Репозиторий Университета

Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent 'leakage' of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent 'leakage' of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent 'leakage' of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

Eukaryotic cells can harbour mitochondria with markedly different transmembrane potentials. Intracellular mitochondrial quality-control mechanisms (e.g. mitophagy) rely on this intracellular variation to distinguish functional and damaged (depolarized) mitochondria. Given that intracellular mitochondrial DNA (mtDNA) genetic variation can induce mitochondrial heterogeneity, mitophagy could remove deleterious mtDNA variants in cells. However, the reliance of mitophagy on the mitochondrial transmembrane potential suggests that mtDNAs with deleterious mutations in ATP synthase can evade the control. This evasion is possible because inhibition of ATP synthase can increase the mitochondrial transmembrane potential. Moreover, the linkage of the mtDNA genotype to individual mitochondrial performance is expected to be weak owing to intracellular mitochondrial intercomplementation. Nonetheless, I reason that intracellular mtDNA quality control is possible and crucial at the zygote stage of the life cycle. Indeed, species with biparental mtDNA inheritance or frequent 'leakage' of paternal mtDNA can be vulnerable to invasion of selfish mtDNAs at the stage of gamete fusion. Here, I critically review recent findings on intracellular mtDNA quality control by mitophagy and discuss other mechanisms by which the nuclear genome can affect the competition of mtDNA variants in the cell. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.

© 2019 Aims: The high sugar and lipid content of the Western diet (WD) is associated with metabolic dysfunction, non-alcoholic steatohepatitis, and it is an established risk factor for neuropsychiatric disorders. Our previous studies reported negative effects of the WD on rodent emotionality, impulsivity, and sociability in adulthood. Here, we investigated the effect of the WD on motor coordination, novelty recognition, and affective behavior in mice as well as molecular and cellular endpoints in brain and peripheral tissues. Main methods: Female C57BL/6 J mice were fed the WD for three weeks and were investigated for glucose tolerance, insulin resistance, liver steatosis, and changes in motor coordination, object recognition, and despair behavior in the swim test. Lipids and liver injury markers, including aspartate-transaminase, alanine-transaminase and urea were measured in blood. Serotonin transporter (SERT) expression, the density of Iba1-positive cells and concentration of malondialdehyde were measured in brain. Key findings: WD-fed mice exhibited impaired glucose tolerance and insulin resistance, a loss of motor coordination, deficits in novel object exploration and recognition, increased helplessness, dyslipidemia, as well as signs of a non-alcoholic steatohepatitis (NASH)-like syndrome: liver steatosis and increased liver injury markers. Importantly, these changes were accompanied by decreased SERT expression, elevated numbers of microglia cells and malondialdehyde levels in, and restricted to, the prefrontal cortex. Significance: The WD induces a spectrum of behaviors that are more reminiscent of ADHD and ASD than previously recognized and suggests that, in addition to the impairment of impulsivity and sociability, the consumption of a WD might be expected to exacerbate motor dysfunction that is also known to be associated with adult ADHD and ASD.

© 2019 Aims: The high sugar and lipid content of the Western diet (WD) is associated with metabolic dysfunction, non-alcoholic steatohepatitis, and it is an established risk factor for neuropsychiatric disorders. Our previous studies reported negative effects of the WD on rodent emotionality, impulsivity, and sociability in adulthood. Here, we investigated the effect of the WD on motor coordination, novelty recognition, and affective behavior in mice as well as molecular and cellular endpoints in brain and peripheral tissues. Main methods: Female C57BL/6 J mice were fed the WD for three weeks and were investigated for glucose tolerance, insulin resistance, liver steatosis, and changes in motor coordination, object recognition, and despair behavior in the swim test. Lipids and liver injury markers, including aspartate-transaminase, alanine-transaminase and urea were measured in blood. Serotonin transporter (SERT) expression, the density of Iba1-positive cells and concentration of malondialdehyde were measured in brain. Key findings: WD-fed mice exhibited impaired glucose tolerance and insulin resistance, a loss of motor coordination, deficits in novel object exploration and recognition, increased helplessness, dyslipidemia, as well as signs of a non-alcoholic steatohepatitis (NASH)-like syndrome: liver steatosis and increased liver injury markers. Importantly, these changes were accompanied by decreased SERT expression, elevated numbers of microglia cells and malondialdehyde levels in, and restricted to, the prefrontal cortex. Significance: The WD induces a spectrum of behaviors that are more reminiscent of ADHD and ASD than previously recognized and suggests that, in addition to the impairment of impulsivity and sociability, the consumption of a WD might be expected to exacerbate motor dysfunction that is also known to be associated with adult ADHD and ASD.

© Springer Nature Switzerland AG 2020. The author considers an important problem of using the Huff model for obtaining quantitative estimates of trade turnover of the shopping center. The aim of the article is to identify the actual limitations of the specified model, which when conducting a practical assessment of potential trade turnover of large objects of commercial real estate in a significant way affect the quantitative results of the calculation and the quality of the conclusions. In accordance with the goal, the author solved the following tasks: –economic and mathematical structure of the Huff model is considered; –the calibration parameters of the model are revealed, the accuracy of which determines the accuracy of calculations and the correctness of conclusions; –an algorithm for estimating the potential trade turnover of the trading center based on a combination of the Huff model and econometric methods is constructed. The hypothesis of the research: For correct application of the Huff model in practice it is necessary to use econometric methods of estimation of calibration parameters. The article shows that the evaluation of calibration parameters of the model significantly affects the accuracy of the evaluation. As a result, the necessity of using empirical data and constructing econometric model based on them is proved by obtaining accurate quantitative estimates. The author presents the algorithm of correct estimation of potential trade turnover of the shopping center using econometric estimation of parameters of the Huff model, empirical and expert data and a calculation example. Conclusions on the use in practice of the Huff model with its methodological and actual limitations are formulated.

© 2019 Elsevier B.V. and Mitochondria Research Society Mitochondria have been widely accepted as the main source of ATP in the cell. The inner mitochondrial membrane (IMM) is important for the maintenance of ATP production and other functions of mitochondria. The electron transport chain (ETC) generates an electrochemical gradient of protons known as the proton-motive force across the IMM and thus produces the mitochondrial membrane potential that is critical to ATP synthesis. One of the main factors regulating the structural and functional integrity of the IMM is the changes in the matrix volume. Mild (reversible) swelling regulates mitochondrial metabolism and function; however, excessive (irreversible) swelling causes mitochondrial dysfunction and cell death. The central mechanism of mitochondrial swelling includes the opening of non-selective channels known as permeability transition pores (PTPs) in the IMM by high mitochondrial Ca2+ and reactive oxygen species (ROS). The mechanisms of reversible and irreversible mitochondrial swelling and transition between these two states are still unknown. The present study elucidates an upgraded biophysical model of reversible and irreversible mitochondrial swelling dynamics. The model provides a description of the PTP regulation dynamics using an additional differential equation. The rigidity tensor was used in numerical simulations of the mitochondrial parameter dynamics with different initial conditions defined by Ca2+ concentration in the sarco/endoplasmic reticulum. We were able to estimate the values of the IMM rigidity tensor components by fitting the model to the previously reported experimental data. Overall, the model provides a better description of the reversible and irreversible mitochondrial swelling dynamics.

© 2020, Springer Nature Switzerland AG. Multifactorial nature of human health and need in personifying the approach to each person in the health saving programs should use modern information and cognitive technologies for the tasks of health assessment and control. The article presents a concept, basic methods, and a structure of intelligent system of health saving (InSyHS), created by the authors to solve these tasks. This system implements the intelligent Internet technology based on modern cognitive methods and information about health, considering all possible health-determining essential factors (nutrition, physical activity, lifestyle, social and nature environment), and doing people to form an active relation to health with the possibility of self-diagnostics (physical and mental reserves, stress, psycho-emotional characteristics), optimization and personalization of personal health saving programs.

© 2020, Springer Nature Switzerland AG. The chapter is devoted to the attacks modeling for Cyber-Physical systems of industrial enterprises with regard to risk assessment. In this chapter the analysis of corporate systems of industrial is held; systems’ attacks and risk assessment techniques were studied; software for attacks modeling are compared. Information models of corporate networks and attacks are developed; describes the design and basic functions of the module for assessing the risks of attacks in the corporate system. Corporate networks of more than 70% of industrial enterprises are potentially vulnerable to hacker attacks. Today, according to research by Positive Technologies analysts, hackers can cross the perimeter and get into the corporate network of 73% of the companies in the industrial segment. In 82% of companies, penetration from the corporate network to the technological one is possible. One of the main opportunities for obtaining unauthorized access to the enterprise network turned out to be administrative control channels. Solving the problem of ensuring the information security of Cyber-Physical systems is an urgent task today.

© Springer Science+Business Media, LLC, part of Springer Nature 2020. DNA mutations govern cancer development. Cancer mutation profiles vary dramatically among the individuals. In some cases, they may serve as the predictors of disease progression and response to therapies. However, the biomarker potential of cancer mutations can be dramatically (several orders of magnitude) enhanced by applying molecular pathway-based approach. We developed Oncobox system for calculation of pathway instability (PI) values for the molecular pathways that are aggregated mutation frequencies of the pathway members normalized on gene lengths and on number of genes in the pathway. PI scores can be effective biomarkers in different types of comparisons, for example, as the cancer type biomarkers and as the predictors of tumor response to target therapies. The latter option is implemented using mutation drug score (MDS) values, which algorithmically rank the drugs capacity of interfering with the mutated molecular pathways. Here, describe the mathematical basis and algorithms for PI and MDS values calculation, validation and implementation. The example analysis is provided encompassing 5956 human tumor mutation profiles of 15 cancer types from The Cancer Genome Atlas (TCGA) project, that totally make 2,316,670 mutations in 19,872 genes and 1748 molecular pathways, thus enabling ranking of 128 clinically approved target drugs. Our results evidence that the Oncobox PI and MDS approaches are highly useful for basic and applied aspects of molecular oncology and pharmacology research.

© 2019 The Authors Background: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. Methods: Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300–1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. Results: The safety population (patients receiving ≥ 1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%–96% and 4%–27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%–73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥ 1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%–83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥ 1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively. Conclusions: The safety profile of retigabine in adults with POS across four open-label studies was generally consistent with data from previous placebo-controlled studies. Discoloration of various tissues occurred in a proportion of patients treated with retigabine and resolved completely in a small number of these patients following treatment discontinuation. In addition, comprehensive eye examination identified a new adverse reaction of acquired vitelliform maculopathy in a limited number of patients.

© 2019 Elsevier B.V. Brain delivery of drugs by nanoparticles is a promising strategy that could open up new possibilities for the chemotherapy of brain tumors. As demonstrated in previous studies, the loading of doxorubicin in poly(lactide-co-glycolide) nanoparticles coated with poloxamer 188 (Dox-PLGA) enabled the brain delivery of this cytostatic that normally cannot penetrate across the blood-brain barrier in free form. The Dox-PLGA nanoparticles produced a very considerable anti-tumor effect against the intracranial 101.8 glioblastoma in rats, thus representing a promising candidate for the chemotherapy of brain tumors that warrants clinical evaluation. The objective of the present study, therefore, was the optimization of the Dox-PLGA formulation and the development of a pilot scale manufacturing process. Optimization of the preparation procedure involved the alteration of the technological parameters such as replacement of the particle stabilizer PVA 30–70 kDa with a presumably safer low molecular mass PVA 9–10 kDa as well as the modification of the external emulsion medium and the homogenization conditions. The optimized procedure enabled an increase of the encapsulation efficiency from 66% to >90% and reduction of the nanoparticle size from 250 nm to 110 nm thus enabling the sterilization by membrane filtration. The pilot scale process was characterized by an excellent reproducibility with very low inter-batch variations. The in vitro hematotoxicity of the nanoparticles was negligible at therapeutically relevant concentrations. The anti-tumor efficacy of the optimized formulation and the ability of the nanoparticles to penetrate into the intracranial tumor and normal brain tissue were confirmed by in vivo experiments.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. Water solubility of prothionamide and its solid dispersions with polyethylene glycol-1500, polyvinylpyrrolidone-10000, and β-cyclodextrin was studied. The most promising results were obtained with the solid dispersion with polyvinylpyrrolidone, which provided a 2.6-fold general increase of drug’s solubility and about a 6-fold dissolution rate increase, the maximal values among the studied drug forms. The results of complex physicochemical studies suggested that the improved drug release was due to micronization and solubilizing action of the polymer. A principal factor was the destruction of the crystal lattice and formation of amorphous particles in the solid dispersion. The obtained data can be useful for the development of modified pharmaceutical forms of prothionamide with improved drug release profile.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. In the context of a post-antibiotic era, the phenomenon of microbial allolysis, which is defined as the partial killing of bacterial population induced by other cells of the same species, may take on greater significance. This phenomenon was revealed in some bacterial species such as Streptococcus pneumoniae and Bacillus subtilis, and has been suspected to occur in some other species or genera, such as enterococci. The mechanisms of this phenomenon, as well as its role in the life of microbial populations still form part of ongoing research. Herein, we describe recent developments in allolysis in the context of its practical benefits as a form of cell death that may give rise to developing new strategies for manipulating the life and death of bacterial communities. We highlight how such findings may be viewed with importance and potential within the fields of medicine, biotechnology, and pharmacology.

© 2019 Elsevier Ltd The effect of different initiators (tert-butyl chloride (t-BuCl) and 2-chloro-2-phenylpropane (CumCl) on the cationic polymerization of isobutylene co-initiated by acidic chloroferrate imidazole-based ionic liquid emimCl-FeCl3 (emimCl: 1-ethyl-3-methylimidazolium chloride, molar fraction of FeCl3 (χ(FeCl3)) ≥ 0.6) in the presence of diisopropyl ether at 0 °C and [IB] = 5.2 M has been investigated. Generally, the use of all above-mentioned initiators results in increase of the monomer conversion from 30% to 60% as well as in decrease of molecular weight from 2500 g mol−1 to 1100 g mol−1 and polydispersity from 2.6 to 1.7, respectively, but does not influence the content of exo-olefin end group. It was demonstrated that CumCl does not initiated directly the polymerization at 0 °C or −20 °C, rather, it decomposed with the formation of the proton, a true initiator of the polymerization. It was also found that addition of small amounts (1% by volume) of benzene or its derivatives into the polymerization system leads to further increase of the monomer conversion (>90%). The rate of isobutylene polymerization depends on basicity of aromatic compounds added and increases in the following order: benzene < toluene ≈ mesitylene.

© 2019 Elsevier Inc. Objective: To evaluate the pathologic response, safety, and feasibility of nephrectomy following receipt of immune checkpoint inhibition (ICI) for renal cell carcinoma (RCC). Methods: Patients who underwent nephrectomy for RCC after exposure to nivolumab monotherapy or combination ipilimumab/nivolumab were reviewed. Primary surgical outcomes included operative time (OT), estimated blood loss (EBL), length of stay (LOS), readmission rates, and complication rates. Pathologic response in the primary and metastatic sites constituted secondary outcomes. Results: Eleven nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. Six patients received 1 to 4 cycles of ipilimumab/nivolumab, while 5 received 2 to 12 infusions of nivolumab preoperatively. Five surgeries were performed laparoscopically, and 4 patients underwent concomitant thrombectomy. One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no detectable malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 ml, and 4 days, respectively. Four patients experienced a complication, including 3 that were addressed with interventional radiology procedures. One patient died of progressive disease >3 months after surgery, and 1 patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. Conclusion: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. Timing of the nephrectomy relative to checkpoint dosing did not seem to impact outcome. Biopsies of lesions responding radiographically to ICI may warrant attention prior to surgical excision.

© 2019, SICOT aisbl. Background: Rupture of the anterior cruciate ligament (ACL) is one of the most common sports injuries of the knee joint. Today, we have a large number of approaches to arthroscopic reconstruction of the anterior cruciate ligament that lead to successful outcomes and allow the patients to return to a significant level of activity post-operatively. Nevertheless, the return to competitions rate stays relatively low. The functional state is thought to be dependent on rotational and anteroposterior stability of the knee. These data encourage search for methods of additional stabilization of the knee joint, one of them being extra-articular tenodesis, or reconstruction of anterolateral ligament of the knee. The aim of the study: To evaluate medium-term results of combined simultaneous arthroscopic reconstruction of anterior cruciate ligament and anterolateral ligament of the knee joint in sportsmen and to access the probability of return to competitions. Materials and methods: The surgeries were performed in 2014–2015 in 50 patients who fulfilled the entry criteria: 20 patients (including 10 professional sportsmen) underwent arthroscopic ACL reconstruction together with reconstruction of anterolateral ligament—group 1 (main group), and 30 patients (including 10 professional sportsmen) underwent arthroscopic ACL reconstruction—group 2 (control group). Results: Group 1: All patients of group 1 were able to return to the pre-operative sports level in two years after the surgery. The mean Tegner Lysholm score was 72.6 ± 6.45 (hereinafter, SE—standard error) before the surgery and 97.4 ± 1.18 after the surgery. The mean IKDC score was 63.1 ± 4.8% before the surgery and 96.3 ± 1.8% after the surgery. Group 2: 20 of 30 patients (66.7%) returned to the pre-operative level of activity and returned to competitions (if they were professional sportsmen) in a year after the surgery. Five of ten patients (50%) (professional sportsmen) returned to competitions. Fifteen of 20 patients (75%) (amateur sportsmen) also returned to competitions. The mean pre-operative Tegner Lysholm score was 69.6 ± 3.5, and the mean post-operative score was 92.1 ± 3.9. The mean pre-operative IKDC score was 73.4 ± 3.2%, and the mean post-operative score was 90.3 ± 3.7%. Conclusion: The results of the study show that more patients with higher functional demands and more professional sportsmen returned to sports. Despite the results of our and other foreign studies, a need remains for studies that will compare outcomes of ALL reconstruction with the same surgical technique in homogenous groups of patients.

© 2019 Elsevier B.V. Due to their unique optical properties upconversion nanoparticles (UCNPs) provide exceptionally high contrast for imaging of true nanoparticle distribution in excised human skin. It makes possible to show penetration of solid nanoparticles in skin treated with chemical enhancers. We demonstrated tracing upconversion nanoparticles in excised human skin by means of optical microscopy at the discrete particle level sensitivity to obtain their penetration profiles, which was validated by laser-ablation inductively-coupled-plasma mass-spectrometry. To demonstrate utilities of our method, UCNPs were coated with polymers, formulated in water and chemical enhancers, and applied on excised human skin mounted on Franz cells, followed by imaging using a custom-built laser-scanning microscope. To evaluate the toxicity impact on skin by polymer-coated UCNPs, we introduced a tissue engineering model of viable epidermis made of decellularized chick embryo skin seeded with keratinocytes. UCNPs formulated in water stopped in stratum corneum, whereas UCNPs formulated in ethanol-water solution crossed stratum corneum and reached viable epidermis – hence, the enhancement effect for solid nanoparticles was detected by optical microscopy. All polymer-coated UCNPs were found nontoxic within the accepted safety levels. The keratinocyte resilience to polyethyleneimine-coated UCNPs was surprising considering cytotoxicity of polyethyleneimine to two-dimensional cell cultures.

© 2019 The Authors Half of individuals with a whiplash injury experience ongoing pain and disability. Many are insufficiently active for good health, increasing their risk of preventable morbidity and mortality, and compounding the effects of the whiplash injury. This paper describes a protocol for evaluating the efficacy of a physical activity promotion intervention in adults with whiplash associated disorders. A multiple-baseline, single case experimental design will be used to evaluate the effects of a physical activity (PA) intervention that includes evidence-based behaviour change activities and relapse prevention strategies for six adults with chronic whiplash. A structured visual analysis supplemented with statistical analysis will be used to analyse: accelerometer-measured PA, confidence completing PA in the presence of neck pain, and pain interference.