Transcranial magnetic stimulation (TMS) provides a unique opportunity to test the causal neurophysiological interactions between interconnnected brain areas. This can be done by applying two coils ...over two different brain areas and deliver subsequent TMS pulses with a certain time interval in the range of few milliseconds (dual-site TMS). In these paradigms, a conditioning stimulus (CS) is first used to activate putative pathways to the motor cortex (M1) from the site of stimulation, while a second, test stimulus (TS), delivered a few ms later probes any changes in excitability that are produced by the input. Dual-site TMS can be used to investigate mechanisms of spike timing dependent plasticity within a certain network. LTP- and LTD-like effects can be induced in M1 following the repeated application of paired pulses over interconnected areas such as contralateral M1, ventral premotor cortex, supplementary motor area or the posterior parietal cortex (PPC). A crucial question is whether dual site TMS effects are limited to M1 or can be used to measure the activity of the other targeted non motor areas. The combination of dual site TMS with electroencephalography (EEG) is a promosing way to overcome these issues (Veniero et al., 2013; Picazio et al., 2014). TMS/EEG allows to measure physiological signals generated at the cortical level by TMS, including those generated in the so-called silent-areas such as PPC and to assess modifications of cortical connectivity.
Mesenchymal stromal cells (MSC) hold promise for both cell replacement and immune modulation strategies owing to their progenitor and non-progenitor functions, respectively. Characterization of MSC ...from different sources is an important and necessary step before clinical use of these cells is widely adopted. Little is known about the biology and function of canine MSC compared to their mouse or human counterparts. This knowledge-gap impedes development of canine evidence-based MSC technologies.
We hypothesized that canine adipose tissue (AT) and bone marrow (BM) MSC (derived from the same dogs) will have similar differentiation and immune modulatory profiles. Our objectives were to evaluate progenitor and non-progenitor functions as well as other characteristics of AT- and BM-MSC including 1) proliferation rate, 2) cell surface marker expression, 3) DNA methylation levels, 4) potential for trilineage differentiation towards osteogenic, adipogenic, and chondrogenic cell fates, and 5) immunomodulatory potency in vitro.
1) AT-MSC proliferated at more than double the rate of BM-MSC (population doubling times in days) for passage (P) 2, AT: 1.69, BM: 3.81; P3, AT: 1.80, BM: 4.06; P4, AT: 2.37, BM: 5.34; P5, AT: 3.20, BM: 7.21). 2) Canine MSC, regardless of source, strongly expressed cell surface markers MHC I, CD29, CD44, and CD90, and were negative for MHC II and CD45. They also showed moderate expression of CD8 and CD73 and mild expression of CD14. Minor differences were found in expression of CD4 and CD34. 3) Global DNA methylation levels were significantly lower in BM-MSC compared to AT-MSC. 4) Little difference was found between AT- and BM-MSC in their potential for adipogenesis and osteogenesis. Chondrogenesis was poor to absent for both sources in spite of adding varying levels of bone-morphogenic protein to our standard transforming growth factor (TGF-β3)-based induction medium. 5) Immunomodulatory capacity was equal regardless of cell source when tested in mitogen-stimulated lymphocyte reactions. Priming of MSC with pro-inflammatory factors interferon-gamma and/or tumour necrosis factor did not increase the lymphocyte suppressive properties of the MSC compared to untreated MSC.
No significant differences were found between AT- and BM-MSC with regard to their immunophenotype, progenitor, and non-progenitor functions. Both MSC populations showed strong adipogenic and osteogenic potential and poor chondrogenic potential. Both significantly suppressed stimulated peripheral blood mononuclear cells. The most significant differences found were the higher isolation success and proliferation rate of AT-MSC, which could be realized as notable benefits of their use over BM-MSC.
There is evidence from human twin and family studies as well as mouse and rat selection experiments that there are considerable interindividual differences in the response of cardiorespiratory ...fitness (CRF) and other cardiometabolic traits to a given exercise programme dose. We developed this consensus statement on exercise response variability following a symposium dedicated to this topic. There is strong evidence from both animal and human studies that exercise training doses lead to variable responses. A genetic component contributes to exercise training response variability.In this consensus statement, we (1) briefly review the literature on exercise response variability and the various sources of variations in CRF response to an exercise programme, (2) introduce the key research designs and corresponding statistical models with an emphasis on randomised controlled designs with or without multiple pretests and post-tests, crossover designs and repeated measures designs, (3) discuss advantages and disadvantages of multiple methods of categorising exercise response levels—a topic that is of particular interest for personalised exercise medicine and (4) outline approaches that may identify determinants and modifiers of CRF exercise response. We also summarise gaps in knowledge and recommend future research to better understand exercise response variability.
All known organisms encode 20 canonical amino acids by base triplets in the genetic code. The cellular translational machinery produces proteins consisting mainly of these amino acids. Several ...hundred natural amino acids serve important functions in metabolism, as scaffold molecules, and in signal transduction. New side chains are generated mainly by post-translational modifications, while others have altered backbones, such as the β- or γ-amino acids, or they undergo stereochemical inversion, e.g., in the case of D-amino acids. In addition, the number of non-canonical amino acids has further increased by chemical syntheses. Since many of these non-canonical amino acids confer resistance to proteolytic degradation, they are potential protease inhibitors and tools for specificity profiling studies in substrate optimization and enzyme inhibition. Other applications include in vitro and in vivo studies of enzyme kinetics, molecular interactions and bioimaging, to name a few. Amino acids with bio-orthogonal labels are particularly attractive, enabling various cross-link and click reactions for structure-functional studies. Here, we cover the latest developments in protease research with non-canonical amino acids, which opens up a great potential, e.g., for novel prodrugs activated by proteases or for other pharmaceutical compounds, some of which have already reached the clinical trial stage.
Summary Objective To estimate the lifetime risk of symptomatic hip osteoarthritis (OA). Design We analyzed data from the Johnston County Osteoarthritis Project a longitudinal population-based study ...of OA in North Carolina, United States ( n = 3068). The weighted baseline sample comprised 18% blacks and 54% women, and the mean age was 63 years (range = 45–93). Symptomatic hip OA was defined as a Kellgren–Lawrence (K–L) radiographic score of ≥2 (anterior–posterior pelvis X-rays) and pain, aching or stiffness on most days, or groin pain, in the same hip. Lifetime risk, defined as the proportion who developed symptomatic hip OA in at least one hip by age 85, among people who live to age 85, was modeled using logistic regression with repeated measures (through generalized estimating equations). Results Lifetime risk of symptomatic hip OA was 25.3% 95% confidence interval (CI) = 21.3–29.3. Lifetime risk was similar by sex, race, highest educational attainment, and hip injury history. We studied lifetime risk by body mass index (BMI) in three forms: at age 18; at baseline and follow-up; and at age 18, baseline and follow-up and found no differences in estimates. Conclusion The burden of symptomatic hip OA is substantial with one in four people developing this condition by age 85. The similar race-specific estimates suggest that racial disparities in total hip replacements are not attributable to differences in disease occurrence. Despite increasing evidence that obesity predicts an increased risk of both hip OA and joint replacement, we found no association between BMI and lifetime risk.
Plant tolerance to insect pests has been indicated to be a unique category of resistance, however, very little information is available on the mechanism of tolerance against insect pests. Tolerance ...is distinctive in terms of the plant's ability to withstand or recover from herbivore injury through growth and compensatory physiological processes. Because plant tolerance involves plant compensatory characteristics, the plant is able to harbor large numbers of herbivores without interfering with the insect pest's physiology or behavior. Some studies have observed that tolerant plants can compensate photosynthetically by avoiding feedback inhibition and impaired electron flow through photosystem II that occurs as a result of insect feeding. Similarly, the up-regulation of peroxidases and other oxidative enzymes during insect feeding, in conjunction with elevated levels of phytohormones can play an important role in providing plant tolerance to insect pests. Hemipteran insects comprise some of the most economically important plant pests (e.g., aphids, whiteflies), due to their ability to achieve high population growth and their potential to transmit plant viruses. In this review, results from studies on plant tolerance to hemipterans are summarized, and potential models to understand tolerance are presented.
The impacts of climate extremes on terrestrial ecosystems are poorly understood but important for predicting carbon cycle feedbacks to climate change. Coupled climate–carbon cycle models typically ...assume that vegetation recovery from extreme drought is immediate and complete, which conflicts with the understanding of basic plant physiology. We examined the recovery of stem growth in trees after severe drought at 1338 forest sites across the globe, comprising 49,339 site-years, and compared the results with simulated recovery in climate-vegetation models. We found pervasive and substantial "legacy effects" of reduced growth and incomplete recovery for 1 to 4 years after severe drought. Legacy effects were most prevalent in dry ecosystems, among Pinaceae, and among species with low hydraulic safety margins. In contrast, limited or no legacy effects after drought were simulated by current climate-vegetation models. Our results highlight hysteresis in ecosystem-level carbon cycling and delayed recovery from climate extremes.
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