Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function inflammed tissues

Activated T cells must mediate effector responses sufficient to clear pathogens while avoiding excessive tissue damage. Here we have combined dynamic intravital microscopy with ex vivo assessments of T cell cytokine responses to generate a detailed spatiotemporal picture of CD4+ T cell effector regulation in the skin. In response to antigen, effector T cells arrested transiently on antigen presenting cells, briefly producing cytokine and then resuming migration. Antigen recognition led to PD-1 upregulation of the programmed death-1 (PD-1) glycoprotein by T cells and blocking its canonical ligand, programmed death-ligand 1 (PD-L1), lengthened the duration of migration arrest and cytokine production, showing that PD-1 interaction with PD-L1 is a major negative feedback regulator of antigen responsiveness. We speculate that the immune system employs a mechanism involving T cell recruitment, transient activation, and rapid desensitization, allowing the T cell response to rapidly adjust to changes in antigen presentation and minimize collateral injury to the host

Investigating the Effect of Mechanical Activation Parameters on Structural Changes and Leaching Rate of Molybdenite Concentrate

AbstractIn this research, mechanical activation (MA) was employed for leaching rate improvement of molybdenite concentrate in nitric acid media. These experiments were performed in two groups: with and without aluminum oxide (alumina). A full factorial design was used for each group of experiments. Leaching rate increment up to 5 times was observed only in 2hours activation procedure. XRD analysis demonstrated structural disordering in activated MoS2. TEM images showed that particle size has been reduced to nanoscale. The initial powder size was 80% between 2-44μm and dropped to about 10nm and 140nm in MA experiments with and without alumina, respectively. This size reduction would be the main reason of leaching rate enhancement which is more achievable in MA in presence of alumina. The results demonstrate that alumina has a motivating effect in activation procedure to achieve a nanostructure molybdenite. Analysis of variance revealed milling speed is the main parameter in MA without alumina, while, ball to powder ratio is the most important factor in MA procedure in presence of alumina on leaching rate

Utjecaj hidroksiapatita na cijeljenje prijeloma kostiju dijabetičnih štakora: biomehanička i radiografska istraživanja

Patients with diabetes mellitus incur a high incidence of fractures. This suggests that the structural integrity of the skeletal system may be compromised. This study was conducted to evaluate the effects of hydroxyapatite (HA) on fracture healing in diabetic rats by biomechanical and radiographic methods. Twenty-four adult male rats were randomly divided into four identical groups. Diabetes was chemically induced in 2 groups by alloxan. After 2 weeks, all the rats were anesthetized and a transverse osteotomy of the right radius was performed under aseptic conditions. In one diabetic and one non-diabetic group, the osteotomy gap was filled with HA while the other 2 groups did not receive HA. Radiographs were taken at 0, 15 and 35 days post operation. All the rats were euthanized 5 weeks post operation, and the radial bones were harvested and prepared for the threepoint bending test. Comparison between the HA treated groups (diabetic and non diabetic), demonstrated that diabetes significantly reduced the capacity of bone to loaded bending forces. The non-treated diabetic group showed fewer radiographic signs of union and remodeling of fractures in comparison with the other three groups. In conclusion the diabetic rats that did not receive HA exhibited inferior biomechanical properties and radiographic signs in comparison with the HA treated groups and the negative control group.Pacijenti sa šećernom bolešću često trpe od prijeloma kostiju. To govori da strukturna cjelovitost koštanoga sustava može biti narušena. Ovo istraživanje poduzeto je radi procjene učinaka hidroksiapatita (HA) na cijeljenje prijeloma kostiju u dijabetičnih štakora uporabom biomehaničkih i radiografskih metoda. Ukupno su 24 štakora bila nasumce podijeljena u četiri jednake skupine. U dvjema skupinama dijabetes je bio kemijski potaknut aloksanom. Nakon dva tjedna svi su štakori bili anestezirani te im je pod septičkim uvjetima učinjena transverzalna osteotomija desnog radiusa. Prostor između odlomaka nakon osteotomije štakorima jedne dijabetične i jedne nedijabetične skupine bio je ispunjen hidroksiapatitom dok štakorima drugih dviju skupina hidroksiapatit nije bio primijenjen. Radiografske snimke bile su uzete 0., 15. i 35. dana nakon operacije. Svi su štakori bili eutanazirani pet tjedana nakon operacije te su im uzete radijalne kosti za trotočkasti test savijanja. Usporedba između skupina obrađivanih hidroksiapatitom (dijabetičnih i nedijabetičnih) pokazala je da dijabetes značajno smanjuje sposobnost savijanja kostiju pri opterećenju. Neobrađivana dijabetična skupina pokazivala je manje radiografskih znakova spajanja i ponovnog cijeljenja prijeloma u usporedbi s drugim trima skupinama. Zaključno se može reći da su štakori kojima hidroksiapatit nije bio primijenjen pokazivali slabija biomehanička svojstva i radiografske znakove u usporedbi s onima kojima je bio primijenjen i onima iz kontrolne skupine

Using a novel concept to measure outcomes in solid organ recipients provided promising results

Objectives: Efforts to evaluate the health of solid organ transplant recipients are hampered by the lack of adequate patient-reported outcome measures (PROMs) targeting this group. We developed the Transplant ePROM (TXP), which is based on a novel measurement model and administered through a mobile application to fill this gap. The main objective of this article is to elucidate how we derived the weights for different items, and to report initial empirical results. Study design and setting: The nine health items in the TXP were fatigue, skin, worry, self-reliance, activities, weight, sexuality, stooling, and memory. Via an online survey solid organ recipient participating in the TransplantLines Biobank and Cohort study (NCT03272841) were asked to describe and then compare their own health state with six other health states. Coefficients for item levels were obtained using a conditional logit model. Results: A total of 232 solid organ transplant recipients (mean age: 54 years) participated. The majority (106) were kidney recipients, followed by lung, liver, and heart recipients. Fatigue was the most frequent complaint (54%). The strongest negative coefficients were found for activities and worry, followed by self-reliance and memory. Conclusion: A set of coefficients and values were developed for TXP. The TXP score approximated an optimal health state for the majority of respondents and recipients of different organs reported comparable health states. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

A Scoping Review of Key Health Items in Self-Report Instruments Used Among Solid Organ Transplant Recipients

The overall aim of this scoping review of the literature is twofold: (1) to provide an overview of all instruments that have been used to assess health-related quality of life (HRQoL) after solid organ transplantation and (2) to provide a list of health items they include to support future studies on the development of a new-generation HRQoL instrument. All studies that administered any form of HRQoL instrument to post-transplant solid organ recipients were identified in a comprehensive search of PubMed (MEDLINE), Embase, and Web of Science, with a cut-off date of May 2018. The search used various combinations of the following keywords: lung, heart, liver, kidney, or pancreas transplantation; quality of life; well-being; patient-reported outcome; instrument; questionnaire; and health survey. In total, 8013 distinct publications were identified and 1218 of these were selected for review. Among the instruments applied, 53 measured generic, 51 organ-specific, 271 domain-specific, and 43 transplant-specific HRQoL. A total of 78 distinct health items grouped into 16 sub-domains were identified and depicted graphically. The majority of publications did not report a logical rationale for the choice of specific HRQoL instrument. The most commonly used types of instruments were generic health instruments, followed by domain-specific instruments. Despite the availability of transplant-specific instruments, few studies applied these types of instruments. Based on the 78 items, further research is planned to develop a patient-centered, transplant-specific HRQoL instrument that is concise, easy to apply (mobile application), and specifically related to the health issues of solid organ recipients

Cellular and Matrix Mechanics of Bioartificial Tissues During Continuous Cyclic Stretch

Bioartificial tissues are useful model systems for studying cell and extra-cellular matrix mechanics. These tissues provide a 3D environment for cells and allow tissue components to be easily modified and quantified. In this study, we fabricated bioartificial tissue rings from a 1 ml solution containing one million cardiac fibroblasts and 1 mg collagen. After 8 days, rings compacted to <1% of original volume and cell number increased 2.4 fold. We initiated continuous cyclic stretching of the rings after 2, 4, or 8 days of incubation, while monitoring the tissue forces. Peak tissue force during each cycle decreased rapidly after initiating stretch, followed by further slow decline. We added 2 μM Cytochalasin-D to some rings prior to initiation of stretch to determine the force contributed by the matrix. Cell force was estimated by subtracting matrix force from tissue force. After 12 h, matrix force-strain curves were highly nonlinear. Cell force-strain curves were linear during loading and showed hysteresis indicating viscoelastic behavior. Cell stiffness increased with stretching frequency from 0.001–0.25 Hz. Cell stiffness decreased with stretch amplitude (5–25%) at 0.1 Hz. The trends in cell stiffness do not fit simple viscoelastic models previously proposed, and suggest possible strain-amplitude related changes during cyclic stretch

Calculation of the efficacy of vaccines against tick infestations on cattle

Articles in International JournalsCattle ticks are responsible for great economic losses in cattle farming worldwide, and their main control method, chemicals, has been showing problems, whether resulting from the development of resistant strains of ticks or environmental contamination. Research studies directed toward developing vaccines against ticks are emerging. One way to evaluate those vaccines is to calculate the percentage of efficacy. The aim of this study was to analyze scientific publications archived in PubMed that used this method of assessment and discuss the main factors that may affect its calculation. Thus, 25 articles addressing this subject were selected. The percentage of efficacy was usually calculated in one of two ways, with one considering the reduced fertility of eggs and the other not. The latter method may underestimate the vaccine efficacy, and the most complete formula for calculating the efficacy reflects how much the vaccine actually affects the infestation. In our view, the use of the complete formula for calculating the percentage of efficacy is broader and more representative of the vaccine effect on the tick population.RESUMO - Carrapatos de bovinos são responsáveis por grandes perdas econômicas para a pecuária bovina mundial e seu principal método de controle, o químico, vem apresentando problemas, seja pelo desenvolvimento de amostras de carrapatos resistentes ou pela contaminação ambiental. Na tentativa de diminuir a utilização dos acaricidas, surgem pesquisas direcionadas ao desenvolvimento de vacinas contra carrapatos. Uma maneira de avaliar essas vacinas é pelo cálculo de percentagem de eficácia. O objetivo deste trabalho foi analisar as publicações científicas indexadas no PubMed que utilizaram este método de avaliação e discutir os principais fatores que podem interferir no seu cálculo. Dessa maneira, selecionaram-se 25 artigos que tratavam desse assunto. A percentagem de eficácia apareceu sendo calculada de duas formas, uma considerando a redução da fertilidade dos ovos e a outra não. Essa última pode subestimar a eficiência da vacina, e a fórmula de cálculo da eficácia mais completa representa o quanto da infestação a vacina realmente reduziu. Em nosso entendimento, a utilização da fórmula completa para o cálculo da percentagem de eficácia é mais abrangente e representativa do efeito da vacina na população de carrapatos

Performance evaluation of scheduling policies for the DRCMPSP

In this study, we consider the dynamic resource-constrained multi-project scheduling problem (DRCMPSP) where projects generate rewards at their completion, completions later than a due date cause tardiness costs and new projects arrive randomly during the ongoing project execution which disturbs the existing project scheduling plan. We model this problem as a discrete Markov decision process and explore the computational limitations of solving the problem by dynamic programming. We run and compare four different solution approaches on small size problems. These solution approaches are: a dynamic programming algorithm to determine a policy that maximises the average profit per unit time net of charges for late project completion, a genetic algorithm which generates a schedule to maximise the total reward of ongoing projects and updates the schedule with each new project arrival, a rule-based algorithm which prioritise processing of tasks with the highest processing durations, and a worst decision algorithm to seek a non-idling policy to minimise the average profit per unit time. Average profits per unit time of generated policies of the solution algorithms are evaluated and compared. The performance of the genetic algorithm is the closest to the optimal policies of the dynamic programming algorithm, but its results are notably suboptimal, up to 67.2\%. Alternative scheduling algorithms are close to optimal with low project arrival probability but quickly deteriorate their performance as the probability increases

Resolving the Role of Actoymyosin Contractility in Cell Microrheology

Einstein's original description of Brownian motion established a direct relationship between thermally-excited random forces and the transport properties of a submicron particle in a viscous liquid. Recent work based on reconstituted actin filament networks suggests that nonthermal forces driven by the motor protein myosin II can induce large non-equilibrium fluctuations that dominate the motion of particles in cytoskeletal networks. Here, using high-resolution particle tracking, we find that thermal forces, not myosin-induced fluctuating forces, drive the motion of submicron particles embedded in the cytoskeleton of living cells. These results resolve the roles of myosin II and contractile actomyosin structures in the motion of nanoparticles lodged in the cytoplasm, reveal the biphasic mechanical architecture of adherent cells—stiff contractile stress fibers interdigitating in a network at the cell cortex and a soft actin meshwork in the body of the cell, validate the method of particle tracking-microrheology, and reconcile seemingly disparate atomic force microscopy (AFM) and particle-tracking microrheology measurements of living cells

β-Adrenergic Inhibition of Contractility in L6 Skeletal Muscle Cells

The β-adrenoceptors (β-ARs) control many cellular processes. Here, we show that β-ARs inhibit calcium depletion-induced cell contractility and subsequent cell detachment of L6 skeletal muscle cells. The mechanism underlying the cell detachment inhibition was studied by using a quantitative cell detachment assay. We demonstrate that cell detachment induced by depletion of extracellular calcium is due to myosin- and ROCK-dependent contractility. The β-AR inhibition of L6 skeletal muscle cell detachment was shown to be mediated by the β2-AR and increased cAMP but was surprisingly not dependent on the classical downstream effectors PKA or Epac, nor was it dependent on PKG, PI3K or PKC. However, inhibition of potassium channels blocks the β2-AR mediated effects. Furthermore, activation of potassium channels fully mimicked the results of β2-AR activation. In conclusion, we present a novel finding that β2-AR signaling inhibits contractility and thus cell detachment in L6 skeletal muscle cells by a cAMP and potassium channel dependent mechanism