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Open-shell oligomers and polymers have exhibited intriguing electronic and magnetic properties, making them highly desirable for a wide range of applications, including ambipolar organic field-effect transistors (OFETs), photodetectors, organic thermoelectrics, and spintronics. Although open-shell ground states have been observed in certain small molecules and doped organic semiconductors, the exploration of open-shell ground-state conjugated polymers is still limited, and the strategies for designing these polymers remain obscure. This review aims to briefly introduce the theory and characterization methods of open-shell conjugated polymers, along with an overview of recent progress and applications. The objective is to stimulate further advancements and investigations in this promising area by shedding light on the potential of open-shell conjugated polymers and the challenges that lie ahead. [ABSTRACT FROM AUTHOR]

Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named hereditary persistence of fetal hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3′ end of the β-globin locus, including a CTCF binding site termed 3′HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3′HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies. [ABSTRACT FROM AUTHOR]

There are many ways in which cells may not adequately behave or respond to their environment, and the molecular mechanisms leading to these defects are as diverse as they are many. In this review, we report on how spatial chromatin organization contributes to the proper expression of genes, relating how CTCF — one of its main architects — contributes to gene regulation. We also touch on the emerging role of long noncoding RNAs in shaping chromatin organization and activity. The HOX gene clusters have been used as paradigm in the study of various biological pathways, and the overview we provide gives emphasis to what research on these loci has revealed about chromatin architecture and its regulation in the control of gene expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • Flocculation leads to profound changes of protein kinases under acetic acid stress. • Phosphoproteome analysis identified key kinases responded to acetic acid stress. • Overexpression of HOG1 and GPX1 reduced ROS content and improved stress tolerance. • Overexpression of protein kinase Akl1 enhanced ethanol fermentation using corn cob. Cell self-flocculation endows yeast strains with improved environmental stress tolerance that benefits bioproduction. Exploration of the metabolic and regulatory network differences between the flocculating and non-flocculating cells is conducive to developing strains with satisfactory fermentation efficiency. In this work, integrated analyses of transcriptome, proteome, and phosphoproteome were performed using flocculating yeast Saccharomyces cerevisiae SPSC01 and its non-flocculating mutant grown under acetic acid stress, and the results revealed prominent changes in protein kinases. Overexpressing the mitogen-activated protein kinase Hog1 upregulated by flocculation led to reduced ROS accumulation and increased glutathione peroxidase activity, leading to improved ethanol production under stress. Among the seven genes encoding protein kinases that were tested, AKL1 showed the best performance when overexpressed, achieving higher ethanol productivity in both corncob hydrolysate and simulated corn stover hydrolysate. These results provide alternative strategies for improving cellulosic ethanol production by engineering key protein kinases in S. cerevisiae. [ABSTRACT FROM AUTHOR]

Regarding the fact that there are significant differences in the developing process of China's regional construction industry, on the basis of the existing research results, we combine the DEA-DA model and PLS structural model to make the empirical research on the spatial differences in Chinese construction industry competitiveness formation mechanism. We find that regional economic development and factors of production greatly contribute to the upgrading of competitiveness, but their impact is a sort of differences; building auxiliary industries, innovation status and industrial organization also have different mechanisms to enhance construction industry competitiveness in different regions; there are different relationships between effectiveness and efficiency in different regions. We realize the innovation both in theory and method as to the industry competitiveness under the spatial dimension; and lay the foundations for further study on the regulation of the joint development of Chinese construction industry competitiveness. [ABSTRACT FROM AUTHOR]

Abstract: 8-Chloro-adenosine (8CA) has shown promise in hematologic and solid tumor models and is in a phase I clinical trial. However, 8CA is intensively metabolized shortly after i.v. administration, with a t 1/2β of approximately 1h. Many carriers have failed to encapsulate 8CA efficiently. To improve its pharmacokinetic properties, 8-chloro-adenosine-5′-O-stearate (8CAS), a lipophilic octadecanoyl analogue of 8CA, was synthesized and incorporated into pegylated liposomes. The liposomes, comprising egg phosphatidylcholine, cholesterol and poly (ethylene glycol) 2000-distearoyl phosphatidylethanolamine (PEG-DSPE), had mean diameters of approximately 100nm and an entrapment efficiency of 69–86%. MTT assays showed that the cytotoxicity of 8CAS and its pegylated liposomes (8CAS-PL) were retained, with IC50 values of 1.0μM and 1.9μM at 72h on MCF-7 cells, respectively, slightly higher than that of 8CA (0.6μM). Pharmacokinetic studies in rats after i.v. injection showed that both 8CAS and 8CAS-PL had increased elimination half-lives (t 1/2, 128.4, 249.2 vs. 74.7min), decreased clearance rates (Cl, 0.0135, 0.00875 vs. 0.2398L/min/kg) and increased area under the concentration–time curve (AUC0−∞, 741.4, 1163.6 vs. 42.0mgmin/L) compared to 8CA. No obvious hematological toxicity was seen for Kunming mice receiving i.v. 8CA or 8CAS-PL at a dosage of 10mg/kg daily. These results indicate that the lipophilic derivation of 8CA and the incorporation of 8CAS is an effective strategy to improve the bioavailability of 8CA. [Copyright &y& Elsevier]

Abstract: pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers’ dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. [Copyright &y& Elsevier]

This study describes the direct association of in vivo burn scar contraction with the level of α-smooth muscle actin (α-SMA) in scar tissue, in a porcine burn model. The expression of α-SMA was investigated in 100 biopsies from 44 6-week old burn scars and in 85 biopsies from 16 2-week old burn wounds. Statistical analysis showed that the levels of α-SMA in 6-week old scars were significantly negatively correlated to scar size (r =−0.68) and the higher levels of α-SMA were observed in smaller scars. Moreover, α-SMA was also found to be significantly positively correlated to re-epithelialisation time (r =0.57) and scar thickness (r =0.58) and higher levels of α-SMA were detected in thicker scars with delayed wound closure. Further statistical analysis revealed that scar contraction can be explained best by the level of α-SMA expression and partially by scar thickness. Other variables, such as different dressings and individual pig, may also partly contribute to scar contraction. At week 2 after-burn, the level of α-SMA expression in 16 burn wounds was significantly related to the depth of burns and wound healing outcome. To our knowledge, this is the first study to provide in vivo evidence of the association of α-SMA expression with scar contraction, scar thickness, re-epithelialisation time and the depth of burn in a large animal burn model with scars similar to human hypertrophic scar. [Copyright &y& Elsevier]

Abstract: Sorafenib is slightly absorbed in the gastrointestinal tract due to its poor solubility in water. To improve its absorption, a novel nanoparticulate formulation-nanomatrix was used in the study. The nanomatrix was a system prepared from a porous material Sylysia® 350 and a pH sensitive polymer Eudragit®. The formulations were optimized by orthogonal design (L9(34)) and their bioavailability were evaluated in rat, comparing to pH-sensitive Eudragit nanoparticles and suspension of sorafenib. In the formulations, the ratio of sorafenib to Eudragit® S100 was found to be more important determinant of the sorafenib bioavailability than the ratio of sorafenib to Sylysia® 350. As for the bioavailability, the AUC0–36h of sorafenib nanomatrix was 13–33 times to that of sorafenib suspension, but only 16.8% to 40.8% that of Eudragit® S100 nanoparticles. This may be resulted from the different drug dispersion degree, release character and bioadhension activity. However, because all the materials used in the nanomatrix formulation are commonly adjuvant, safe, easy to get and cheap, above all, the nanomatrix formulation can solve the stability and scaling up problems in the nanoparticles, it had potential to develop into a product in the future. [Copyright &y& Elsevier]

Abstract: This study describes the ultrasound assessment of burn scars in paediatric patients and the association of these scar thickness with laser Doppler imaging (LDI) determined burn depth. A total of 60 ultrasound scar assessments were conducted on 33 scars from 21 paediatric burn patients at 3, 6 and 9 months after-burn. The mean of peak scar thickness was 0.39±0.032cm, with the thickest at 6 months (0.40±0.036cm). There were 17 scald burn scars (0.34±0.045cm), 4 contact burn scars (0.61±0.092cm), and 10 flame burn scars (0.42±0.058cm). Each group of scars followed normal distributions. Twenty-three scars had original burns successfully scanned by LDI and various depths of burns were presented by different colours according to blood perfusion units (PU), with dark blue <125, light blue 125–250, and green 250–440PU. The thickness of these scars was significantly different between the predominant colours of burns, with the thinnest scars for green coloured burns and the thickest for dark blue coloured burns. Within light blue burns, grafted burns healed with significantly thinner scars than non-grafted burns. This study indicates that LDI can be used for predicting the risk of hypertrophic scarring and for guiding burn care. To our knowledge, this is the first study to correlate the thickness of burns scars by ultrasound scan with burn depth determined by LDI. [Copyright &y& Elsevier]

Please cite this paper as: Fetuin-A promotes primary keratinocyte migration: independent of epidermal growth factor receptor signalling. Experimental Dermatology 2010; 19: e289-e292. Abstract: Previously, we reported that fetuin-A is a major component of ovine foetal skin and significantly enhances 'wound closure' in primary keratinocyte cultures. In this study, we found that in human newborn foreskin, a high level of fetuin-A protein is detected throughout the dermis. However, in adult skin a low level of fetuin-A is observed throughout the epidermal and dermal layers, except at regions surrounding hair follicles and at the epidermal-dermal junction where the level of fetuin-A is relatively high. Fetuin-A significantly induces actin-rich protrusions in human primary keratinocytes. Interestingly, blockade of epidermal growth factor (EGF) receptor signalling has a limited effect on fetuin-A promoted 'wound closure' on primary human keratinocytes, but significantly inhibits fetuin-A's effect on HaCaT cells. These results indicate that high levels of fetuin-A may partially contribute to less scar formation in newborn foreskin and that the effect of fetuin-A on primary keratinocyte migration is independent of EGF receptor signalling. [ABSTRACT FROM AUTHOR]

Abstract: This is a study to compare wound healing among three types of dressings on a porcine model with deep-dermal-partial-thickness burns. The burns in this study were from eight animal trials conducted in the past for other purposes and only burns with a uniform pale appearance that had served as controls in original experiments were selected. In total, there were 57 burns in 33 pigs, using one of following three dressings: Acticoat (Silver) (3 trials), Jelonet (Gauze) (3 trials), and Solosite Gel/Jelonet (Gel/Gauze) (2 trials). The wound healing assessments included wound re-epithelialisation during a 6-week period, clinical and histological scar assessments at week 6 after burn. Of all wound healing/scar assessments, only re-epithelialisation showed statistical difference between dressings. Earlier re-epithelialisation was observed in Gel/Gauze dressings compared to Silver and/or Gauze dressings. However, this study revealed huge variation in wound healing outcome between 3 trials within both Silver and/or Gauze dressings, supported by significant differences on re-epithelialisation, clinical and histological scar measurements. In addition, it was found that larger animals healed better than smaller ones, based on weights from 21 pigs. Of all dressings, Silver delivers the best protection for wound colonization/infection. Wound colonization/infection was found to confine wound healing and lead to thinner RND in scars. From this study, we cannot find enough evidence to suggest the beneficial effect of one dressing(s) over others on burn wound healing outcome on a porcine model with small deep-dermal-partial-thickness burns with a relative small sample size. [Copyright &y& Elsevier]

To investigate the effect of different enteric polymers on the characteristics of pH-sensitive nanoparticles, Rhodamine 6G (Rho) was incorporated in various pH-sensitive nanoparticles. The different patterns of pH-dependent release profiles were observed, although some polymers have the same dissolving pH. The distribution, adhesion and transition of different nanoparticles in rat gut showed significant difference, closely related to the release characteristics of nanoparticles, and their release behaviour are dependent on the dissolving pH and the structure of the polymers, as well as the drug property. Most nanoparticle formulations decreased the distribution and adhesion of Rho in the stomach but increased these values in the intestine. The nanocarriers also control the drug release sites and release rate in the GI tract. In conclusion, pH-sensitive nanoparticles seem favourable for drug absorption and it is important to choose the proper materials to obtain the suitable characteristics for the oral pH-sensitive nanoparticles. [ABSTRACT FROM AUTHOR]

Background: Silver dressings have been widely and successfully used to prevent cutaneous wounds, including burns, chronic ulcers, dermatitis and other cutaneous conditions, from infection. However, in a few cases, skin discolouration or argyria-like appearances have been reported. This study investigated the level of silver in scar tissue post-burn injury following application of Acticoat™, a silver dressing. Methods: A porcine deep dermal partial thickness burn model was used. Burn wounds were treated with this silver dressing until completion of re-epithelialization, and silver levels were measured in a total of 160 scars and normal tissues. Results: The mean level of silver in scar tissue covered with silver dressings was 136 μg/g, while the silver level in normal skin was less than 0.747 μg/g. A number of wounds had a slate-grey appearance, and dissection of the scars revealed brown-black pigment mostly in the middle and deep dermis within the scar. The level of silver and the severity of the slate-grey discolouration were correlated with the length of time of the silver dressing application. Conclusions: These results show that silver deposition in cutaneous scar tissue is a common phenomenon, and higher levels of silver deposits and severe skin discolouration are correlated with an increase in the duration of this silver dressing application. [ABSTRACT FROM AUTHOR]

Abstract: This study describes the evaluation of a clinical scar scale for our porcine burn scars, which includes scar cosmetic outcome, colour, height and hair, supplemented with reference porcine scar photographs representing each scar outcome and scar colour scores. A total of 72 porcine burn scars at week 6 after burn were rated in vivo and/or on photographs. Good agreements were achieved for both intra-rater reliability (correlation is 0.86–0.98) and inter-rater reliability (ICC=80–85%). The results showed statistically significant correlations for each pair in this clinical scar scale (p <0.01), with the best correlation found between scar cosmetic outcome and scar colour. A multivariate principle components analysis revealed that this clinical scar assessment was highly correlated with scar histology, wound size, and re-epithelialisation data (p <0.001). More severe scars are clinically characterised by darker purple colouration, more elevation, no presence of hair, histologically by thicker scar tissue, thinner remaining normal dermis, are more likely to have worse contraction, and slower re-epithelialisation. This study demonstrates that our clinical scar scale is a reliable, independent and valuable tool for assessing porcine burn outcome and truthfully reflects scar appearance and function. To our knowledge, this is the first study demonstrating a high correlation between clinical scar assessment and scar histology, wound contraction and re-epithelialisation data on porcine burn scars. We believe that the successful use of porcine scar scales is invaluable for assessing potential human burn treatments. [Copyright &y& Elsevier]

We further study the competition among loner, cooperative and defective strategies by considering an evolutionary prisoner's dilemma (PD) game with some troublemakers in the random network by means of Monte Carlo simulations. It can be observed that the frequency of cooperators (fc) decreases with increasing of loners' (e) and defectors' payoffs (b). In particular, fc has a sharp decline when the loners' payoffs approximate 1.0. In addition, we find that introduction of troublemaker strategies prevents the uniform defection in the spatial evolutionary PD games for large b values and small e values. In practice, it also prevents cooperative strategies and defective strategies from vanishing for large e values. [ABSTRACT FROM AUTHOR]

Abstract: This retrospective review examines healing in different sites on a porcine burn model; 24 pairs of burns on 18 pigs from other animal trials were selected for analysis. Each pair of burns was located on the either the cranial or the caudal part of the thoracic ribs region, on the same side of the animal. The burns were 40–50cm2 in size and of uniform deep-dermal partial thickness. Caudal burns healed significantly better than cranial burns, demonstrated by earlier closure of wounds, less scar formation and better cosmesis. To our knowledge, this is the first detailed study reporting that burn healing is affected by location on a porcine burn model. We recommend that similar symmetrical burns should be used for future comparative assessments of burn healing. [Copyright &y& Elsevier]

In thermal deep-dermal burns, surgical debridement is normally used in conjunction with skin grafting or skin substitutes and debridement alone as a burn treatment is not usually practiced. The current study addresses whether or not debridement alone would enhance burn wound healing on small deep-dermal-partial thickness burns. This was a prospective and blinded experimental trial using a porcine deep-dermal-partial thickness burn model. Four burns, approximately 50 cm2 in size, were created on each of eight pigs. Two burns from each pig were immediately surgically debrided and the other two were not debrided as the internal control. Hydrate gel together with paraffin gauze were used to cover the burns for four pigs and silver dressings for the other four. Clinical assessment of wound healing was conducted over a 6-week period. Skin samples were collected at the end of the experiment and histopathological evaluation was performed. The results show thinner scar formation and lower scar height in the debrided compared with nondebrided wounds in the hydrate gel/paraffin gauze groups. There were no statistically significant differences in wound healing assessment between the debrided and nondebrided wounds dressed with silver dressings. This study provides supporting evidence that immediate debridement with an appropriate dressing and without skin grafting may promote wound healing, suggesting its potential benefit for clinical patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • Adding caffeic and rosmarinic acids before the alcoholic fermentation of red wine. • The evolution of colors and polyphenolics was figured out by CIELAB and HPLC-MS. • The addition enhanced chromatic quality and copigmentation effect. • The addition can be applied as an alternative strategy for making premium red wines. Although phenolic copigments are rarely colored, they can still influence color expression in red wine copigmentation. Here, prefermentative agents, such as caffeic and rosmarinic acids, were added as copigments during Cabernet Sauvignon red winemaking. The evolution of colors and polyphenols was analyzed by tristimulus colorimetry and high-performance liquid chromatography-tandem mass spectrometry during brewing and aging periods. The results showed that the addition of caffeic and rosmarinic copigments was beneficial to obtain more saturated and vivid hue of wines. The changes in color were correlated with a significant increase in anthocyanins concentration. Moreover, the results demonstrated that the addition of the two phenolic copigments increased the concentration of total phenols and enhanced the copigmentation effect, indicating improved chromatic intensity and color stability of wines. Therefore, the addition of caffeic and rosmarinic acids is a simple and useful enological technique to obtain red wines with high color quality and aging potential. [ABSTRACT FROM AUTHOR]

Summary: It is well established that ligand-gated chloride flux across the plasma membrane modulates neuronal excitability. We find that a voltage-dependent Cl− conductance increases neuronal excitability in immature rodents as well, enhancing the time course of NMDA receptor-mediated miniature excitatory postsynaptic potentials (mEPSPs). This Cl− conductance is activated by CaMKII, is electrophysiologically identical to the CaMKII-activated CLC-3 conductance in nonneuronal cells, and is absent in clc-3−/− mice. Systematically decreasing [Cl−]i to mimic postnatal [Cl−]i regulation progressively decreases the amplitude and decay time constant of spontaneous mEPSPs. This Cl−-dependent change in synaptic strength is absent in clc-3 −/− mice. Using surface biotinylation, immunohistochemistry, electron microscopy, and coimmunoprecipitation studies, we find that CLC-3 channels are localized on the plasma membrane, at postsynaptic sites, and in association with NMDA receptors. This is the first demonstration that a voltage-dependent chloride conductance modulates neuronal excitability. By increasing postsynaptic potentials in a Cl− dependent fashion, CLC-3 channels regulate neuronal excitability postsynaptically in immature neurons. [Copyright &y& Elsevier]

Abstract: The present study was geared at the long-term stability and the changes in oral bioavailability of CyA Eudragit® S100 nanoparticles stabilized by suspending agents. CyA Eudragit® S100 nanoparticle colloids were prepared by quasi-emulsion solvent diffusion technique and they were mixed with Xanthan gum to obtain suspended nanoparticle colloids. The suspended nanoparticle colloids were preserved at different temperatures for different period of time, as long as 18 months. During the storage period, the CyA concentration, particle size, pH and viscosity were determined. The results indicated that CyA concentration, particle size and viscosity of the colloids had no obvious change. However, the pH increased slightly from 5.5 to about 6.4. The results of bioavailability and pharmacokinetic study revealed that all formulations of nanoparticles showed higher C max and higher AUC0–24 values than that of reference (Neoral®). The relative bioavailability of S-CyA-S100 NP initial compared with Neoral® was 162.8%. The C max and AUC0–24 values of nanoparticle formulations at 12 and 18 months were both lower than that of the initial. The bioequivalency was suggested between the tested nanoparticle formulations at the initial and 12 months. It was deduced by surface analysis, TEM observation, in vitro release as well as the characteristics of Eudragit® S100 that the decrease in bioavailability might be due to the pH change of the nanoparticle colloid. [Copyright &y& Elsevier]

Background: Approximately 40% of mammalian mRNA sequences contain AUG trinucleotides upstream of the main coding sequence, with a quarter of these AUGs demarcating open reading frames of 20 or more codons. In order to investigate whether these open reading frames may encode functional peptides, we have carried out a comparative genomic analysis of human and mouse mRNA 'untranslated regions' using sequences from the RefSeq mRNA sequence database. Results: We have identified over 200 upstream open reading frames which are strongly conserved between the human and mouse genomes. Consensus sequences associated with efficient initiation of translation are overrepresented at the AUG trinucleotides of these upstream open reading frames, while comparative analysis of their DNA and putative peptide sequences shows evidence of purifying selection. Conclusion: The occurrence of a large number of conserved upstream open reading frames, in association with features consistent with protein translation, strongly suggests evolutionary maintenance of the coding sequence and indicates probable functional expression of the peptides encoded within these upstream open reading frames. [ABSTRACT FROM AUTHOR]

Abstract: Angiogenesis, the process of new blood vessel formation from preexisting capillaries, is a multistep process. The principle cell type in this process is endothelial cells which are required to undergo proliferation, migration, differentiation, and coalescence into cord-like structures with a central lumen. However, the molecular and cellular mechanisms that regulate this process require further investigation. In this study, we have used the fibrin/fibrinogen-based three-dimensional culture to enrich for primary cultured mouse aortic endothelial cells, and to induce endothelial cell capillary morphogenesis. We found among all the cell surface markers examined that only TEM7 expression was up-regulated upon endothelial cells capillary morphogenesis. In addition, inhibition of capillary morphogenesis by serum stimulation completely blocked TEM7 expression. In contrast, stimulation of endothelial cell capillary morphogenesis with PMA enhanced TEM7 expression. Furthermore, incubation of endothelial cells with a recombinant extracellular domain of TEM7 blocked capillary morphogenesis in three-dimensional cultures. These results suggest that TEM7 is a novel protein whose cell surface expression is essential during endothelial cell capillary morphogenesis. [Copyright &y& Elsevier]

The rat aortic ring model is well utilized for evaluation of angiogenesis. We report here an alternative assay employing an ex vivo mouse aorta angiogenesis model that can be extensively manipulated and serially evaluated using digital-assisted image analysis. Mouse aortas were harvested, cut into 2-mm disks, and cultured in fibrin matrix with growth media. Radial vascular outgrowths arose from the cut edge of the aortic disk and were digitally photographed and serially quantified. A variety of culture conditions were evaluated to determine their ability to alter angiogenesis in this model. Vessel outgrowth became apparent on day 3 and continued through day 10 with linear growth occurring between days 3 and 6. Increasing concentrations of serum from 0% to 40% resulted in stimulation of angiogenesis after day 3. Suramin and endostatin dramatically inhibited angiogenesis, which was more profound when applied at day 0 than when linear growth could be identified (day 3). Cells isolated from vessel outgrowths were predominantly endothelial in origin by immunocytochemistry and FACS analysis. We demonstrate that angiogenesis in an ex vivo murine model can be easily quantified using digital image analysis, responds appropriately to stimulation and inhibition, and exhibits differential results based on time of inhibitor administration. Antiangiogenic agents may be most effective if administered before development of accelerated vessel growth. [Copyright &y& Elsevier]

The pH-sensitive cyclosporine A (CyA) nanoparticles were prepared by the solvent displacement method with enteric dissolved polymer of hydroxypropyl methylcellulose phthalate (HPMCP; including HP50 and HP55). The CyA nanoparticles were analyzed by HPLC for yield and encapsulation efficiency, dynamic light scattering for particle size and transmission electron microscopy (TEM) for morphology. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids were evaluated in rats, compared with the current available CyA microemulsion (Neoral®). The bioavailability of CyA-HP55 nanoparticle colloids with various suspending agents was also investigated. The results obtained demonstrated that the pH-sensitive CyA nanoparticles with a particle size of 50–60 nm and encapsulation efficiency over 95% could be reproducibly prepared. The bioavailability of CyA-HP50 and CyA-HP55 nanoparticle colloids calculated by the AUC0–72 were 82.3% and 119.6%, similar to the reference of Neoral, while the bioavailability of CyA-HP55 nanoparticle colloids was found to be higher than that of CyA-HP50 nanoparticle colloids. The increase of mean residence time (MRT) and the decrease of elimination constant of the central compartment (K10) for both CyA-HP50 and CyA-HP55 nanoparticle colloids compared with the reference indicated significant sustained release of CyA from the nanoparticles. The effects of the suspending agents on the bioavailability of CyA-HP55 nanoparticles were observed, and the bioavailability decreased as the concentration of suspending agents or the viscosity of the nanoparticle colloids increased. [Copyright &y& Elsevier]

Dysfunction of the Na+,K+-ATPase (Na+,K+-pump), due to reduced energy supply or increased endogenous ouabain-like inhibitors, likely occurs under pathological conditions in the central nervous system. In cultured mouse cortical neurons, we examined the hypothesis that a mild non-toxic inhibition of the Na+,K+-ATPase could synergistically sensitize the vulnerability of neurons to normally non-lethal apoptotic signals. Ouabain at a low concentration of 0.1 μM slightly lessened the Na+,K+-pump activity measured as an ouabain-sensitive current, yet did not affect K+ homeostasis and viability of cortical neurons. Co-exposure to 0.1 μM ouabain plus non-lethal C2-ceramide (5 μM) or β-amyloid 1–42 (5 μM), however, induced marked intracellular K+ loss, caspase-3 cleavage, DNA laddering, and synergistically triggered neuronal death. The caspase inhibitor Z-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD-FMK) predominantly blocked the caspase activation and neuronal death. These results suggest that slight impairment of Na+,K+-pump activity may amplify the disruption of K+ homeostasis in the presence of a non-lethal apoptotic insult, leading to activation of apoptotic cascade and substantial neuronal injury. [Copyright &y& Elsevier]

The biological changes in suspension cultures of Taxus cuspidata caused by dimethyl sulphoxide (DMSO) and ethanol, two commonly used solvents for water-insoluble elicitors, were investigated. The activities of peroxidase (POD) and superoxide dismutase (SOD) changed remarkably after the addition of small amount (0.4% (v/v)) of DMSO compared to those of the control culture at 4 h, however, they were less affected by small amount (0.4% (v/v)) of ethanol within 20 h. The biomass, cell viability, contents of intra/extracellular proteins did not change obviously when the amounts of DMSO and ethanol were below 1% (v/v) and 0.4% (v/v), respectively, but they varied significantly when the contents of DMSO and ethanol were 4% (v/v) and 1% (v/v), respectively. Obvious DNA fragmentation occurred in the case of ethanol at 2% (v/v), while no DNA fragments were observed in the case of DMSO at the same concentration level. It is inferred that DMSO below 1% (v/v) is a better solvent for investigating the effects of water-insoluble elicitors at a long-term contact, while ethanol less than 0.4% (v/v) is more suitable for a short-term contact. [Copyright &y& Elsevier]

Histone deacetylase (HDAC) inhibitors have been demonstrated to regulate myeloid cell differentiation. In the present study the effects of the HDAC inhibitor trichostatin A (TSA) on the tetraspanin cell surface antigen CD9 were determined in primary murine macrophages. TSA inhibited CD9 protein and message expression and was optimal by 48 h. TSA did not induce similar effects on other surface markers and resulted in a modest increase or no effect on CD54 and CD11b, respectively. These effects were concentration dependent and concomitant with increased histone H4 acetylation. While interferon-γ (IFN-γ) and TSA had similar effects on CD9 expression, transcriptional profiling demonstrated significant differences in the genes activated by these stimuli. Notably CD14 message was down-regulated by IFN-γ while increased by TSA. These results demonstrate that HDAC inhibition may modulate macrophage function in part through changes in the expression of membrane proteins associated with matrix interactions. [Copyright &y& Elsevier]

CD9, a member of the tetraspanin family is a cell surface marker expressed on myeloid and nonmyeloid as well as on neoplastic cells. The present study has focused on the role of inflammation and macrophage activation in the regulation of CD9 expression. We report that the expression of CD9 on primary cultures of murine peritoneal macrophages was down regulated by Interferon-γ, IFN-γ. This down regulation was concentration-dependent and maximal by 48 h. The changes in surface expression were consistent with similar reductions in CD9 protein and message levels by Western and Northern blot analyses. The mechanism by which IFN-γ decreases CD9 expression appears to be through the Stat1 signaling pathway as Stat1 knockout mice did not demonstrate any reduction in CD9 expression by IFN-γ treatment. These results represent the first evidence for the down regulation of CD9 expression with macrophage activation. [Copyright &y& Elsevier]

Frizzled genes encode a family of Wnt ligand receptors, which have a conserved cysteine-rich Wnt binding domain and include both transmembrane and secreted forms. Work by others has shown that experimental perturbation of Wnt signaling results in aberrant hair formation, hair growth, and hair structure. To date, however, there is no information on the contribution of individual Frizzled proteins to hair development. We now report that Frizzled-3 expression in skin is restricted to the epidermis and to the developing hair follicle. Northern analysis on total mouse skin mRNA revealed a single Frizzled-3 transcript of 3.7 kb. Reverse transcription–polymerase chain reaction and in situ hybridization analysis revealed Frizzled-3 expression in epidermal and hair follicle keratinocytes. Frizzled-3 transcripts are first detected in discrete foci in the developing epidermis of 13 d embryos and later in the hair follicle placodes of 15 d embryos, suggesting a role for this Frizzled isoform in follicle development. In 17 d embryos and 1 d old newborn mice Frizzled-3 expression is limited to suprabasal keratinocytes and is not seen in pelage follicles until 3 d postpartum. In 7 d old neonatal skin, Frizzled-3 is expressed throughout the epidermis and in the outer cell layers of hair follicles. We have also identified the mRNA encoding human Frizzled-3 in epidermal keratinocytes and in the HaCaT keratinocyte cell line. Human Frizzled-3 mRNA encodes a 666 amino acid protein with 97.8% identity to the mouse protein. The human Frizzled-3 gene was mapped using a radiation-hybrid cell line panel to the short arm of chromosome 8 between the markers WI-1172 and WI-8496 near the loci for the Hypotrichosis of Marie Unna and Hairless genes. [ABSTRACT FROM AUTHOR]

• Smartphone-combined ratiometric probe was proposed for cephalexin detection. • Carbon dot and CdTe QDs were as internal and responsive fluorophore, respectively. • The portable device was constructed according to the color change under UV lamp. • This method offers a portable, simple and visual determination of cephalexin. A smartphone-combined dual-emission ratiometric fluorescence probe for specifically and visibly detecting cephalexin was first designed. In the probe, blue-emitting fluorescent carbon dots (CDs) was synthesized and covered with a layer of silica spacer. Red-emitting fluorescent CdTe QDs (r-QDs) was grafted onto the silica nanospheres as an analytical probe. Then, the cephalexin antibody was covalent grafted to the ratio sensor to increase the selectivity. The ratio of fluorescence intensity (FL) of r-QDs and CDs was quenched with the increasing concentration of cephalexin. The detection method has good linear response in the range of 1–500 μM and the detection limit was 0.7 μM. Then portable device based on smartphone detection was constructed according to the color change under UV lamp. The detection image was obtained through the smartphone camera, and the color picker APP installed in the smartphone captured the RGB value of the image. In addition, this method was also used to determine the amount of cephalexin in milk samples with recovery of 94.1%-102.2%. These results showed that it was a portable, simple and visible method to detect cephalexin in food analysis and environmental monitoring. [ABSTRACT FROM AUTHOR]

Chromatin remodelers are important in maintaining the dynamic chromatin state in eukaryotic cells, which is essential for epigenetic regulation. Among the remodelers, the multi-subunits complex INO80 plays crucial roles in transcriptional regulation. However, current knowledge of chromatin regulation of the core subunit Ino80 on stress adaptation remains mysterious. Here we revealed that overexpressing the chromatin remodeler Ino80 elevated tolerance to multiple stresses in budding yeast Saccharomyces cerevisiae. Analyses of differential chromatin accessibility and global transcription levels revealed an enrichment of genes involved in NCR (nitrogen catabolite repression) under acetic acid stress. We demonstrated that Ino80 overexpression reduced the histone H3 occupancy in the promoter region of the glutamate dehydrogenase gene GDH2 and the allantoinase gene DAL1. Consistently, the decreased occupancy of nucleosome was revealed in the Ino80-inactivation mutant. Further analyses showed that Ino80 was recruited to the specific DNA locus in the promoter region of GDH2. Consistently, Ino80 overexpression facilitated the utilization of non-preferred nitrogen source to enhance ethanol yield under prolonged acetic acid stress. These results demonstrate that Ino80 plays a crucial role in coordinating carbon and nitrogen metabolism during stress adaptation. [ABSTRACT FROM AUTHOR]

Background: Understanding how transcription occurs requires the integration of genome-wide and locus-specific information gleaned from robust technologies. Chromatin immunoprecipitation (ChIP) is a staple in gene expression studies, and while genome-wide methods are available, high-throughput approaches to analyze defined regions are lacking. Results: Here, we present carbon copy-ChIP (2C-ChIP), a versatile, inexpensive, and high-throughput technique to quantitatively measure the abundance of DNA sequences in ChIP samples. This method combines ChIP with ligation-mediated amplification (LMA) and deep sequencing to probe large genomic regions of interest. 2C-ChIP recapitulates results from benchmark ChIP approaches. We applied 2C-ChIP to the HOXA cluster to find that a region where H3K27me3 and SUZ12 linger encodes HOXA-AS2, a long non-coding RNA that enhances gene expression during cellular differentiation. Conclusions: 2C-ChIP fills the need for a robust molecular biology tool designed to probe dedicated genomic regions in a high-throughput setting. The flexible nature of the 2C-ChIP approach allows rapid changes in experimental design at relatively low cost, making it a highly efficient method for chromatin analysis. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are stable and abundantly expressed in vivo but are abnormally expressed in several diseases. This study aimed to identify circRNAs acting as potential biomarkers for cardiovascular disease (CVD). Research were retrieved from the articles published by September 2018 in eight databases to compare circRNA expression profiles between CVD and non‐CVD in human and animal models. Meta‐analysis under a random effects model was conducted. Subgroup analysis of tissue, species, and disease‐specific circRNAs was examined. Sensitivity analysis was performed to explain the uncertainty among all studies. Diagnostic accuracy of circRNAs in CVD was analyzed to testify the discriminative ability. Bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was conducted. Among 6,284 differentially expressed circRNAs from 32 original studies, only 322 circRNAs were reported in three or more studies. The meta‐analysis identified 63 significantly dysregulated circRNAs, 44 upregulated and 19 downregulated. Among the tissue‐specific or disease‐specific circRNAs identified in the subgroup analysis, two circRNAs (circCDKN2BAS and circMACF1) showed the potential to be circulating biomarkers for CVD. Sensitivity analysis demonstrated 69% of circRNAs were in conformity with the overall analysis. The pooled diagnostic odds ratio was 2.94 (95% confidence interval [CI], 2.35–3.58), and the overall area under the curve value was 0.86 (95% CI, 0.83–0.89). GO and KEGG enrichment analyses indicated that the target genes of circRNAs participate in cardiogenesis‐related processes and pathways. This study demonstrates circRNAs have a high diagnostic value as potential biomarkers for CVD, and two candidate circRNAs, circCDKN2BAS and circMACF1, are potential circulating biomarkers for CVD diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Focuses on the identification of GLI1 oncogene in the etiology of basal cell carcinoma. Increase in expression of GlI1 in basal cell carcinoma; Frequency of the nucleotide changes in the general population; Variation between wild-type GLI1 and the original human GlI1 clone.

This study investigates crystallographic orientations to exhibit fractures in silicon, such as those on the (100) plane cracks which travel along the [011] direction. Molecular dynamics simulations are performed to investigate the competing processes of cleavage bond-breaking and amorphisation under a uniaxial tensile load (mode I load) in the (100) [011] Si system. Notably, we observe two types of crack propagation behaviour: (1) downward step mechanism followed by small fracture steps on the alternating {111} plane and (2) zigzag propagation mechanism. Our simulations also show that local structural amorphisations of the lattice which act as the self-protecting mechanism of crack propagation contribute to the preservation of the crack on the {100} plane. [ABSTRACT FROM AUTHOR]

Phycocyanin is a blue fluorescent protein with multi-bioactive functions. However, the multi-bioactivities and spectral stability of phycocyanin are susceptible to external environmental conditions, which limit its wide application. Here, the structure, properties, and biological activity of phycocyanin were discussed. This review highlights the significance of the microcapsules' wall materials which commonly protect phycocyanin from environmental interference and summarizes the current preparation principles and characteristics of microcapsules in food and pharma industries, including spray drying, electrospinning, electrospraying, liposome delivery, sharp-hole coagulation baths, and ion gelation. Moreover, the major technical challenge and corresponding countermeasures of phycocyanin microencapsulation are also appraised, providing insights for the broader application of phycocyanin. [ABSTRACT FROM AUTHOR]

Lead selenide (PbSe) thin films were deposited on fluorine doped tin oxide (FTO) glass by a facile one-step pulse voltage electrodeposition method, and used as counter electrode (CE) in CdS/CdSe quantum dot-sensitized solar cells (QDSSCs). A power conversion efficiency of 4.67% is received for the CdS/CdSe co-sensitized solar cells, which is much better than that of 2.39% received using Pt CEs. The enhanced performance is attributed to the extended absorption in the near infrared region, superior electrocatalytic activity and p -type conductivity with a reflection of the incident light at the back electrode in addition. The physical and chemical properties were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM), energy-dispersive spectroscopy (EDS), reflectance spectra, electrochemical impedance spectroscopy (EIS) and Tafel polarization measurements. The present work provides a facile pathway to an efficient CE in the QDSSCs. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia has been accepted as a new geriatric syndrome, which will become a common and important public health challenge. And angiotensin-converting enzyme inhibitors (ACEIs) have been shown to improve exercise capacity in elderly without heart failure. Objectives: To evaluate the effect of angiotensin-converting enzyme inhibitors (ACEIs) on physical function in elderly. Data Sources: The Cochrane Library, PubMed, EMBASE and Web of Science were searched. Eligibility Criteria: All researches included were randomized controlled trials (RCTs) which compared any kind of ACEIs with placebo or other anti-hypertensives in elderly, and provided empirical data of grip strength and 6-min walk distance change from baseline. Study Appraisal and Synthesis Methods: Risk of bias was systematically assessed by using the Cochrane risk of bias tool. Data of grip strength and 6-min walk distance change from baseline were collected and mean differences (MDs) were calculated along with 95 % CI (confidence interval) by using a random effects model. Results: In 3 RCTs including 337 elderly participants, ACEIs ( n = 178) did not significantly improved 6-min walk distance (13.45, 95 % CI: −16.71 to 43.61; P = 0.38) versus placebo or other antihypertensives ( n = 159). In 3 RCTs including 499 elderly participants, grip strength was not significantly different (−0.67, 95 % CI: −1.53 to 0.19; P = 0.12) between ACEIs ( n = 260) and placebo or other antihypertensives ( n = 239). Limitations: There exists only 4 RCTs and the number of participants is limited. Pooling of data were from different trials including different participant characteristics. And intervention is not strictly consistent. Conclusion: This study shows that ACEIs can not significantly improve walk distance or the age-related decline of muscle strength for older participants in clinical trials. [ABSTRACT FROM AUTHOR]

It screens the input and output indicators of the total factor productivity of Chinese regional construction industry with the method of added value. On this basis, it uses the super-efficiency DEA method to analyze the Malmquist productivity index of construction industry in 31 Chinese provinces from 2006 to 2009. Finally, it identifies the key factors affecting the productivity of China's construction industry, with the method of analysis of variance. With the effective combination of the above three methods, we successfully achieve the objective study in three aspects, that is, the measurement model for productivity, the selection of indicators and the identification of factors, so as to shape a more scientific structure for studying the change of productivity. It finds that the main reason for the steady increase in total factor productivity is technological progress and the improvement in the scale efficiency is just a kind of short-term behavior which is not the key issue. And one key issue to be solved is the improvement of pure technology efficiency. Three indicators, "science and technology investment", "human capital of construction industry", "economy level", exert a great influence on the improvement of the productivity of Chinese regional construction industry. [ABSTRACT FROM AUTHOR]

This work proposes a method for estimating the weight distribution of a network with Gauss edge weights using a time series collected from controlled measurements of the stable dynamics of the network. Comparing the weight distribution obtained using this method with that using another scheme demonstrates that the former is effective and accurate for estimating the weight distribution P(w) of coupled oscillator networks in a broad coupling strength region. This method enables the topological properties of underlying networks to be determined from only a time series of measurements because it depends on no prior information about the dynamical system. In addition, the method is rather robust against noise. [ABSTRACT FROM AUTHOR]

The Chinese white wax scale insect, Ericerus pela, can survive at extremely low temperatures, and some overwintering individuals exhibit supercooling at temperatures below -30°C. To investigate the deep supercooling ability of E. pela, transcriptomic and proteomic analyses were performed to delineate the major gene and protein families responsible for the deep supercooling ability of overwintering females. Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that genes involved in the mitogen-activated protein kinase, calcium, and PI3K-Akt signaling pathways and pathways associated with the biosynthesis of soluble sugars, sugar alcohols and free amino acids were dominant. Proteins responsible for low-temperature stress, such as cold acclimation proteins, glycerol biosynthesis-related enzymes and heat shock proteins (HSPs) were identified. However, no antifreeze proteins (AFPs) were identified through sequence similarity search methods. A random forest approach identified 388 putative AFPs in the proteome. The AFP gene ep-afp was expressed in Escherichia coli, and the expressed protein exhibited a thermal hysteresis activity of 0.97°C, suggesting its potential role in the deep supercooling ability of E. pela. [ABSTRACT FROM AUTHOR]

Abstract: The interaction of nanocarriers with cells including their transcellular behavior is vital not only for a drug delivery system, but also for the safety of nanomaterials. In an attempt to clarify how the structures of polymers impact the transport mechanisms of their nanocarriers in epithelial cells, three amphiphilic polymers (PEEP–PCL, PEG–PCL and PEG–DSPE) with different hydrophilic or hydrophobic blocks were synthesized or chosen to form different micelle systems here. The endocytosis, exocytosis, intracellular colocalization, paracellular permeability and transcytosis of these micelle systems were compared using Förster resonance energy transfer analysis, real-time confocal images, colocalization assay, transepithelial electrical resistance study, and so on. All micelle systems were found intact during the studies with cells. The endocytosis and exocytosis studies with undifferentiated MDCK cells and the transcytosis study with differentiated MDCK monolayers all indicated the fact that PEG–DSPE micelles achieved the most and fastest transport, followed by PEG–PCL and PEEP–PCL in order. These might be because DSPE has higher hydrophobicity than PCL while PEG has lower hydrophilicity than PEEP. Different in hydrophilic or hydrophobic structures, all kinds of micelles demonstrated similar pathways during endocytosis and exocytosis, both caveolae- and clathrin-mediated but with difference in degree. The colocalization studies revealed different behaviors in intracellular trafficking among the three polymer micelles, suggesting the decisive role of hydrophilic shells on this process. Finally, all micelle systems did not impact the paracellular permeability of test cell monolayer. In conclusion, the hydrophilic and hydrophobic structures of test micelles could influence their transport ability, intracellular trafficking and the transport level under each pathway in MDCK cells. [Copyright &y& Elsevier]

Abstract: Many alternative therapies are used as first aid treatment for burns, despite limited evidence supporting their use. In this study, Aloe vera, saliva and a tea tree oil impregnated dressing (Burnaid®) were applied as first aid to a porcine deep dermal contact burn, compared to a control of nothing. After burn creation, the treatments were applied for 20min and the wounds observed at weekly dressing changes for 6 weeks. Results showed that the alternative treatments did significantly decrease subdermal temperature within the skin during the treatment period. However, they did not decrease the microflora or improve re-epithelialisation, scar strength, scar depth or cosmetic appearance of the scar and cannot be recommended for the first aid treatment of partial thickness burns. [Copyright &y& Elsevier]

Using our porcine model of deep dermal partial thickness burn injury, various cooling techniques (15 °C running water, 2 °C running water, ice) of first aid were applied for 20 minutes compared with a control (ambient temperature). The subdermal temperatures were monitored during the treatment and wounds observed and photographed weekly for 6 weeks, observing reepithelialization, wound surface area and cosmetic appearance. Tissue histology and scar tensile strength were examined 6 weeks after burn. The 2 °C and ice treatments decreased the subdermal temperature the fastest and lowest, however, generally the 15 and 2 °C treated wounds had better outcomes in terms of reepithelialization, scar histology, and scar appearance. These findings provide evidence to support the current first aid guidelines of cold tap water (approximately 15 °C) for 20 minutes as being beneficial in helping to heal the burn wound. Colder water at 2 °C is also beneficial. Ice should not be used. [ABSTRACT FROM AUTHOR]

Abstract: Two biodegradable cationic lipids, stearylamine and DC-Chol, were chosen to investigate the effect of cationic lipids on the in vitro and in vivo characteristics of hydrophilic proteins or peptides of low isoelectric point. Thrombin inhibitor recombinant hirudin variant-2 (rHV2) was selected as the model drug. The cationic lipids were found to achieve higher entrapment efficiency of rHV2 in liposomes than zwitterionic lipids. The positively charged liposomes became less positive and relatively stable in serum after loading rHV2. The cationic liposomes induced sustained release of rHV2 in the presence of plasma, significantly prolonged the antithrombotic efficacy and plasma level of rHV2 after intravenous injection in rats in comparison with neutral lipid liposomes, especially for stearylamine group. Both clotting times correlated well with plasma rHV2 levels. No serious adverse events were observed and physical state of rats was satisfactory for all the formulations. Electrostatic interaction between negative charge of rHV2 and cationic liposomes was confirmed and it might affect all the characteristics of rHV2 loaded cationic vehicles. The findings suggest that cationic liposomes may be a potential sustained-release delivery system for parenteral administration of hydrophilic proteins or peptides with low isoelectric point to prolong efficacy and improve bioavailability. [Copyright &y& Elsevier]

Summary: Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel localized at apical cell membranes and exists in macromolecular complexes with a variety of signaling and transporter molecules. Here, we report that the multidrug resistance protein 4 (MRP4), a cAMP transporter, functionally and physically associates with CFTR. Adenosine-stimulated CFTR-mediated chloride currents are potentiated by MRP4 inhibition, and this potentiation is directly coupled to attenuated cAMP efflux through the apical cAMP transporter. CFTR single-channel recordings and FRET-based intracellular cAMP dynamics suggest that a compartmentalized coupling of cAMP transporter and CFTR occurs via the PDZ scaffolding protein, PDZK1, forming a macromolecular complex at apical surfaces of gut epithelia. Disrupting this complex abrogates the functional coupling of cAMP transporter activity to CFTR function. Mrp4 knockout mice are more prone to CFTR-mediated secretory diarrhea. Our findings have important implications for disorders such as inflammatory bowel disease and secretory diarrhea. [Copyright &y& Elsevier]

Abstract: Here we investigated thermo-sensitive Pluronic® F127 (PF127) hydrogel for the controlled release of peptide and protein drugs after subcutaneous injection, using an antithrombotic polypeptide, recombinant hirudin variant-2 (rHV2), as the model drug. The in vitro release experiment performed with a membrane-less model at 37 °C showed that the release of antithrombotic activity of rHV2 from PF127 gel followed zero-order kinetics and correlated well with the weight percentage of PF127 dissolved, indicating a dissolution-controlled release mechanism. The in vivo result obtained after subcutaneous injection of rHV2-loaded PF127 gel in normal rats demonstrated that PF127 gel improved the bioavailability, prolonged the antithrombotic effect of rHV2, and induced detectable plasma rHV2 concentration for a longer time in comparison with rHV2 aqueous solution. Differential scanning calorimetry, dynamic light scattering and Fourier transform infrared spectroscopy provided evidence of the interaction between PF127 and rHV2, but such interaction was unlikely to interfere the feasibility of this drug delivery system. Our current in vitro and in vivo study suggested that PF127 gel may be useful as an injectable delivery vehicle for peptides and proteins with short half-lives to prolong their therapeutic effect, increase their bioavailability and improve the clinic outcome. [Copyright &y& Elsevier]