation and increased bone marrow fat accumulation. We identified histone deacetylase 9 (HDAC9) and RPTOR-independent companion of MTOR complex 2 (RICTOR) as the direct targets of miR-188. Notably, BMSC-specific inhibition of miR-188 by intra-bone marrow injection of aptamer-antagomiR-188 increased bone formation and decreased bone marrow fat accumulation in aged mice. Together, our results indicate that miR-188 is a key regulator of the age-related switch between osteogenesis and adipogenesis of BMSCs and may represent a potential therapeutic target for age-related bone loss.

Relationships between age-related biochemical markers of bone turnover and OPG, TGF-ß1 and TGF-ß2 in native Chinese women.

Osteoprotegerin (OPG), transforming growth factor-ß1 (TGF-ß1) and TGF-ß2 are cytokines closely associated with bone metabolism. However, their association with bone turnover markers in native Chinese women remains unknown. The study aims to investigate the relationship between bone metabolism related cytokines including OPG, TGF-ß1, TGF-ß2 and bone turnover markers in native Chinese women. The cross-sectional study was conducted on 691 healthy Chinese women (20-80 years old). Levels of OPG, TGF-ß1, TGF-ß2, serum bone-specific alkaline phosphatase (BAP), osteocalcin (OC), cross-linked N-terminal telopeptides of type I collagen (sNTX), cross-linked C-terminal telopeptides of type I collagen (sCTX), urinary NTX (uNTX), urinary CTX (uCTX) and total urinary deoxypyridinoline (uDPD) were determined. The present study showed that OPG and TGF-ß2 had positive correlation with BAP, OC, uNTX, uCTX and uDPD, while TGF-ß1 showed negative correlation with BAP, OC, sCTX, uNTX and uCTX, and most of the coefficients of partial correlation remained significant after adjustments for age and body mass index (BMI). Multiple linear regression stepwise analysis showed that OPG and TGF-ß2 were positive determinative factors for BAP, sCTX, uNTX and uCTX, which could explain 0.6-16.6% of the variation in these markers. TGF-ß1 was a negative determinative factor for BAP, OC, sCTX and uCTX, which could explain 0.7-7.3% of the variation in these markers. This study suggested that measuring bone turnover indicators and serum cytokines simultaneously might help evaluating changes in bone turnover rate caused by aging or menopause in women.

Physical accessibility in primary health care settings: results from California on-site reviews.

BACKGROUND: People with disabilities report physical barriers in doctors' offices that affect the quality of care. Whether most or few doctors' offices are accessible is not known. We address this gap with data on 2389 primary care provider facilities. OBJECTIVES: The analysis seeks to describe overall primary care office physical accessibility and identify (1) in which areas offices meet access criteria, (2) which accessibility criteria are most often not met, and (3) whether there are urban/non-urban differences. METHODS: Reviewers rated medical offices using a 55-item instrument that assessed parking, exterior access, building entrance, interior public spaces, doctor's office interior, and the presence of accessible exam equipment. Five health plans that serve California Medicaid patients conducted reviews of providers signed with their plans. Data from the plans were merged, coded, and a descriptive analysis conducted. RESULTS: An accessible weight scale was present in 3.6% and a height adjustable examination table in 8.4% of the sites. Other high prevalence access barriers were in bathrooms and examination rooms. Parking, exterior access, building access, and interior public spaces generally met the access criteria, except for van accessible parking. CONCLUSIONS: These findings provide a base for quantitative expectations about accessibility nationwide, and indicate significant barriers exist. They show it is possible to conduct a large number of accessibility site reviews, providing one model to meet the Affordable Care Act requirement for provider accessibility information. Physical access is important as it may affect the quality of care and willingness of patients to engage in preventive care.