Exosomes derived from platelet-rich plasma administration in site mediate cartilage protection in subtalar osteoarthritis

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Subtalar osteoarthritis (STOA) is often secondary to chronic ankle sprains, which seriously affects the quality of life of patients. Due to its etiology and pathogenesis was not studied equivocally yet, there is currently a lack of effective conservative treatments. Although they have been used for tissue repair, platelet-rich plasma-derived exosomes (PRP-Exo) have the disadvantage of low retention and short-lived therapeutic effects. This study aimed to determine whether incorporation of PRP-Exo in thermosensitive hydrogel (Gel) increased their retention in the joint and thereby playing a therapeutic role on STOA due to chronic mechanical instability established by transecting lateral ligaments (anterior talofibular ligament (ATFL)/calcaneal fibular ligament (CFL)).
PRP-Exo incorporated Gel (Exo-Gel) system, composed of <em>Poloxamer</em>-407 and <em>188</em> mixture-based thermoresponsive hydrogel matrix in an optimal ratio, was determined by its release ability of Exo and rheology of Gel response to a different temperature. The biological activity of Exo-Gel was evaluated in vitro, and the therapeutic effect of Exo-Gel on STOA was evaluated in vivo.
Exo released from Exo-Gel continuously for 28 days could promote the proliferation and migration of mouse bone mesenchymal stem cells (mBMSCs) and chondrocytes, at the same time enhance the chondrogenic differentiation of mBMSCs, and inhibit inflammation-induced chondrocyte degeneration. In vivo experiments confirmed that Exo-Gel increased the local retention of Exo, inhibited the apoptosis and hypertrophy of chondrocytes, enhanced their proliferation, and potentially played the role in stem cell recruitment to delay the development of STOA. Thus, Delivery of PRP-Exo incorporated in thermosensitive Gel provides a novel approach of cell-free therapy and has therapeutic effect on STOA.

Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target

Traumatic brain injury (TBI) is known as an acute degenerative pathology of the central nervous system, and has been shown to increase brain aquaporin 4 (AQP4) expression. Various molecular mechanisms affect AQP4 expression, including neuronal high mobility group box 1, forkhead box O3a, vascular endothelial growth factor, hypoxia-inducible factor-1 α (HIF-1 α) sirtuin 2, NF-κB, Malat1, nerve growth factor and Angiotensin II receptor type 1. In addition, inhibition of AQP4 with FK-506, MK-801 (indirectly by targeting N-methyl-D-aspartate receptor), inactivation of adenosine A2A receptor, levetiracetam, adjudin, progesterone, estrogen, V1aR inhibitor, hypertonic saline, erythropoietin, <em>poloxamer</em> <em>188</em>, brilliant blue G, HIF-1alpha inhibitor, normobaric oxygen therapy, astaxanthin, epigallocatechin-3-gallate, sesamin, thaliporphine, magnesium, prebiotic fiber, resveratrol and omega-3, as well as AQP4 gene silencing lead to reduced edema upon TBI. This review summarizes current knowledge and evidence on the relationship between AQP4 and TBI, and the potential mechanisms involved.

Solvent-Free Fabrication of Biphasic Lipid-Based Microparticles with Tunable Structure

Lipid-based biphasic microparticles are generally produced by long and complex techniques based on double emulsions. In this study, spray congealing was used as a solvent-free fabrication method with improved processability to transform water-in-oil non-aqueous emulsions into spherical solid lipid-based particles with a biphasic structure (b-MPs).
Emulsions were prepared by melt emulsification using different compositions of lipids (Dynasan<sup>®</sup>118 and Compritol<sup>®</sup>888 ATO), surfactants (Cetylstearyl alcohol and Span<sup>®</sup>60) and hydrophilic carriers (PEGs, Gelucire<sup>®</sup>48/16 and <em>Poloxamer</em> <em>188</em>).
First, pseudo-ternary phase diagrams were constructed to identify the area corresponding to each emulsion type (coarse emulsion or microemulsion). The hydrophobicity of the lipid mostly affected the interfacial tension, and thus the microstructure of the emulsion. Emulsions were then processed by spray congealing and the obtained b-MPs were characterized in terms of thermal and chemical properties (by DSC and FT-IR), external and internal morphology (by SEM, CLSM and Raman mapping).
Solid free-flowing spherical particles (main size range 200-355 µm) with different architectures were successfully produced: microemulsions led to the formation of particles with a homogeneous internal structure, while coarse emulsions generated “multicores-shell” particles consisting of variable size hydrophilic cores evenly distributed within the crystalline lipid phase. Depending on their composition and structure, b-MPs could achieve various release profiles, representing a more versatile system than microparticles based on a single lipid phase. The formulation and technological strategy proposed, provides a feasible and cost-effective way of fabricating b-MPs with tunable internal structure and release behavior.

 

Genome DNA Leakage of Adeno-Associated Virus Under Freeze-Thaw Stress

Adeno-associated virus (AAV) has become an emerging tool for human gene therapies. Currently, AAV gene therapies are subjected to multiple freeze-thaw cycles during manufacturing, storage, transportation, and administration. While studies have shown that multiple freeze-thaw cycles led to a decrease in transduction efficiency, the AAV degradation mechanism during freeze-thaw is not well understood.
Here, we have characterized the impact of freeze-thaw on AAV8 by employing a variety of assays, which revealed significant increases in the amount of free single-stranded DNA (ssDNA) in AAV8 formulations after multiple freeze-thaw cycles. Subsequent analysis using Next Generation Sequencing (NGS) revealed that the ssDNA primarily consisted of genome DNA, indicating that the increased ssDNA leaked out from AAV8.
Experiments performed using different serotypes of AAV confirmed the pervasiveness of such behavior amongst AAVs. In addition, formulation screening studies were performed to understand the impact on genome DNA leakage from AAV. The formulation screening results showed that the addition of 10% sucrose and 0.1% <em>poloxamer</em> <em>188</em> to Dulbecco’s phosphate-buffered saline (DPBS) reduced the leakage of ssDNA in AAV samples after freeze-thaw cycles compared to the base formulation of DPBS alone. These findings shed new light on the degradation mechanism of AAVs and stabilization of the AAV-based gene therapies.

Sustained Delivery of Lactoferrin Using Poloxamer Gels for Local Bone Regeneration in a Rat Calvarial Defect Model

Lactoferrin (LF) is a multifunctional milk glycoprotein that promotes bone regeneration. Local delivery of LF at the bone defect site is a promising approach for enhancement of bone regeneration, but efficient systems for sustained local delivery are still largely missing. The aim of this study was to investigate the potential of the poloxamers for sustained delivery of LF to enhance local bone regeneration. The developed LF/poloxamer formulations were liquid at room temperature (20 °C) transforming to a sustained releasing gel depot at body temperature (37 °C). In vitro release studies demonstrated an initial burst release (~50%), followed by slower release of LF for up to 72 h.
[Linking template=”rowtwo” search=” Poloxamer 188″ site=”genprice.com” header=”h3″ classTable=” Poloxamer 188 2″ limit=”19″ start=”0″ linkProductCatalogNumber=”true” showSupplier=”true” showName=”true” showCatalogNumber=”true” showSize=”true” showPrice=”true” ]
 Poloxamer, with and without LF, increased osteoblast viability at 72 h (p < 0.05) compared to control, and the immune response from THP-1 cells was mild when compared to the suture material. In rat calvarial defects, the LF/poloxamer group had lower bone volume than the controls (p = 0.0435). No difference was observed in tissue mineral density and lower bone defect coverage scores (p = 0.0267) at 12 weeks after surgery. In conclusion, LF/poloxamer formulations support cell viability and do not induce an unfavourable immune response; however, LF delivery via the current formulation of LF200/poloxamer gel did not demonstrate enhanced bone regeneration and was not compatible with the rat calvarial defect model.

Postural Balance Ability and the Effect of Visual Restriction on Older Dancers and Non-Dancers

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Dance has been suggested to be an advantageous exercise modality for improving postural balance performance and reducing the risk of falls in the older population. The main purpose of this study was to investigate whether visual restriction impacts older dancers and non-dancers differently during a quiet stance balance performance test.
We hypothesized higher balance performance and greater balance deterioration due to visual restriction in dancers compared with non-dancers, indicating the superior contribution of the visual channel in the expected higher balance performances of dancers. Sixty-nine (38 men, 31 women, 74 ± 6 years) healthy older adults participated and were grouped into a Greek traditional dance group (n = 31, two to three times/week for 1.5 h/session, minimum of 3 years) and a non-dancer control group (n = 38, no systematic exercise history).
The participants completed an assessment of one-legged quiet stance trials using both left and right legs and with eyes open while standing barefoot on a force plate (Wii, A/D converter, 1,000 Hz; Biovision) and two-legged trials with both eyes open and closed. The possible differences in the anthropometric and one-legged balance parameters were examined by a univariate ANOVA with group and sex as fixed factors.
This ANOVA was performed using the same fixed factors and vision as the repeated measures factor for the two-legged balance parameters. In the one-legged task, the dance group showed significantly lower values in anteroposterior and mediolateral sway amplitudes (p = 0.001 and p = 0.035) and path length measured in both directions (p = 0.001) compared with the non-dancers. In the two-legged stance, we found a significant vision effect on path length (p < 0.001) and anteroposterior amplitude (p < 0.001), whereas mediolateral amplitude did not differ significantly (p = 0.439) between closed and open eyes. The dance group had a significantly lower CoP path length (p = 0.006) and anteroposterior (p = 0.001) and mediolateral sway amplitudes (p = 0.003) both in the eyes-open and eyes-closed trials compared with the control group.
The superior balance performance in the two postural tasks found in the dancers is possibly the result of the coordinated, aesthetically oriented intersegmental movements, including alternations between one- and two-legged stance phases, that comes with dance. Visual restriction resulted in a similar deterioration of balance performance in both groups, thus suggesting that the contribution of the visual channel alone cannot explain the superior balance performance of dancers.

Refractive corneal inlay implantation outcomes: a preliminary systematic review

Purpose: To review all case series of refractive corneal inlay implantation: Flexivue (Presbia, Netherlands), Invue (BioVision, Brügg, Switzerland) and Icolens (Neoptics, Hünenberg, Switzerland) performed in presbyopia patients and to evaluate the reported visual outcomes. In addition, our aim is to provide assessment for complications and to report the satisfaction rates.
Methods: PubMed, Web of Science and Scopus databases were consulted using “refractive corneal inlay”, “Flexivue Inlay”, “Invue Inlay” and “Icolens inlay” as keywords. 147 articles were found, and they were assessed considering the inclusion and exclusion criteria. After filtering, this systemic review included ten articles, published between 2011 and 2020.
Results: 308 eyes from 308 participants were enrolled in this systematic review. Mean maximum follow-up was 13.9 months. Nine of the ten case series included used femtosecond laser for the corneal pocket creation. Mean pocket depth was 293.75 µm. 77.5% of the eyes reported a postoperative uncorrected near visual acuity of 20/32 or better, and 19.20% of the inlay-implanted eyes achieved an uncorrected distance visual acuity of 20/20 or better. The most prominent complications were halos, pain, photophobia, and poor distance visual acuity. 27 eyes (8.7%) had to be explanted due to complications, such as near-distance spectacle dependence or blurred distance vision.
Conclusion: Refractive corneal inlay outcomes demonstrated high efficacy, safety, and satisfaction rates. Furthermore, it is a reversible technique. However, the findings must be viewed with caution due potential conflict of interest. Further research with higher sample size is needed to validate these findings.
Keywords: Flexivue inlay; Icolens inlay; Invue inlay; Refractive inlay.

Quantifying Visual Image Quality: A Bayesian View

Image quality assessment (IQA) models aim to establish a quantitative relationship between visual images and their quality as perceived by human observers. IQA modeling plays a special bridging role between vision science and engineering practice, both as a test-bed for vision theories and computational biovision models and as a powerful tool that could potentially have a profound impact on a broad range of image processing, computer vision, and computer graphics applications for design, optimization, and evaluation purposes.
The growth of IQA research has accelerated over the past two decades. In this review, we present an overview of IQA methods from a Bayesian perspective, with the goals of unifying a wide spectrum of IQA approaches under a common framework and providing useful references to fundamental concepts accessible to vision scientists and image processing practitioners.
We discuss the implications of the successes and limitations of modern IQA methods for biological vision and the prospect for vision science to inform the design of future artificial vision systems. (The detailed model taxonomy can be found at http://ivc.uwaterloo.ca/research/bayesianIQA/.) Expected final online publication date for the Annual Review of Vision Science, Volume 7 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Nitric oxide in infertile females in the niger-delta region of Nigeria

Background: Infertility is a public health challenge and it is a distressing personal tragedy for couples, more so for the female partners. Risk factors and causes of infertility vary from region to region. Reactive species is of current interest in the pathogenesis and management of infertility, especially in the Niger-Delta Region of Nigeria where environmental hazards of oil exploration exists.
Aim: The overall goal of this study was to determine and compare the serum reactive species levels (nitric oxide) in fertile and infertile women attending the infertility clinic at the Delta State University Teaching Hospital, Oghara, and Central Hospital, Warri.
Methods: This was a prospective case-control study in which 70 women evaluated for infertility were recruited into the study. A fertile patient matched for age and body mass index (BMI) attending family planning clinic was selected as control. Serum nitric oxide estimation was done using the BioVision Nitric Oxide Colorimetric Assay Kit. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS). Student’s t-test was applied to compare the serum levels of nitric acid and the differences were considered significant if P < 0.05.
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Results: Infertile women had significantly higher mean serum nitric oxide levels than fertile women: 34.33 (SD 5.93) μmol/L versus 18.27 (SD 2.63) μmol/L (P < 0.001). Women with secondary infertility had significantly higher mean levels of nitric oxide than those with primary infertility: 38.13 (SD 3.39) μmol/L versus 22.72 (SD 4.36) μmol/L (P < 0.001).
Conclusion: The study showed that serum nitric oxide level was significantly elevated in women with infertility compared to women of proven fertility. Hence, oxidative stress from reactive species may be a contributory factor to infertility in women in the Niger-Delta Region of Nigeria.

Drugs(1) Identification of the PA1113 Gene Product as an ABC Transporter Involved in the Uptake of Carbenicillin in Pseudomonas aeruginosa PAO1

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The resistance of Pseudomonas aeruginosa to antibiotics is multi factorial and complex. Whereas efflux pumps such as MexAB-OprM have been thought to predominate, here we show that a novel ATP Binding Cassette (ABC) transporter that mediates influx of carbenicillin from the periplasm to the cytoplasm and away from its cell wall target plays an important role in the resistance of P. aeruginosa to this antibiotic.
Treatment of P. aeruginosa with verapamil, an inhibitor of ABC transporters in eukaryotic cells, increases its sensitivity to carbenicillin.
Using amino acid sequence homology with known verapamil protein targets as a probe, we determined that the PA1113 gene product, an ABC transporter, mediates carbenicillin uptake into the bacterial cytoplasm.
Docking and pharmacological analyses showed that verapamil and carbenicillin compete for the same site on the PA1113 gene protein, explaining the inhibitory effect of verapamil on carbenicillin uptake, and furthermore suggest that the PA1113 ABC transporter accounts for about 30% of P. aeruginosa carbenicillin resistance.
Our findings demonstrate that the PA1113 gene product helps mediate carbenicillin resistance by transporting it away from its cell wall target and represents a promising new therapeutic target.

MexXY RND pump of Pseudomonas aeruginosa PA7 effluxes bi-anionic β-lactams carbenicillin and sulbenicillin when it partners with the outer membrane factor OprA but not with OprM

Antibiotic resistance in Pseudomonas aeruginosa is a serious concern in healthcare systems. Among the determinants of antibiotic resistance in P. aeruginosa, efflux pumps belonging to the resistance-nodulation-division (RND) family confer resistance to a broad range of antibacterial compounds.
The MexXY efflux system is widely overexpressed in P. aeruginosa isolates from cystic fibrosis (CF) patients. MexXY can form functional complexes with two different outer membrane factors (OMFs), OprA and OprM. In this study, using state-of-the-art genetic tools, the substrate specificities of MexXY-OprA and MexXY-OprM complexes were determined.
Our results show, for the first time, that the substrate profile of the MexXY system from P. aeruginosa PA7 can vary depending on which OM factor (OprM or OprA) it complexes with. While both MexXY-OprA and MexXY-OprM complexes are capable of effluxing aminoglycosides, the bi-anionic β-lactam molecules carbenicillin and sulbenicillin were found to only be the substrate of MexXY-OprA. Our study therefore shows that by partnering with different OMF proteins MexY can expand its substrate profile.

Octenidine/carbenicillin GUMBOS as potential treatment for oropharyngeal gonorrhoea

Background: Reducing Neisseria gonorrhoeae colonies in the oropharynx is a viable solution to minimize the transmission of this bacterium amongst individuals.
Objectives: A strategy involving the electrostatic interaction between a common antiseptic and a discontinued antibiotic (i.e. octenidine and carbenicillin) was evaluated as a potential treatment for gonorrhoea. Octenidine/carbenicillin is a novel group of uniform materials based on organic salts (GUMBOS) with inherent in vitro antibacterial activity that comes from its parent antiseptic and antibacterial ions, octenidine and carbenicillin, respectively.
Methods: Antibacterial activities for octenidine dihydrochloride, disodium carbenicillin, octenidine/carbenicillin and stoichiometrically equivalent 1:1 octenidine dihydrochloride to disodium carbenicillin were assessed using the Kirby-Bauer disc diffusion assay for N. gonorrhoeae (ATCC 49226) and three clinical isolates. Predictive permeability using the Parallel Artificial Membrane Permeability Assay and cytotoxicity against HeLa cells was also evaluated.
Results: Additive in vitro antibacterial activities against N. gonorrhoeae were observed in this study, which suggests octenidine/carbenicillin could be a useful agent in reducing N. gonorrhoeae transmission and minimizing gonorrhoea infections.
Octenidine/carbenicillin also exhibited bioequivalence to azithromycin and doxycycline, two currently prescribed antibiotics. Likewise, octenidine/carbenicillin had improved predicted permeability compared with octenidine dihydrochloride.
Conclusions: Antimicrobial GUMBOS synthesized in this study could be used as an adjunctive treatment approach to current drug therapies for oropharyngeal gonorrhoea infection control and prevention.

SERS investigation and high sensitive detection of carbenicillin disodium drug on the Ag substrate.

The reliable and ultrasensitive detection of antibiotic drug residue is of great interest for environmental protection and human health. Herein, we propose a simple SERS strategy based on Ag nanoparticles (NPs) as substrate with the assistance of aggregation agent (MgSO4) for the SERS investigation and the high sensitive detection of antibiotic drug carbenicillin disodium (CBDM).
The density functional theory calculation was performed for the assignment and identification of Raman bands of the CBDM molecule. The results indicate that the CBDM molecule is close to the Ag NP substrate surface through the carboxyl group. The CBDM molecules on Ag NP substrate exhibit the largest SERS enhancement, when the concentration of MgSO4 is 1 × 10-2 mol/L and the pH value of CBDM solution is 6.
By this SERS method, the limit of detection of CBDM is 0.63 × 10-8 mol/L, which is lower than the standard of European Union for the maximum residue limit of antibiotic drug (1.2 × 10-8 mol/L). And, a quantitative detection method of CBDM can be established. There is a good linear relationship (R2 = 0.9908) in the concentration range of 1.0 × 10-8-1.0 × 10-3 mol/L.
It proves that the proposed SERS method is a simple, rapid (within 6 min), reliable and highly sensitive scheme with a good reproducibility for the detection of CBDM. And, the proposed SERS strategy can also be applied for the high sensitive detection and identification of other antibiotic drug (penicillin).

Mechanisms of RsaL mediated tolerance to ciprofloxacin and carbenicillin in Pseudomonas aeruginosa.

The Pseudomonas aeruginosa RsaL is a negative regulator of the quorum sensing signal synthesis gene lasI. The expression of RsaL is directly activated by the LasI cognate regulator LasR. Thus, RsaL and LasI-LasR (LasI/R) form a regulatory loop.
Further studies revealed that RsaL is a global regulator which controls the expression of numerous genes through quorum sensing system dependent and independent pathways. However, whether RsaL is involved in antibiotic tolerance remains elusive. In this study, we found that the mutation of rsaL increased bacterial tolerance to ciprofloxacin and carbenicillin.
Through motif search, gene expression analyses and electrophoretic mobility shift assays, we found that RsaL directly represses the expression of the narK1K2GHJI operon, which is involved in the tolerance to ciprofloxacin. We further demonstrated that the narK1K2GHJI operon is directly regulated by LasR. In combination, our study revealed a novel operon under the control of the RsaL, LasI/R regulatory loop.

Metal-carbenicillin framework-based nanoantibiotics with enhanced penetration and highly efficient inhibition of MRSA.

The development of effective therapies to control methicillin-resistant Staphylococcus aureus (MRSA) infections is challenging because antibiotics can be degraded by the production of certain enzymes, for example, β-lactamases. Additionally, the antibiotics themselves fail to penetrate the full depth of biofilms formed from extracellular polymers.
Nanoparticle-based carriers can deliver antibiotics with better biofilm penetration, thus combating bacterial resistance. In this study, we describe a general approach for the construction of β-lactam antibiotics and β-lactamase inhibitors co-delivery of nanoantibiotics based on metal-carbenicillin framework-coated mesoporous silica nanoparticles (MSN) to overcome MRSA.
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Carbenicillin, a β-lactam antibiotic, was used as an organic ligand that coordinates with Fe3+ to form a metal-carbenicillin framework to block the pores of the MSN.
Furthermore, these β-lactamase inhibitor-loaded nanoantibiotics were stable under physiological conditions and could synchronously release antibiotic molecules and inhibitors at the bacterial infection site to achieve a better elimination of antibiotic resistant bacterial strains and biofilms.
We confirmed that these β-lactamase inhibitor-loaded nanoantibiotics had better penetration depth into biofilms and an obvious effect on the inhibition of MRSA both in vitro and in vivo.

Biofunctional Hyaluronic Acid/κ-Carrageenan Injectable Hydrogels for Improved Drug Delivery and Wound Healing

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The in situ injectable hydrogel system offers a widespread range of biomedical applications in prompt chronic wound treatment and management, as it provides self-healing, maintains a moist wound microenvironment, and offers good antibacterial properties.
This study aimed to develop and evaluate biopolymer-based thermoreversible injectable hydrogels for effective wound-healing applications and the controlled drug delivery of meropenem. The injectable hydrogel was developed using the solvent casting method and evaluated for structural changes using proton nuclear magnetic resonance, Fourier transforms infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy.
The results indicated the self-assembly of hyaluronic acid and kappa-carrageenan and the thermal stability of the fabricated injectable hydrogel with tunable gelation properties.
The viscosity assessment indicated the in-situ gelling ability and injectability of the hydrogels at various temperatures. The fabricated hydrogel was loaded with meropenem, and the drug release from the hydrogel in phosphate buffer saline (PBS) with a pH of 7.4 was 96.12%, and the simulated wound fluid with a pH of 6.8 was observed to be at 94.73% at 24 h, which corresponds to the sustained delivery of meropenem. Antibacterial studies on P. aeruginosa, S. aureus, and E. coli with meropenem-laden hydrogel showed higher zones of inhibition.
The in vivo studies in Sprague Dawley (SD) rats presented accelerated healing with the drug-loaded injectable hydrogel, while 90% wound closure with the unloaded injectable hydrogel, 70% in the positive control group (SC drug), and 60% in the negative control group was observed (normal saline) after fourteen days. In vivo wound closure analysis confirmed that the developed polymeric hydrogel has synergistic wound-healing potential.

Effect of κ-carrageenan on the gelation properties of oyster protein

Proteins and polysaccharides commonly coexist in the food system, forming complexes and coacervates to make tailor-made food. In this study, the effects of κ-carrageenan on the rheological behavior, network structure, textures, and molecular force of oyster protein (OP treated with high-pressure homogenization were investigated.
Rheological results showed that κ-carrageenan improved the storage modulus of OP, and the higher concentration of κ-carrageenan accelerated the gelation of OP.
The second derivative of infrared spectroscopy revealed that κ-carrageenan contributed to the formation of β-sheet in OP. Molecular force and texture analysis showed that κ-carrageenan might promote the increase of hydrophobic bonds and disulfide bonds, which was helpful to enhance gel strength.
The microstructure showed that the OP gel with 1.5% κ-carrageenan had a compact network structure with abundant minor mesh and sheet edge. This study reveals the gelation mechanism of OP/κ-carrageenan and provides the theoretical basis for developing innovative oyster products.

Efficacy of a carrageenan gel in increasing clearance of anal HPV infections in men: interim analysis of a double-blind randomized controlled trial

Pre-clinical studies demonstrated carrageenan’s anti-human papillomavirus (HPV) activity. We assessed efficacy of a carrageenan-based gel compared to a placebo gel in increasing the clearance of anal HPV infections among gay, bisexual, and other men who have sex with men (gbMSM).
Of 255 enrolled gbMSM, 134 were HPV-positive at baseline and had valid HPV results for ≥2 visits. Carrageenan did not differ from placebo in clearing all baseline infections (HR=0.84, 95% CI: 0.31-2.27), based on having two consecutive HPV-negative visits following at least one HPV-positive. There were no remarkable differences for analyses at the HPV-type level or by HIV status.

Combination of Colchicine and Ticagrelor Inhibits Carrageenan-Induced Thrombi in Mice

The formation of a thrombus is closely related to oxidative stress and inflammation. Colchicine is one of the most commonly prescribed medication for gout treatment, with anti-inflammation and antioxidative stress properties. Therefore, we speculated that it is possible for colchicine to treat thrombosis.
In this study, we used carrageenan to induce thrombosis in BALB/c mice and fed mice with colchicine, ticagrelor, and their combination, respectively. We found colchicine inhibited carrageenan-induced thrombi in mouse tail, and the inhibition was enhanced by ticagrelor. 
In vitro, colchicine inhibited thrombin-induced retraction of human platelet clots. Mechanically, colchicine inhibited platelet activation by reducing the expression of platelet receptors, protease-activated receptor 4 (PAR4) and CD36, and inactivating of AKT and ERK1/2 pathways.
Furthermore, in human umbilical vein endothelial cells (HUVECs), colchicine showed antioxidative stress effects through increasing protein expression of glutathione peroxidase-1 (GPx-1), and mRNA levels of forkhead box O3 (FOXO3a) and superoxide dismutase 2 (SOD2). In RAW264.7 cells, colchicine reduced LPS-enhanced inflammatory response through attenuating toll-like receptor 4 (TLR4) activation.
In addition, colchicine reduced LPS or ox-LDL-induced monocyte adhesion to HUVECs by inhibiting intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) levels. Taken together, our study demonstrates that colchicine exerts antithrombotic function by attenuating platelet activation and inhibiting oxidative stress and inflammation. We also provide a potential new strategy for clinical treatment.

Thermal and acidic denaturation of phycocyanin from Arthrospira platensis: Effects of complexation with λ-carrageenan on blue color stability

The pH and temperature sensitivity of the natural blue pigment phycocyanin from Arthrospira platensis limits its application as food colorant. This study examines the effect of protein stabilization by the anionic polysaccharide λ-carrageenan on phycocyanins color appearance at pH 2.5-6.0, unheated and after heat treatments (70/90 °C). Electrostatic interactions, hydrophobic interactions, hydrogen bonds and disulfide-bridges were assessed by adding NaCl, urea and dithiothreitol (DTT) to the samples.
Measurements of the zeta potential, transmittance and two-dimensional gel electrophoresis coupled to mass spectrometry confirmed electrostatic interactions around the zero surface charge of phycocyanin over a broad pH range (∼4.1-6.4). Despite a color shift towards turquoise, the color remained stable during heating, especially below of pH 3.5.
Precipitation was inhibited over the entire pH range. Overall, electrostatic complexation of phycocyanin and λ-carrageenan is a promising technique to stabilize proteinaceous colorants, helping to reduce food waste and foster a shift to renewable materials.

Spray-drying microencapsulation of tea extracts using green starch, alginate or carrageenan as carrier materials

Tea industry generates many by-products which could be used to produce and incorporate bioactive tea extracts (TE) into nutraceuticals, cosmetics and/or clinical applications. However, sensibility to external factors is a major disadvantage hindering its utilization.
This study deals with the implementation and characterization of suitable biopolymer delivery systems based on starch, carrageenan or alginate, as microencapsulation, to stabilize and protect TE through innovative thin-carbohydrate-coated formulations.
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TE were spray-dried and microencapsulated in recycled carrier materials (alginate, carrageenan or starch). Product yields varied from 55 to 58%. High microencapsulation and loading efficiencies were achieved (60-93% and 65-84%, respectively). Antioxidant capacity varied from 32 to 46 g Trolox/100 g extract, within different carrier-systems; which also showed promising rheological and UV-protective properties when transformed into gels. Total phenolic content, particle-size distribution, HPSEC-analysis, SEM-analysis and FTIR-analysis were also performed.
In sum, this paper characterizes and discusses the high potential of these recycled carbohydrate-coated microparticles for future applications.

Induction of differentiation by pyruvate and DMEM in the human retinal pigment epithelium cell line ARPE-19.

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Cultured retinal pigment epithelium (RPE) may become a therapeutic option for transplantation in retinal disease. However maintaining a native RPE phenotype in vitro has proven challenging. The human RPE cell-line ARPE-19 is used widely as an alternative to primary RPE. It is grown in DMEM/F12 medium as standard, but its phenotype is dependent on culture conditions, and many differentiation markers are usually absent.
The purpose of this study was to examine how this sensitive phenotype of ARPE-19 can be modulated by growth media with or without the metabolite pyruvate to elucidate better RPE growth conditions.
METHODS
ARPE-19 cells at passages p22 to p28 were cultured on filters for up to 3 months in DMEM/F12 or DMEM media with or without pyruvate and 1% fetal calf serum. Assessment of differentiation was performed using pigmentation, immunocytochemistry, protein/mRNA expression, transepithelial resistance, VEGF secretion, and ultrastructure.
RESULTS
Pyruvate, in combination with DMEM, induced dark pigmentation and promoted differentiation markers such as CRALBP and MerTK. Importantly, RPE65 protein was detected by Western blotting and was enhanced by pyruvate, high glucose, and DMEM. ARPE-19 cells maintained in this medium could also phagocytose human photoreceptor outer segments (POS). VEGF secretion was greater in DMEM cultures and was affected by glucose but not by pyruvate. Pigmentation never occurred in DMEM/F12.
CONCLUSIONS
This study demonstrated important differentiation markers, including pigmentation and Western blots of RPE65 protein, and showed human POS phagocytosis in ARPE-19 cultures using a simple differentiation protocol. The results favor the use of high-glucose DMEM with pyruvate for future RPE differentiation studies.

Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington’s disease: morphological and behavioral outcomes.

Transplantation of mesenchymal stem cells (MSCs) may offer a viable treatment for Huntington’s disease (HD). We tested the efficacy of MSC transplants to reduce deficits in a 3-nitropropionic acid (3NP) rat model of HD. Five groups of rats (Sham, 3NP, 3NP+vehicle, 3NP+TP(low), 3NP+TP(high)), were given PBS or 3NP intraperitoneally, twice daily for 42 days.
On day 28, rats in all groups except Sham and 3NP, received intrastriatal injections of either 200,000 MSCs (TP(low)), 400,000 (TP(high)) MSCs or DMEM (VH, the vehicle for transplantation).
MSCs survived 72 days without inducing a strong inflammatory response from the striatum. Behavioral sparing was observed on tests of supported-hindlimb-retraction, unsupported-hindlimb-retraction, visual paw placement and stepping ability for 3NP+TP(low) rats and on the unsupported-hindlimb-retraction and rotarod tasks for 3NP+VH rats.
Relative to 3NP controls, all treated groups were protected from 3NP-induced enlargement of the lateral ventricles. In vitro, MSCs expressed transcripts for numerous neurotrophic factors. In vivo, increased striatal labeling in BDNF, collagen type-I and fibronectin (but not GDNF or CNTF) was observed in the brains of MSC-transplanted rats but not in DMEM-treated rats.
In addition, none of the transplanted MSCs expressed neural phenotypes. These findings suggest that factors other than neuronal replacement underlie the behavioral sparing observed in 3NP rats after MSC transplantation.

Proliferation and gene expression of osteoblasts cultured in DMEM containing the ionic products of dicalcium silicate coating.

The medium containing ionic products of dicalcium silicate (Ca(2)SiO(4)) for culturing the osteoblast-like cells (MG63) were prepared by immersing the plasma sprayed Ca(2)SiO(4) coatings in DMEM solution for 24h. The normal DMEM was also used to culture the MG63 cells as the control group.
The results obtained from this work showed that the proliferation of MG63 cell was more significant in the group containing ionic products of Ca(2)SiO(4) coatings than in the control group. The cell cycle distribution indicated that the decreased G(0)/G(1) phase and increased S phase occurred in the cells cultured in the DMEM containing ionic products of Ca(2)SiO(4) coatings.
The analysis of osteogenic genes indicated that the ionic products of Ca(2)SiO(4) coating enhanced the expression of osteoblast-related genes and promote differentiation of MG63 cells at initial period. Moreover, the ionic products of Ca(2)SiO(4) coating differentially regulated osteoclastogenic gene expression by up-regulated OPG and down-regulated RANKL.

Choice of DMEM, formulated with or without pyruvate, plays an important role in assessing the in vitro cytotoxicity of oxidants and prooxidant nutraceuticals.

There is much interest in the positive health effects of nutraceuticals, in particular, polyphenols, which have both antioxidant and prooxidant characteristics. Pyruvate, a scavenger of hydrogen peroxide, is a component in some, but not in all, commercial formulations of cell culture media, Dulbecco’s modified Eagle’s medium in particular.
This study showed that the cytotoxicities to human fibroblasts of hydrogen peroxide, tert-butyl hydroperoxide, and various prooxidant nutraceuticals were lessened in Dulbecco’s modified Eagle’s medium formulated with pyruvate, as compared to the same medium but formulated without pyruvate.
Intracellular glutathione was unaffected in cells treated with hydrogen peroxide in Dulbecco’s modified Eagle’s medium formulated with pyruvate, as compared to medium formulated without pyruvate.
In these studies, intracellular glutathione was analyzed in acid-soluble cell extracts by determining the oxidation of reduced glutathione by 5,5′-dithiobis(2-nitrobenzoic acid) to glutathione disulfide, with the formation of the yellow chromagen, 5-thio-2-nitrobenzoic acid, measured spectrophotometrically at 412 nm and by the visualization of reduced glutathione in cells stained with the fluorescent dye, Cell Tracker Green 5-chloromethylfluorescein diacetate.
A survey of various cell culture media, formulated with and without pyruvate, confirmed that the level of added hydrogen peroxide was greatly lessened in those media formulated with pyruvate. This study suggested that the pyruvate status of Dulbecco’s modified Eagle’s medium be specified in the experimental design, especially in studies involving oxidative stress.

The effect of chitosan hydrogel containing DMEM/F12 medium on full-thickness skin defects after deep dermal burn.

Burn wound excision is considered necessary to prepare skin for grafting, and the success of graft “take” is thought to be dependent on the vascular supply to the wound. We previously showed that photocrosslinkable chitosan hydrogel containing DMEM/F12 medium (medium-Az-CH-LA) is a biocompatible and biodegradable biomaterial that promotes re-epithelialization and neovascularization.
The current study was designed to determine the effect of medium-Az-CH-LA on deep dermal burn. Sixteen male Wistar rats were randomly divided into two groups that were treated with medium-Az-CH-LA (n=5) or a collagen sponge (n=5). Under anesthesia, the dorsal fur was shaved and the skin was exposed to water at 95 degrees C for 10s. After 2h, damaged tissue was removed from the fascia and dressed with medium-Az-CH-LA or a collagen sponge. Specimens were obtained after 2, 4, 6, 8, 12, 16 and 32 days for histological analysis.
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There was no significant difference in the time required for wound closure between the two groups, but the thickness of the granulation tissue in the medium-Az-CH-LA-treated group was greater than that in the collagen sponge-treated group. Moreover, degradation and neovascularization occurred earlier in the group treated with medium-Az-CH-LA compared with the collagen sponge-treated group.
These findings suggest that early degradative and angiogenic activities of medium-Az-CH-LA may be beneficial for granulation tissue formation in deep dermal burn wounds.

Ferric Ammonium Citrate Upregulates PD-L1 Expression through Generation of Reactive Oxygen Species

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Iron plays an important role in macrophage polarization by altering metabolic and redox status. However, the impact of iron on the immune status of macrophages is still controversial. In this study, we report that ferric ammonium citrate (FAC) upregulates PD-L1 expression in macrophages.
FAC not only altered the phenotype of macrophages but also led to enriching immune-modulatory T cell subsets. Since iron is known to be a constituent of coenzymes facilitating metabolic processes in mitochondria, we examined the metabolic status of FAC-overloaded macrophages by measuring the oxygen consumption rate (OCR) and the represented coenzyme, aconitase.
In addition to enhancement of metabolic processes, FAC accelerated the Fenton reaction in macrophages, which also contributed to the facilitation of oxygen consumption. We reasoned that the enhancement of the OCR leads to the production of reactive oxygen species (ROS), which are directly linked to PD-L1 induction.
Using ferrostatin, rotenone, and N-acetyl-L-cysteine, we confirmed that metabolic and redox regulation is responsible for FAC-mediated PD-L1 expression.
Furthermore, we suggested that FAC-induced ROS production may explain FAC-mediated pro- and anti-inflammatory responses in macrophages. These findings may extend our understanding of regulating iron concentration during immune checkpoint therapy in cancer patients.

Ferric ammoniumcitrate (FAC)-induced inhibition of osteoblast proliferation/differentiation and its reversal by soybean-derived peptides (SDP)

Ferric citrate has been used to treat hyperphosphatemia, a prevalent symptom in patients with chronic kidney disease while ferric ammonium citrate (FAC), a more dissolvable format, is widely used as food additive. However, excess iron is associated with osteoporosis.
Dietary soybean products have been shown to prevent the progression of osteoporosis. In this study, a group of peptides, referred as P3, was identified from the enzymolysis of soybean protein isolates, and its biological functions were investigated. The results showed that MC3T3-E1 cell cycle progression from G0/G1 to S phase was accelerated by P3 treatment. MC3T3-E1 cell proliferation was enhanced by P3 via ERK1/2 activation.
Importantly, P3 treatment abolished the antiproliferative effect of FAC on MC3T3-E1 cell. In addition, P3 treatment increased the expression of ALP, COL-1, OCN, consequently promoting the differentiation and mineralization of MC3T3-E1 cells via activation of p38 MAPK pathway.
Consequently, P3 treatment was able to reverse the inhibitory effect of FAC on osteoblasts differentiation and mineralization. Our findings suggest P3, as a dietary supplement, has a potential therapeutic function to attenuate the adverse effects of FAC on bone metabolism and to prevent osteoporosis progression.

Ammonium Ferric Citrate induced Ferroptosis in Non-Small-Cell Lung Carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity

The morbidity and mortality rates associated with non-small-cell lung carcinoma (NSCLC) are increasing every year, placing new demands on existing therapies and drugs. Ammonium ferric citrate (AFC) is often used as a food additive for iron supplementation; however, to our knowledge, no studies have investigated whether AFC can induce ferroptosis in NSCLC.
In this study, we demonstrated that specific concentrations of AFC effectively inhibit the proliferation and invasion of lung cancer cell lines in vitro using a cell proliferation inhibition test, a transwell assay, and flow cytometry analysis of cell cycle and apoptosis. In addition, AFC significantly induced oxidative stress injury in lung cancer cell lines.
A quantitative polymerase chain reaction assay showed that AFC markedly reduced the expression levels of cell growth factors, negative regulators of ferroptosis, and autophagy regulators. Lastly, a protein-protein interaction analysis revealed that glutathione peroxidase 4 (GPX4) exerted its biological role through the regulation of the GSS/GSR complex and downstream GGT family proteins.
When the expression of GPX4 changes, its biological activities, such as the glutathione metabolic process, cellular biosynthetic process, cellular response to chemical stimulus, and antioxidant activity, change accordingly, thereby affecting the survival quality and physiological and biochemical activities of cells.
Overall, this study verifies that AFC has the biological activity of activating oxidative stress injury in NSCLC cell lines, leading to a decrease in their autophagy and inducing ferroptosis. We also confirmed that the GPX4-GSS/GSR-GGT axis is a crucial target of AFC-induced ferroptosis.

Increasing Intracellular Levels of Iron with Ferric Ammonium Citrate Leads to Reduced P-glycoprotein Expression in Human Immortalised Brain Microvascular Endothelial Cells

Purpose: P-glycoprotein (P-gp) at the blood-brain barrier (BBB) precludes the brain penetration of many xenobiotics and mediates brain-to-blood clearance of β-amyloid, which accumulates in the Alzheimer’s disease (AD) brain. Zinc and copper are reported to modulate BBB expression and function of P-gp; however, the impact of exogenous iron, which accumulates in AD, on P-gp dynamics remains unknown.
Methods: P-gp protein and MDR1 transcript levels were assessed in immortalised human cerebral microvascular endothelial (hCMEC/D3) cells treated with ferric ammonium citrate (FAC; 250 μM, 72 h), by Western blotting and RT-qPCR, respectively. P-gp function was assessed using rhodamine-123 and [3H]-digoxin accumulation. Intracellular reactive oxygen species (ROS) levels were determined using 2′,7′-dichlorofluorescin diacetate and intracellular iron levels quantified using a ferrozine assay.
Results: FAC treatment significantly reduced P-gp protein (36%) and MDR1 mRNA (16%) levels, with no significant change in rhodamine-123 or [3H]-digoxin accumulation. While P-gp/MDR1 downregulation was associated with elevated ROS and intracellular iron, MDR1 downregulation was not attenuated with the antioxidant N-acetylcysteine nor the iron chelators desferrioxamine and deferiprone, suggesting the involvement of a ROS-independent mechanism or incomplete iron chelation.
Conclusions: These studies demonstrate that iron negatively regulates P-gp expression at the BBB, potentially impacting CNS drug delivery and brain β-amyloid clearance.
Keywords: P-glycoprotein; blood-brain barrier; efflux transporter; iron; reactive oxygen species.

Structures of disodium hydrogen citrate mono-hydrate, Na 2 HC 6 H 5 O 7(H 2 O), and di-ammonium sodium citrate, (NH 4) 2 NaC 6 H 5 O 7, from powder diffraction data

The crystal structures of disodium hydrogen citrate monohydrate, Na2HC6H5O7(H2O), and di-ammonium sodium citrate, (NH4)2NaC6H5O7, have been solved and refined using laboratory X-ray powder diffraction data, and optimized using density functional techniques. In NaHC6H5O7(H2O), the NaO6 coordination polyhedra share edges, forming zigzag layers lying parallel to the bc plane.
The hydro-phobic methyl-ene groups occupy the inter-layer spaces. The carb-oxy-lic acid group makes a strong charge-assisted hydrogen bond to the central carboxyl-ate group. The hydroxyl group makes an intra-molecular hydrogen bond to an ionized terminal carboxyl-ate oxygen atom. Each hydrogen atom of the water mol-ecule acts as a donor, to a terminal carboxyl-ate and the hydroxyl group. Both the Na substructure and the hydrogen bonding differ from those of the known phase Na2HC6H5O7(H2O)1.5.
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In (NH4)2NaC6H5O7, the NaO6 coordination octa-hedra share corners, making double zigzag chains propagating along the b-axis direction. Each hydrogen atom of the ammonium ions acts as a donor in a discrete N-H⋯O hydrogen bond. The hydroxyl group forms an intra-molecular O-H⋯O hydrogen bond to a terminal carboxyl-ate oxygen atom.

Fluorimetry of selenium in body fluids after digestion with nitric acid, magnesium nitrate hexahydrate, and hydrochloric acid.

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A digestion procedure involving nitric acid, magnesium nitrate hexahydrate, and hydrochloric acid suffices for selenium determinations in whole blood, serum, and urine by molecular fluorescence spectrometry. To test the accuracy of the method we compared the results with those from hydride-generation atomic absorption spectrometry, and we also analyzed reference materials.

Ab Initio Molecular Dynamics Study of Aqueous Solutions of Magnesium and Calcium Nitrates: Hydration Shell Structure, Dynamics and Vibrational Echo Spectroscopy

Ab initio molecular dynamics simulations are performed to study the hydration shell structure, dynamics, and vibrational echo spectroscopy of aqueous Mg(NO3)2 and Ca(NO3)2 solutions. The hydration shell structure is probed through calculations of various ion-ion and ion-water radial and spatial distribution functions. On the dynamical side, calculations have been made for the hydrogen bond dynamics of hydration shells and also residence dynamics and lifetimes of water in different solvation environments.
Subsequently, we looked at the dynamics of frequency fluctuations of OD modes of heavy water in different hydration environments. Specifically, the temporal decay of spectral observables of two-dimensional infrared (2DIR) spectroscopy, three pulse echo peak shift (3PEPS) measurements and also of time correlations of frequency fluctuations are calculated to investigate the dynamics of vibrational spectral diffusion of water in different hydration environments in these solutions.
The OD stretch frequencies of water molecules in the vicinity of both divalent cations are found to be red-shifted and also fluctuating at a slower rate than other water molecules present in the solutions. The Mg2+ ions are found to be strongly hydrated which can be linked to their lower tendency to form contact ion-pairs and essentially no water exchange between the cationic hydration shells and bulk during the time scale of the current simulations.
The stronger hydration of Mg2+ ions make their hydration shells structurally and dynamically more rigid and make the dynamics of hydrogen bonds and vibrational spectral diffusion, as revealed through spectral observables of 2DIR and 3PEPS slower than that for the Ca2+ ions.
The structural and spectral dynamics of water molecules outside the cationic solvation shells in the Mg(NO3)2 solution are also found to be relatively slower than that of the Ca(NO3)2 solution and pure water which show the effects of stronger electric fields of Mg2+ ions extending beyond their first hydration shells. Also, water molecules in the hydration shells of the NO3– ions are found to relax at a slower rate in the Mg(NO3)2 solution which manifests the effect countercations have on anionic hydration shells for divalent metal nitrate solutions.

Effect of molten sodium nitrate on the decomposition pathways of hydrated magnesium hydroxycarbonate to magnesium oxide probed by in situ total scattering

The effect of NaNO3 and its physical state on the thermal decomposition pathways of hydrated magnesium hydroxycarbonate (hydromagnesite, HM) towards MgO was examined by in situ total scattering. Pair distribution function (PDF) analysis of these data allowed us to probe the structural evolution of pristine and NaNO3-promoted HM. A multivariate curve resolution alternating least squares (MCR-ALS) analysis identified the intermediate phases and their evolution upon the decomposition of both precursors to MgO.
The total scattering results are discussed in relation with thermogravimetric measurements coupled with off-gas analysis. MgO is obtained from pristine HM (N2, 10 °C min-1) through an amorphous magnesium carbonate intermediate (AMC), formed after the partial removal of water of crystallization from HM.
The decomposition continues via a gradual release of water (due to dehydration and dehydroxylation) and, in the last step, via decarbonation, leading to crystalline MgO. The presence of molten NaNO3 alters the decomposition pathways of HM, proceeding now through AMC and crystalline MgCO3.
These results demonstrate that molten NaNO3 facilitates the release of water (from both water of crystallization and through dehydroxylation) and decarbonation, and promotes the crystallization of MgCO3 and MgO in comparison to pristine HM. MgO formed from the pristine HM precursor shows a smaller average crystallite size than NaNO3-promoted HM and preserves the initial nano-plate-like morphology of HM.
NaNO3-promoted HM was decomposed to MgO that is characterized by a larger average crystallite size and irregular morphology. Additionally, in situ SEM allowed visualization of the morphological evolution of HM promoted with NaNO3 at a micrometre scale.

Magnesium reduces cadmium accumulation by decreasing the nitrate reductase-mediated nitric oxide production in Panax notoginseng roots.

Panax notoginseng is a traditional medicinal herb in China. However, the high capacity of its roots to accumulate cadmium (Cd) poses a potential risk to human health. Our previous study showed that nitrate reductase (NR)-dependent nitric oxide (NO) production promoted Cd accumulation in P. notoginseng root cell walls.
In this study, the role of Mg in the regulation of NO production and Cd accumulation in P. notoginseng roots was characterized. Exposure of P. notoginseng roots to increasing concentrations of Cd resulted in a linear increase in NO production.
The application of 2 mM Mg for 24 h significantly alleviated Cd-induced NO production and Cd accumulation in roots, which coincided with a significant decrease in the NR activity. Western analysis suggested that Mg increased the interaction between the 14-3-3 protein and NR, which might have been a reason for the Mg-mediated decrease in NR activity and NO production under Cd stress.
These results suggested that Mg-mediated alleviation of Cd-induced NO production and Cd accumulation is achieved by enhancement of the interaction between the 14-3-3 protein and NR in P. notoginseng roots.

Electrochemical nitrate removal with simultaneous magnesium recovery from a mimicked RO brine assisted by in situ chloride ions.

Electrochemical reduction is effective to remove nitrate but byproducts such as ammonia and nitrite would need chloride addition for indirect oxidation to nitrogen gas.
Herein, electrochemical nitrate reduction was investigated to remove nitrate from a mimicked reverse osmosis (RO) brine containing chloride that eliminates the need for external chloride addition. Both Cu/Zn and Ti nano cathodes exhibited the best performance of nitrate removal with >97 % removal in either Na2SO4 or NaCl electrolyte, although with different products.
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Complete nitrate reduction to nitrogen gas was realized in the RO brine whose complex composition decreased the electrode efficiency, for example from 71.4 ± 0.2%-49.4 ± 0.3 % with the Cu/Zn cathode after 5 cycles of operation.
Magnesium was recovered at the same time of nitrate removal and the purity of Mg(II) could reach 96.8 ± 2.0 % after proper pH pre-treatment. In a preliminary adsorption study, a key byproduct – chlorate was reduced by 49.8 ± 2.7 % after 3-h adsorption by 100 g L-1 activated carbon.
These results have demonstrated the simultaneous electrochemical nitrate removal and resource recovery from a complex water like a RO brine and provided new information such as byproduct management and electrode deterioration.

The Influence of Synthesis Method on Characteristics of Buffer and Organic Solutions of Thermo- and pH-Responsive Poly( N-[3-(diethylamino)propyl]methacrylamide)s

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Thermo- and pH-responsive poly(N-[3-(diethylamino)propyl]methacrylamide)s were synthesized by free radical polymerization and RAFT polymerization. The molar masses of the samples were 33,000-35,000 g∙mol-1. Investigations of the dilute solutions showed that the prepared samples were flexible chain polymers.
The behavior of the synthesized polymers in the buffer solutions was analyzed by turbidity and light scattering at a pH range of 7-13 and a concentration range of 0.0002-0.008 g·cm-3. When the concentrated solutions were at a low temperature, there were macromolecules and aggregates, which were formed due to the interaction of hydrophobic units. For the investigated samples, the lower critical solution temperatures were equal.
The phase separation temperatures decreased as pH increased. The influence of polydispersity index on the characteristics of the samples in the solutions was analyzed. The radii of molecules of poly(N-[3-(diethylamino)propyl]methacrylamide) obtained by RAFT polymerization at this temperature at the onset and end of the phase separation interval were lower than ones for samples synthesized by conventional free radical polymerization.
Keywords: aggregation; conformational and hydrodynamic characteristics; phase separation temperatures; poly(N-[3-(diethylamino)propyl]methacrylamide); synthesis; thermo- and pH- responsive polymers.

Detonation nanodiamonds as enhancers of E. coli photodynamic inactivation by phthalocyanines in a high molarity buffer solution

Antimicrobial therapy, especially inactivation of multi-antibiotic-resistant strains, requires creating new approaches for drug action and targeted delivery in different environmental conditions. In this work, detonation nanodiamonds (DNDs) were used to deliver polycationic zinc phthalocyanines to E. coli cells.
It is shown that in aqueous solutions, zinc phthalocyanines with cholinyl peripheral substituents form complexes with negatively charged DND based on electrostatic interactions.
About 40-70 phthalocyanine molecules can bind to a single DND particle, depending on the number of charged groups of the dye molecule. During the complex formation, quenching of phthalocyanine fluorescence and a decrease in its ability to generate reactive oxygen species were observed.
In the presence of bacterial cells, phthalocyanine left the complex and induced a photodynamic effect, the magnitude of which depended on the phthalocyanine charge, the molarity of the buffer solution, and the stoichiometry of the phthalocyanine-DND complex. It was found that at physiological values of the ionic strength of the solution, the photodynamic effect of phthalocyanine with a charge of 8+ in combination with a DND is higher than that of the initial phthalocyanine. Thus, nanodiamonds are a promising platform for the delivery of photosensitizers in antimicrobial therapy.
Keywords: Detonation nanodiamond; Photodynamic inactivation; Phthalocyanine.

Tunneling in the Hydrogen-Transfer Reaction from a Vitamin E Analog to an Inclusion Complex of 2,2-Diphenyl-1-picrylhydrazyl Radical with β-Cyclodextrin in an Aqueous Buffer Solution at Ambient Temperature

Recently, increasing attention has been paid to quantum mechanical behavior in biology. In this study, we investigated the involvement of quantum mechanical tunneling in the hydrogen-transfer reaction from Trolox, a water-soluble analog of vitamin E (α-tocopherol), to 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) in a phosphate buffer solution (0.05 M, pH 7.0).
DPPH• was used as a reactivity model of reactive oxygen species and solubilized in water using β-cyclodextrin (β-CD). The second-order rate constants, kH and kD, in 0.05 M phosphate buffer solutions prepared with H2O (pH 7.0) and D2O (pD 7.0), respectively, were determined for the reaction between Trolox and DPPH•, using a stopped-flow technique at various temperatures (283-303 K).
Large kinetic isotope effects (KIE, kH/kD) were observed for the hydrogen-transfer reaction from Trolox to the β-CD-solubilized DPPH• in the whole temperature range. The isotopic ratio of the Arrhenius prefactor (AH/AD = 0.003), as well as the isotopic difference in the activation energies (19 kJ mol-1), indicated that quantum mechanical tunneling plays a role in the reaction.

Buffer concentration dramatically affects the stability of S-nitrosothiols in aqueous solutions

S-nitrosothiols (RSNOs) are an important group of nitric oxide (NO)-donating compounds with low toxicity and wide biomedical applications. In this paper, we, for the first time, demonstrate that the concentration of buffer remarkably affects the stability of RSNOs including naturally occurring S-nitrosoglutathione (GSNO) and synthetic S-nitroso-N-acetylpenicillamine (SNAP).
For a solution with a high concentration of GSNO (e.g., 50 mM) and an initial near-neutral pH, the optimal buffer concentration is close to the GSNO concentration under our experimental conditions. A lower buffer concentration does not have adequate buffer capacity to resist the pH drop caused by GSNO decomposition.
The decreased solution pH further accelerates GSNO decomposition because GSNO is most stable at near-neutral pH according to our density-functional theory (DFT) calculations. A higher-than-optimal buffer concentration also reduces the GSNO stability because buffer ingredients including phosphate, Tris base, and HEPES consume NO/N2O3. In contrast to GSNO, the highest SNAP stability is obtained when the starting solution at a neutral pH does not contain buffer, and the stability decreases as the buffer concentration increases.
This is because SNAP is more stable at mildly acidic pH and the SNAP decomposition-induced pH drop stabilizes the donor. When the RSNO concentration is low (e.g., 1 mM), the buffer concentration also matters because any excess buffer accelerates the donor decomposition.
Since the effect of buffer concentration was previously overlooked and suboptimal buffer concentrations were often used, this paper will aid in the formulation of RSNO solutions to obtain the maximum stability for prolonged storage and sustained NO release.

In-solution buffer-free digestion allows full-sequence coverage and complete characterization of post-translational modifications of the receptor-binding domain of SARS-CoV-2 in a single ESI-MS spectrum

Subunit vaccines based on the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 provide one of the most promising strategies to fight the COVID-19 pandemic. The detailed characterization of the protein primary structure by mass spectrometry (MS) is mandatory, as described in ICHQ6B guidelines.
In this work, several recombinant RBD proteins produced in five expression systems were characterized using a non-conventional protocol known as in-solution buffer-free digestion (BFD). In a single ESI-MS spectrum, BFD allowed very high sequence coverage (≥ 99%) and the detection of highly hydrophilic regions, including very short and hydrophilic peptides (2-8 amino acids), and the His6-tagged C-terminal peptide carrying several post-translational modifications at Cys538 such as cysteinylation, homocysteinylation, glutathionylation, truncated glutathionylation, and cyanylation, among others. The analysis using the conventional digestion protocol allowed lower sequence coverage (80-90%) and did not detect peptides carrying most of the above-mentioned PTMs.
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The two C-terminal peptides of a dimer [RBD(319-541)-(His)6]2 linked by an intermolecular disulfide bond (Cys538-Cys538) with twelve histidine residues were only detected by BFD. This protocol allows the detection of the four disulfide bonds present in the native RBD, low-abundance scrambling variants, free cysteine residues, O-glycoforms, and incomplete processing of the N-terminal end, if present. Artifacts generated by the in-solution BFD protocol were also characterized. BFD can be easily implemented; it has been applied to the characterization of the active pharmaceutical ingredient of two RBD-based vaccines, and we foresee that it can be also helpful to the characterization of mutated RBDs.

Biglycan Has a Major Role in Maintenance of Mature Tendon Mechanics

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Decorin and biglycan are two small leucine-rich proteoglycans (SLRPs) that regulate collagen fibrillogenesis and extracellular matrix assembly in tendon.

The objective of this study was to determine the individual roles of these molecules in maintaining the structural and mechanical properties of tendon during homeostasis in mature mice. We hypothesized that knockdown of decorin in mature tendons would result in detrimental changes to tendon structure and mechanics while knockdown of biglycan would have a minor effect on these parameters.
To achieve this objective, we created tamoxifen-inducible mouse knockdown models targeting decorin or biglycan inactivation. This enables the evaluation of the roles of these SLRPs in mature tendon without the abnormal tendon development caused by conventional knockout models.
Contrary to our hypothesis, knockdown of decorin resulted in minor alterations to tendon structure and no changes to mechanics while knockdown of biglycan resulted in broad changes to tendon structure and mechanics. Specifically, knockdown of biglycan resulted in reduced insertion modulus, maximum stress, dynamic modulus, stress relaxation, and increased collagen fiber realignment during loading.
Knockdown of decorin and biglycan produced similar changes to tendon microstructure by increasing the collagen fibril diameter relative to wild-type controls. Biglycan knockdown also decreased the cell nuclear aspect ratio, indicating a more spindle-like nuclear shape. Overall, the extensive changes to tendon structure and mechanics after knockout of biglycan, but not decorin, provides evidence that biglycan plays a major role in the maintenance of tendon structure and mechanics in mature mice during homeostasis. This article is protected by copyright. All rights reserved.

Whole genome sequencing has the potential to improve treatment for rifampicin-resistant tuberculosis in high burden settings: a retrospective cohort study

Background Treatment of multidrug-resistant or rifampicin-resistant tuberculosis (MDR/RR-TB), although improved in recent years with shorter, more tolerable regimens, remains largely standardised and based on limited drug susceptibility testing (DST). More individualised treatment with expanded DST access is likely to improve patient outcomes.
Methods To assess the potential of TB drug resistance prediction based on whole genome sequencing (WGS) to provide more effective treatment regimens, we applied current South African treatment recommendations to a retrospective cohort of MDR/RR-TB patients from Khayelitsha, Cape Town.
Routine DST and clinical data were used to retrospectively categorise patients into a recommended regimen, either a standardised short regimen or a longer individualised regimen. Potential regimen changes were then described with the addition of WGS-derived DST.
Findings WGS data were available for 1274 MDR/RR-TB patient treatment episodes across 2008-2017. Among 834 patients initially eligible for the shorter regimen, 385 (46%) may have benefited from reduced drug dosage or removing ineffective drugs when WGS data were considered.
A further 187 (22%) may have benefited from more effective adjusted regimens. Among 440 patients initially eligible for a longer individualised regimen, 153 (35%) could have been switched to the short regimen.
Overall, 305 (24%) patients had MDR/RR-TB with second-line TB drug resistance, where the availability of WGS-derived DST would have allowed more effective treatment individualization. 
Interpretation These data suggest considerable benefits could accrue from routine access to WGS-derived resistance prediction. Advances in culture-free sequencing and expansion of the reference resistance mutation catalogue will increase the utility of WGS resistance prediction.
Funding Swiss National Science Foundation, South African National Research Foundation, and Wellcome Trust.

Working in a care home during the COVID-19 pandemic: How has the pandemic changed working practices? A qualitative study

Background: The pandemic has significantly affected care homes’ residents and families through the national visiting restrictions. However, less is known on the impact these changes have had on the care home workforce. The aim of this research was to explore the impact of COVID-19 on the working practices of care home staff, caring for people living with dementia.
Methods: Remote qualitative, semi-structured interviews were conducted with care home staff caring for people living with dementia (PLWD) in the UK.
Results: Participants were recruited to the larger programme of research via convenience sampling. Interviews were conducted via telephone or online platforms. This research employed inductive thematic analysis. Sixteen care home staff were included in this study.
Three overarching themes were developed from the analysis that conveyed changes to the everyday working practices of the care home workforce and the impact such changes posed to staff wellbeing: (1) Practical implications of working in a care home during the COVID-19 pandemic; (2); Staff values and changes to the staff roles (3): Impact to the care home staff and concerns for the care sector.
Conclusions: The COVID-19 pandemic has significantly disrupted the daily working practices of care home staff, with staff forced to adopt additional roles on top of increased workloads to compensate for the loss of external agencies and support. Support and guidance must be offered urgently to inform care home staff on how to best adapt to their new working practices, ensuring that they are adequately trained.
Keywords: COVID-19; Care homes; Care workforce; Nursing homes; Older people; Pandemics; Working practices.

Has EVAR changed the outcomes of ruptured abdominal aortic aneurysms? A decades worth of experience in an Australian Teaching Hospital

Background: Ruptured abdominal aortic aneurysms (rAAA) are associated with significant mortality, and equipoise remains as to whether patients managed with endovascular stent grafts (rEVAR) demonstrate better outcomes when compared to traditional open repair (OR). This study sought to examine the outcomes of patients presenting with rAAA to our institution and assess the perioperative outcomes and outpatient mortality of patients over the past decade.
Methods: A retrospective analysis was conducted. Patients treated for rAAA between 2010 and 2019 were identified from a search of the hospital database for ACHI and ICD-10 codes for repair of AAA. Demographic, operative and post-operative variables were collected from electronic medical records of identified patients.
Results: Eighty patients were identified, 51 of whom presented with a rAAA. The majority of repairs were rEVARs (59%). Median age was 76 years. Median length of admission to ICU was 3 days, and median length of hospital admission was 10 days. Overall in-patient mortality was 26%, with rates of 39% at 3 years and 47% at 5 years. No significant difference in outpatient mortality was found in patients undergoing rEVAR compared to OR, with rates of 61% at 5 years compared to 65% at 5 years, respectively (p = 0.8).
Conclusion: Perioperative outcomes of our cohort of patients undergoing endovascular repair compared to open repair for ruptured and symptomatic AAAs are comparable over the past decade. Given equipoise remains between repair methods, further observational studies are required to quantify benefits of OR and endovascular repairs for ruptured and symptomatic AAAs.
Keywords: EVAR; aneurysm; open AAA repair; rupture.

A Poultry Value Chain Intervention Promoting Diversified Diets Has Limited Impact on Maternal and Child Diet Adequacy During the Lean Season in a Cluster Randomized Controlled Trial

Background: SELEVER is a nutrition- and gender-sensitive poultry value chain project designed and implemented by international NGO Tanager which consists of poultry market facilitation and behavior change activities aiming at increasing poultry production and improving diets without free inputs transfer.
Objectives: The study aimed at assessing the impact of SELEVER on diets of women and children during the lean season.
Methods: Within a cluster-randomized controlled trial, 45 communes were assigned to one of three arms, including 1) SELEVER interventions; 2) SELEVER with an intensive hygiene and sanitation component (SELEVER + WASH); and 3) a control group without intervention. Two rounds of survey were conducted 2 years apart during the lean season. Primary dietary outcomes were the probability of adequacy (PA) of iron, zinc and vitamin A intakes, mean PA (MPA) of 11 micronutrients and individual dietary diversity score collected through quantitative 24-hour recall in longitudinal samples of women and index children (2-4 years old) in 1,054 households; and minimum acceptable diet in the repeated cross-sectional sample of their younger sibling aged 6-23 months. Impacts were assessed by intention-to-treat analysis of covariance.
Results: Relative to control, SELEVER interventions (groups 1 + 2) increased the PA of iron intakes in women by 1.8 pp (P = 0.030). We found no further impact on primary outcomes, although eggs consumption increased in index children (+0.73 pp, P = 0.010; +0.69 kcal/d, P = 0.036). Across the three groups, we observed negative effects of SELEVER on the PA of zinc intakes in women relative to SELEVER + WASH (-4.1 pp, P = 0.038), and on a variety of secondary dietary outcomes relative to both other groups. The study was registered on the ISCRCTN registry (ISRCTN16686478).
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Conclusions: information-only-based value-chain interventions may not have meaningful positive effects on diets of women and children in the lean season in settings with largely inadequate diets. We found suggestive evidence that synergies between intervention components may have introduced heterogeneity in effects on diet.
Keywords: behavior change communication; cluster-randomized controlled trial; dietary diversity; micronutrient intake; nutrition-sensitive poultry value chain.

Determination of volatile phenols in red wines by dispersive liquid-liquid microextraction and gas chromatography-mass spectrometry detection.

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A new method was developed for analysing 4-ethylguaiacol and 4-ethylphenol in the aroma of red wines using dispersive liquid-liquid microextraction (DLLME) coupled with gas chromatography-mass spectrometry detection (GC-MS).
Parameters such as extraction solvent, sample volume and disperser solvent were studied and optimised to obtain the best extraction results with the minimum interference from other substances, thus giving clean chromatograms. The response linearity was studied in the usual concentration ranges of analytes in wines (50-1500 microg/L). Repeatability and reproducibility of this method were lower than 5% for both volatile phenols.
Limits of detection and limits of quantification were also determined, and the values found were 28 and 95 microg/L for 4-ethylguaiacol and 44 and 147 microg/L for 4-ethylphenol, respectively.
This new method has been used for the determination of the volatile phenols concentration in different samples of Tannat wine affected by Brettanomyces contamination.

High-performance liquid chromatography method development and validation for simultaneous determination of five model compounds, antipyrine, metoprolol, ketoprofen, furosemide and phenol red, as a tool for the standardization of rat in situ intestinal permeability studies using timed wavelength detection.

A simple, precise, accurate and rugged reversed-phase high-performance liquid chromatography (HPLC) method has been developed and validated for the simultaneous determination of five permeability model compounds, viz. antipyrine, metoprolol, ketoprofen, furosemide and phenol red.
The method was intended to standardize rat in situ single-pass intestinal perfusion studies to assess the intestinal permeability of drugs in the market as well as new chemical entities. Optimum resolution was achieved by gradient elution on a Symmetry Shield C-18 analytical column with the mobile phase consisting of a mixture of aqueous potassium dihydrogen orthophosphate (pH 5.5; 0.01 m) and methanol at a flow rate of 1.5 mL/min.
The retention times of antipyrine, metoprolol, ketoprofen, phenol red and furosemide were about 9, 12, 13, 16 and 17 min, respectively. Data acquisition was carried out using a photo diode array detector in the wavelength range 210-600 nm. Extraction of chromatograms was carried out by timed wavelength.
Data obtained in all studies indicated that the method was suitable for the intended purpose. The validated method was found to be linear and precise in the working range. Suitability of storage under various conditions and freeze/thaw impact at cold temperature were established to ensure complete sample recovery without any stability issues. Recovery very close to the spiked amounts indicated that the method was highly accurate and suitable for use on routine basis.

A simple and rapid high-performance liquid chromatography method for determining furosemide, hydrochlorothiazide, and phenol red: applicability to intestinal permeability studies.

A simple reversed-phase high-performance liquid chromatography (HPLC) method with ultraviolet detection at 280 nm was developed for simultaneous quantitation of furosemide and hydrochlorothiazide along with phenol red as a nonabsorbable marker for in situ permeability studies in anaesthetized rats.
A jejunal segment of approximately 10 cm was isolated and cannulated in both ends for inlet and outlet solution. The perfusate was collected every 10 min, and samples were analyzed using the developed method.
The mobile phase was acetonitrile-water-triethylamine-glacial acetic acid (41.5 + 57.4 + 0.1 + 0.9, adjusted to pH 5.6) at a flow rate of 1 mL/min; the run time was 9 min. The calibration graphs were linear for all 3 compounds (r>> 0.999) across the concentration range of 7.93-125 microg/mL for phenol red and 6.25-100 microg/mL for hydrochlorothiazide and furosemide.
The limits of quantitation were 7.2, 8.9, and 6.8 microg/mL for furosemide, hydrochlorothiazide, and phenol red, respectively. The coefficients of variation for intraassay and interassay precision were less than or equal to 7.6%, and the accuracy was between 93.2-103.4%. Using the single pass intestinal perfusion technique and the suggested HPLC method for sample analysis, mean values of 0.25 x 10(-4) (+/-0.16) cm/s and 0.22 x 10(-4) (+/-0.13) cm/s were obtained for furosemide and hydrochlorothiazide, respectively.

Construction of a colorimetric sensor array based on the coupling reaction to identify phenols

Phenols are harmful to the human body and the environment. Since there are a variety of phenols in actual samples, this requires a sensor which possesses the ability to simultaneously distinguish them. Herein, we report a colorimetric sensor array, which uses two nanozymes (Fe-N-C nanozymes and Cu-N-C nanozymes) as electronic tongues for fingerprint identification of six phenols (2,4,6-trichlorophenol (2,4,6-Tri), 4-nitrophenol (P-np), phenol (Phe), 3-chlorophenol (3-CP), 4-chlorophenol (4-CP), and o-nitrophenol (O-np)) in the environment.
Nanozymes catalyzed the reaction of hydrogen peroxide, different phenols and 4-aminoantipyrine (4-AAP) to produce different color variations. These signal changes as fingerprints encouraged us to develop a pattern recognition method for the identification of phenols by linear discriminant analysis (LDA). The six phenols at 50 nM have their own response patterns, respectively. Surprisingly, this sensor array had distinguished the six phenols in actual samples successfully.

Ultrafast Proton-Transfer Reaction in Phenol-(Ammonia) n Clusters: An Ab Initio Molecular Dynamics Investigation

The ability of phenol to transfer a proton to surrounding ammonia molecules in a phenol-(ammonia)n cluster depends on the relative orientation of ammonia molecules, and a critical field of about 285 MV cm-1 is essential along the O-H bond for the proton-transfer process. Ab initio MD simulations reveal that the proton-transfer process from phenol to ammonia cluster is spontaneous when the cluster has at least eight ammonia molecules, and the proton-transfer event is almost instantaneous (about 20-120 fs).
These simulations also reveal that the rate-determining step for the proton-transfer process is the reorganization of the solvent around the OH group.
During the solvent reorganization process, the fluctuations in the solvent occur until a particular set of configurations projects the field in excess of the critical electric field along the O-H bond which drives the proton-transfer process. Further, the proton-transfer process follows a curvilinear path which includes the O-H bond elongation and out-of-plane movement of the proton and can be referred to as a “bend-to-break” process.

Inhibition studies of bacterial α-carbonic anhydrases with phenols

The α-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacterial pathogens Neisseria gonorrhoeae (NgCAα) and Vibrio cholerae (VchCAα) were investigated for their inhibition by a panel of phenols and phenolic acids. Mono-, di- and tri-substituted phenols incorporating additional hydroxyl/hydroxymethyl, amino, acetamido, carboxyl, halogeno and carboxyethenyl moieties were included in the study.
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The best NgCAα inhibitrs were phenol, 3-aminophenol, 4-hydroxy-benzylalcohol, 3-amino-4-chlorophenol and paracetamol, with KI values of 0.6-1.7 µM. The most effective VchCAα inhibitrs were phenol, 3-amino-4-chlorophenol and 4-hydroxy-benzyl-alcohol, with KI values of 0.7-1.2 µM. Small changes in the phenol scaffold led to drastic effects on the bacterial CA inhibitory activity. This class of underinvestigated bacterial CA inhibitors may thus lead to effective compounds for fighting drug resistant bacteria.