Velocities of Mesenchymal Cells May be Ill-Defined

The dynamics of single cell migration on flat surfaces is usually modeled by a Langevin-like problem consisting of ballistic motion for short periods and random walk. for long periods. Conversely, recent studies have revealed a previously neglected random motion at very short intervals, what would rule out the possibility of defining the cell instantaneous velocity and a robust measurement procedure. A previous attempt to address this issue considered an anisotropic migration model, which takes into account a polarization orientation along which the velocity is well-defined, and a direction orthogonal to the polarization vector that describes the random walk. Although the numerically and analytically calculated mean square displacement and auto-correlation agree with experimental data for that model, the velocity distribution peaks at zero, which contradicts experimental observations of a constant drift in the polarization direction. Moreover, Potts model simulations indicate that instantaneous velocity cannot be measured for any direction. Here, we consider dynamical equations for cell polarization, which is measurable and introduce a polarization-dependent displacement, circumventing the problem of ill defined instantaneous velocity. Polarization is a well-defined quantity, preserves memory for short intervals, and provides a robust measurement procedure for characterizing cell migration. We consider cell polarization dynamics to follow a modified Langevin equation that yields cell displacement distribution that peaks at positive values, in agreement with experiments and Potts model simulations. Furthermore, displacement autocorrelation functions present two different time scales, improving the agreement between theoretical fits and experiments or simulations

Ethylene-induced Transcriptional And Hormonal Responses At The Onset Of Sugarcane Ripening

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)The effects of ethephon as a sugarcane ripener are attributed to ethylene. However, the role of this phytohormone at the molecular level is unknown. We performed a transcriptome analysis combined with the evaluation of sucrose metabolism and hormone profiling of sugarcane plants sprayed with ethephon or aminoethoxyvinylglycine (AVG), an ethylene inhibitor, at the onset of ripening. The differential response between ethephon and AVG on sucrose level and sucrose synthase activity in internodes indicates ethylene as a potential regulator of sink strength. The correlation between hormone levels and transcriptional changes suggests ethylene as a trigger of multiple hormone signal cascades, with approximately 18% of differentially expressed genes involved in hormone biosynthesis, metabolism, signalling, and response. A defence response elicited in leaves favoured salicylic acid over the ethylene/jasmonic acid pathway, while the upper internode was prone to respond to ethylene with strong stimuli on ethylene biosynthesis and signalling genes. Besides, ethylene acted synergistically with abscisic acid, another ripening factor, and antagonistically with gibberellin and auxin. We identified potential ethylene target genes and characterized the hormonal status during ripening, providing insights into the action of ethylene at the site of sucrose accumulation. A molecular model of ethylene interplay with other hormones is proposed.7Sao Paulo Research Foundation (FAPESP) [2008/52146-0, 2008/57495-3, 2013/15576-5, 2012/13920-8, 2008/54201-9]National Council for Scientific and Technological Development (CNPq) [140767/2012-6, 160132/2011-3]ECMGMSMMRVRCNPqNational Science Foundation [DBI-0521250]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway

<p>Abstract</p> <p>Background</p> <p>In addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral μ-opioid receptor (MOR) activation are able to direct block PGE₂-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE₂-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated.</p> <p>Results</p> <p>Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE₂-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (≅ 43%).</p> <p>Conclusions</p> <p>The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.</p

Medical rescuers’ occupational health during COVID-19 : contribution of coping and emotion regulation on burnout, trauma and post-traumatic growth

The COVID-19 pandemic places unique challenges to medical rescuers’ occupational health. Thus, it is crucial to assess its direct and indirect impacts on key psychological outcomes and adaptation strategies. This study aims to analyse the impact of this pandemic on medical rescuers’ coping and emotion regulation strategies, and their levels of work-related psychological outcomes, such as burnout, trauma and post-traumatic growth. Additionally, it aims to analyse the contribution of coping and emotion regulation strategies, employed to manage the COVID-19 pandemic, on burnout, trauma and post-traumatic growth. A sample of 111 medical rescuers answered the Brief Cope, Emotion Regulation Questionnaire, Oldenburg Burnout Inventory, Impact of Event Scale-Revised and Post-Traumatic Growth Inventory. Medical rescuers resorted moderately to coping and emotion regulation strategies, since the beginning of COVID-19. They presented moderate burnout and post-traumatic growth and low trauma. Coping presented a higher weight on burnout, trauma and post-traumatic growth, than emotion regulation. Expressive suppression and dysfunctional coping predicted burnout and trauma, and problem and emotion-focused coping predicted post-traumatic growth. Dysfunctional coping mediated and, thus, exacerbated the effect of expressive suppression on burnout and on trauma. Practitioners should pay closer attention to professionals with higher burnout and trauma. Occupational practices should focus on reducing dysfunctional coping and expressive suppression and promoting problem-focused coping.Resumo: A pandemia COVID-19 coloca desafios únicos à saúde ocupacional dos profissionais do pré-hospitalar. Assim, é fundamental avaliar o seu impacto psicológico, para sintomatologia direta ou indiretamente relacionada com a COVID-19. Pretende-se analisar o impacto desta pandemia nos outcomes psicológicos laborais, como burnout, trauma e crescimento pós-traumático, e nas estratégias de coping e regulação emocional. Pretende-se também analisar o contributo do coping e regulação emocional para estes outcomes. Uma amostra de 111 profissionais de emergência médica pré-hospitalar responderam ao Brief Cope, Emotion Regulation Questionnaire, Oldenburg Burnout Inventory, Impact of Event Scale-Revised e Post-Traumatic Growth Inventory. Os profissionais recorreram moderadamente a estratégias de coping e regulação emocional, desde o início da pandemia. Reportaram moderado burnout e crescimento pós-traumático e baixo trauma. O coping apresentou maior peso para os outcomes. A supressão emocional e o coping disfuncional contribuíram para o burnout e trauma, e coping problema e emoção contribuíram para o crescimento pós-traumático. O coping disfuncional mediou e exarcebou o efeito da supressão emocional no burnout e trauma. Assim, poderá ser dada especial atenção a profissionais com elevado burnout e trauma e as práticas poderão ser focadas na redução do coping disfuncional e supressão emocional, bem como na promoção do coping problema.info:eu-repo/semantics/publishedVersio

Effect of physical stimuli on hair follicle deposition of clobetasol-loaded Lipid Nanocarriers

Clobetasol propionate (CLO) is a potent glucocorticoid used to treat inflammation-based skin, scalp, and hair disorders. In such conditions, hair follicles (HF) are not only the target site but can also act as drug reservoirs when certain formulations are topically applied. Recently, we have demonstrated nanostructured lipid carriers (NLC) containing CLO presenting epidermal-targeting potential. Here, the focus was evaluating the HF uptake provided by such nanoparticles in comparison to a commercial cream and investigating the influence of different physical stimuli [i.e., infrared (IR) irradiation (with and without metallic nanoparticles-MNP), ultrasound (US) (with and without vibration) and mechanical massage] on their follicular targeting potential. Nanosystems presented sizes around 180 nm (PdI < 0.2) and negative zeta potential. The formulation did not alter skin water loss measurements and was stable for at least 30 days at 5 °C. Nanoparticles released the drug in a sustained fashion for more than 3 days and increased passively about 40 times CLO follicular uptake compared to the commercial cream. Confocal images confirmed the enhanced follicular delivery. On the one hand, NLC application followed by IR for heat generation showed no benefit in terms of HF targeting even at higher temperatures generated by metallic nanoparticle heating. On the other hand, upon US treatment, CLO retention was significantly increased in deeper skin layers. The addition of mechanical vibration to the US treatment led to higher follicular accumulation compared to passive exposure to NLC without stimuli. However, from all evaluated stimuli, manual massage presented the highest follicular targeting potential, driving more than double the amount of CLO into the HF than NLC passive application. In conclusion, NLC showed great potential for delivering CLO to HF, and a simple massage was capable of doubling follicular retention

Intrauterine Blood Plasma Platelet-Therapy Mitigates Persistent Breeding-Induced Endometritis, Reduces Uterine Infections, and Improves Embryo Recovery in Mares

Microorganisms, including pathogenic or opportunistic bacteria and fungi, may gain access to the uterus during breeding, and infectious endometritis plays a major role in equine subfertility. This study aimed to assess the post-breeding inflammatory response, endometrial culture, and embryo recovery of mares susceptible to persistent breeding-induced endometritis (PBIE) treated with plasma-rich (PRP) or -poor (PPP) plasma. Mares (n = 12) susceptible to PBIE had three cycles randomly assigned to receive intrauterine infusions of lactate ringer solution (LRS, control), or autologous PRP or PPP pre- (−48 and −24 h) and post-breeding (6 and 24 h). Mares were bred with fresh semen from one stallion. Intrauterine fluid accumulation (IUF) and endometrial neutrophils were assessed every 24 h up to 96 h post-breeding. Uterine cytokines (Ilβ, IL6, CXCL8, and IL10) were evaluated before (0 h), 6, and 24 h post-breeding, and endometrial culture three and nine days after breed. Embryo flushing was performed 8 days post-ovulation. Data were analyzed with mixed model, Tukey’s post-hoc test, and multivariate regression. PRP treatment reduced endometrial neutrophils, post-breeding IUF, and pro-inflammatory cytokines when compared to control-assigned cycles, but not significantly different than PPP. Controls had a significantly higher percentage of positive bacterial cultures (33%) in comparison to PRP-assigned cycles (0%), whereas cycles treated with PPP were not significantly different from the other groups (25%). The PRP-assigned cycles had significantly greater embryo recovery rates (83%) than the control (33%), though not significantly different than PPP (60%). Plasma infusion reduced the duration and intensity of the post-breeding inflammatory response and improved embryo recovery in mares susceptible to PBIE. Platelets incrementally downregulate PBIE and appear to have a dose-dependent antimicrobial property

Iontophoresis on minoxidil sulphate-loaded chitosan nanoparticles accelerates drug release, decreasing their targeting effect to hair follicles

The experiments described in this paper tested the hypothesis whether iontophoresis applied on a chitosan nanoparticle formulation could combine the enhanced drug accumulation into the follicular casts obtained using iontophoresis and the sustained drug release, reducing dermal exposure, provided by nanoparticles. Results showed that even though iontophoresis presented comparable minoxidil targeting potential to hair follicles than passive delivery of chitosan-nanoparticles (4.1 ± 0.9 and 5.3 ± 1.0 µg cm-2, respectively), it was less effective on preventing dermal exposure, since chitosan-nanoparticles presented a drug permeation in the receptor solution of 15.3 ± 4.3 µg cm-2 after 6 h of iontophoresis, while drug amounts from passive nanoparticle delivery were not detected. Drug release experiments showed particles were not able to sustain the drug release under the influence of a potential gradient. In conclusion, the application of MXS-loaded chitosan nanoparticles remains the best way to target MXS to the hair follicles while preventing dermal exposure