Synthesis and biological evaluation of colchicine C-ring analogues tethered with aliphatic linkers suitable for prodrug derivatisation

Colchicine was modified at the 10-OCH₃ position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62–99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III β-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.     

It is getting hotter in here: determining and projecting the impacts of global environmental change on drylands

Drylands occupy large portions of the Earth, and are a key terrestrial biome from the socio-ecological point of view. In spite of their extent and importance, the impacts of global environmental change on them remain poorly understood. In this introduction, we review some of the main expected impacts of global change in drylands, quantify research efforts on the topic, and highlight how the articles included in this theme issue contribute to fill current gaps in our knowledge. Our literature analyses identify key under-studied areas that need more research (e.g. countries such as Mauritania, Mali, Burkina Faso, Chad and Somalia, and deserts such as the Thar, Kavir and Taklamakan), and indicate that most global change research carried out to date in drylands has been done on a unidisciplinary basis. The contributions included here use a wide array of organisms (from micro-organisms to humans), spatial scales (from local to global) and topics (from plant demography to poverty alleviation) to examine key issues to the socio-ecological impacts of global change in drylands. These papers highlight the complexities and difficulties associated with the prediction of such impacts. They also identify the increased use of long-term experiments and multidisciplinary approaches as priority areas for future dryland research. Major advances in our ability to predict and understand global change impacts on drylands can be achieved by explicitly considering how the responses of individuals, populations and communities will in turn affect ecosystem services. Future research should explore linkages between these responses and their effects on water and climate, as well as the provisioning of services for human development and well-being.     

A meta-analysis of seaweed impacts on seagrasses: generalities and knowledge gaps

Seagrasses are important habitat-formers and ecosystem engineers that are under threat from bloom-forming seaweeds. These seaweeds have been suggested to outcompete the seagrasses, particularly when facilitated by eutrophication, causing regime shifts where green meadows and clear waters are replaced with unstable sediments, turbid waters, hypoxia, and poor habitat conditions for fishes and invertebrates. Understanding the situations under which seaweeds impact seagrasses on local patch scales can help proactive management and prevent losses at greater scales. Here, we provide a quantitative review of available published manipulative experiments (all conducted at the patch-scale), to test which attributes of seaweeds and seagrasses (e.g., their abundances, sizes, morphology, taxonomy, attachment type, or origin) influence impacts. Weighted and unweighted meta-analyses (Hedges d metric) of 59 experiments showed generally high variability in attribute-impact relationships. Our main significant findings were that (a) abundant seaweeds had stronger negative impacts on seagrasses than sparse seaweeds, (b) unattached and epiphytic seaweeds had stronger impacts than 'rooted' seaweeds, and (c) small seagrass species were more susceptible than larger species. Findings (a) and (c) were rather intuitive. It was more surprising that 'rooted' seaweeds had comparatively small impacts, particularly given that this category included the infamous invasive Caulerpa species. This result may reflect that seaweed biomass and/or shading and metabolic by-products like anoxia and sulphides could be lower for rooted seaweeds. In conclusion, our results represent simple and robust first-order generalities about seaweed impacts on seagrasses. This review also documented a limited number of primary studies. We therefore identified major knowledge gaps that need to be addressed before general predictive models on seaweed-seagrass interactions can be build, in order to effectively protect seagrass habitats from detrimental competition from seaweeds.     

Anti-IL-2 treatment impairs the expansion of T(reg) cell population during acute malaria and enhances the Th1 cell response at the chronic disease

Plasmodium chabaudi infection induces a rapid and intense splenic CD4(+) T cell response that contributes to both disease pathogenesis and the control of acute parasitemia. The subsequent development of clinical immunity to disease occurs concomitantly with the persistence of low levels of chronic parasitemia. The suppressive activity of regulatory T (T(reg)) cells has been implicated in both development of clinical immunity and parasite persistence. To evaluate whether IL-2 is required to induce and to sustain the suppressive activity of T(reg) cells in malaria, we examined in detail the effects of anti-IL-2 treatment with JES6-1 monoclonal antibody (mAb) on the splenic CD4(+) T cell response during acute and chronic P. chabaudi AS infection in C57BL/6 mice. JES6-1 treatment on days 0, 2 and 4 of infection partially inhibits the expansion of the CD4(+)CD25(+)Foxp3(+) cell population during acute malaria. Despite the concomitant secretion of IL-2 and expression of high affinity IL-2 receptor by large CD4(+) T cells, JES6-1 treatment does not impair effector CD4(+) T cell activation and IFN-γ production. However, at the chronic phase of the disease, an enhancement of cellular and humoral responses occurs in JES6-1-treated mice, with increased production of TNF-α and parasite-specific IgG2a antibodies. Furthermore, JES6-1 mAb completely blocked the in vitro proliferation of CD4(+) T cells from non-treated chronic mice, while it further increased the response of CD4(+) T cells from JES6-1-treated chronic mice. We conclude that JES6-1 treatment impairs the expansion of T(reg) cell population during early P. chabaudi malaria and enhances the Th1 cell response in the late phase of the disease.     

Caffeine ingestion reverses the circadian rhythm effects on neuromuscular performance in highly resistance-trained men

Purpose

To investigate whether caffeine ingestion counteracts the morning reduction in neuromuscular performance associated with the circadian rhythm pattern.

Methods

Twelve highly resistance-trained men underwent a battery of neuromuscular tests under three different conditions; i) morning (10:00 a.m.) with caffeine ingestion (i.e., 3 mg kg⁻¹; AM_CAFF trial); ii) morning (10:00 a.m.) with placebo ingestion (AM_PLAC trial); and iii) afternoon (18:00 p.m.) with placebo ingestion (PM_PLAC trial). A randomized, double-blind, crossover, placebo controlled experimental design was used, with all subjects serving as their own controls. The neuromuscular test battery consisted in the measurement of bar displacement velocity during free-weight full-squat (SQ) and bench press (BP) exercises against loads that elicit maximum strength (75% 1RM load) and muscle power adaptations (1 m s⁻¹ load). Isometric maximum voluntary contraction (MVC_LEG) and isometric electrically evoked strength of the right knee (EVOK_LEG) were measured to identify caffeine''s action mechanisms. Steroid hormone levels (serum testosterone, cortisol and growth hormone) were evaluated at the beginning of each trial (PRE). In addition, plasma norepinephrine (NE) and epinephrine were measured PRE and at the end of each trial following a standardized intense (85% 1RM) 6 repetitions bout of SQ (POST).

Results

In the PM_PLAC trial, dynamic muscle strength and power output were significantly enhanced compared with AM_PLAC treatment (3.0%–7.5%; p≤0.05). During AM_CAFF trial, muscle strength and power output increased above AM_PLAC levels (4.6%–5.7%; p≤0.05) except for BP velocity with 1 m s⁻¹ load (p = 0.06). During AM_CAFF, EVOK_LEG and NE (a surrogate of maximal muscle sympathetic nerve activation) were increased above AM_PLAC trial (14.6% and 96.8% respectively; p≤0.05).

Conclusions

These results indicate that caffeine ingestion reverses the morning neuromuscular declines in highly resistance-trained men, raising performance to the levels of the afternoon trial. Our electrical stimulation data, along with the NE values, suggest that caffeine increases neuromuscular performance having a direct effect in the muscle.     

Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS

There are numerous studies describing the signaling mechanisms that mediate oligodendrocyte precursor cell (OPC) proliferation and differentiation, although the contribution of the cellular prion protein (PrP(c)) to this process remains unclear. PrP(c) is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein involved in diverse cellular processes during the development and maturation of the mammalian central nervous system (CNS). Here we describe how PrP(c) influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrP(c) proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyte lineage markers. In addition, numerous NG2-positive cells were observed in cortical regions of adult PrP(c) knockout mice, although no significant changes in myelination can be seen, probably due to the death of surplus cells.     

Miscanthus × giganteus productivity: the effects of management in different environments

Miscanthus × giganteus is a C₄ perennial grass that shows great potential as a high‐yielding biomass crop. Scant research has been published that reports M. × giganteus growth and biomass yields in different environments in the United States. This study investigated the establishment success, plant growth, and dry biomass yield of M. × giganteus during its first three seasons at four locations (Urbana, IL; Lexington, KY; Mead, NE; Adelphia, NJ) in the United States. Three nitrogen rates (0, 60, and 120 kg ha^?1) were applied at each location each year. Good survival of M. × giganteus during its first winter was observed at KY, NE, and NJ (79–100%), and poor survival at IL (25%), due to late planting and cold winter temperatures. Site soil conditions, and growing‐season precipitation and temperature had the greatest impact on dry biomass yield between season 2 (2009) and season 3 (2010). Ideal 2010 weather conditions at NE resulted in significant yield increases (P < 0.0001) of 15.6–27.4 Mg ha^?1 from 2009 to 2010. Small yield increases in KY of 17.1 Mg ha^?1 in 2009 to 19.0 Mg ha^?1 in 2010 could be attributed to excessive spring rain and hot dry conditions late in the growing season. Average M. ×giganteus biomass yields in NJ decreased from 16.9 to 9.7 Mg ha^?1 between 2009 and 2010 and were related to hot dry weather, and poor soil conditions. Season 3 yields were positively correlated with end‐of‐season plant height () and tiller density (). Nitrogen fertilization had no significant effect on plant height, tiller density, or dry biomass yield at any of the sites during 2009 or 2010.     

Membrane composition of jetted lipid vesicles: a Raman spectroscopy study

Microfluidic jetting is a promising method to produce giant unilamellar phospholipid vesicles for mimicking living cells in biomedical studies. We have investigated the chemical composition of membranes of vesicles prepared using this approach by means of Raman scattering spectroscopy. The membranes of all jetted vesicles are found to contain residuals of the organic solvent decane used in the preparation of the initial planar membrane. The decane inclusions are randomly distributed over the vesicle surface area and vary in thickness from a few to several tens of nanometers. Our findings point out that the membrane properties of jetted vesicles may differ considerably from those of vesicles prepared by other methods and from those of living cells. (© 2012 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)