The effect of pressure on the growth of tumour cell colonies

This paper describes some experiments on the manner in which external pressure affects cell colony growth in general, and tumour growth in particular. More precisely, our results show that cell colony borders growing under high-pressure conditions have geometrical and dynamical properties that are markedly different from those corresponding to growth under homeostatic, normal pressure conditions. These behaviours are characterized by means of the so-called dynamical exponents of each type of growth. These are shown to correspond to statistical properties of solutions of some stochastic partial differential equations that account for the evolution of the interface between the expanding colony and the surrounding medium.     

华南丘陵地区农林复合生态系统晚稻田甲烷和氧化亚氮排放

采用静态箱-气相色谱法对晚稻田甲烷(CH4)和氧化亚氮(N2O)排放进行田间原位测定。结果表明,有植株参与的稻田CH4排放通量季节变化与地下5cm温度呈显著正相关关系。稻田CH4和N2O季节平均排放通量在有植株参与时分别为1.16±0.38mgm-2h-1和42.33±20.00μgm-2h-1,而无植株参与的分别为0.15±0.11mgm-2h-1和51.69±15.87μgm-2h-1。水稻种植对CH4的排放影响较大,对N2O的排放影响较小,有植株参与的稻田CH4平均排放量显著高于无植株参与的稻田,N2O的平均排放量无显著差异。     

Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention

Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell growth, differentiation, and survival. This absolute requirement for polyamines and the need to maintain intracellular levels within specific ranges require a highly regulated metabolic pathway primed for rapid changes in response to cellular growth signals, environmental changes, and stress. Although the polyamine metabolic pathway is strictly regulated in normal cells, dysregulation of polyamine metabolism is a frequent event in cancer. Recent studies suggest that the polyamine catabolic pathway may be involved in the etiology of some epithelial cancers. The catabolism of spermine to spermidine utilizes either the one-step enzymatic reaction of spermine oxidase (SMO) or the two-step process of spermidine/spermine N ¹-acetyltransferase (SSAT) coupled with the peroxisomal enzyme N ¹-acetylpolyamine oxidase. Both catabolic pathways produce hydrogen peroxide and a reactive aldehyde that are capable of damaging DNA and other critical cellular components. The catabolic pathway also depletes the intracellular concentrations of spermidine and spermine, which are free radical scavengers. Consequently, the polyamine catabolic pathway in general and specifically SMO and SSAT provide exciting new targets for chemoprevention and/or chemotherapy.     

Interactions between cognitive and sensory load while planning and controlling complex gait adaptations in Parkinson’s disease

Background

Recent research has argued that removal of relevant sensory information during the planning and control of simple, self-paced walking can result in increased demand on central processing resources in Parkinson’s disease (PD). However, little is known about more complex gait tasks that require planning of gait adaptations to cross over an obstacle in PD.

Methods

In order to understand the interaction between availability of visual information relevant for self-motion and cognitive load, the current study evaluated PD participants and healthy controls while walking toward and stepping over an obstacle in three visual feedback conditions: (i) no visual restrictions; (ii) vision of the obstacle and their lower limbs while in complete darkness; (iii) vision of the obstacle only while in complete darkness; as well as two conditions including a cognitive load (with a dual task versus without a dual task). Each walk trial was divided into an early and late phase to examine changes associated with planning of step adjustments when approaching the obstacle.

Results

Interactions between visual feedback and dual task conditions during the obstacle approach were not significant. Patients with PD had greater deceleration and step time variability in the late phase of the obstacle approach phase while walking in both dark conditions compared to control participants. Additionally, participants with PD had a greater number of obstacle contacts when vision of their lower limbs was not available specifically during the dual task condition. Dual task performance was worse in PD compared to healthy control participants, but notably only while walking in the dark regardless of visual feedback.

Conclusions

These results suggest that reducing visual feedback while approaching an obstacle shifts processing to somatosensory feedback to guide movement which imposes a greater demand on planning resources. These results are key to fully understanding why trips and falls occur in those with PD.

     

Multivalent nanobodies targeting death receptor 5 elicit superior tumor cell killing through efficient caspase induction

Multiple therapeutic agonists of death receptor 5 (DR5) have been developed and are under clinical evaluation. Although these agonists demonstrate significant anti-tumor activity in preclinical models, the clinical efficacy in human cancer patients has been notably disappointing. One possible explanation might be that the current classes of therapeutic molecules are not sufficiently potent to elicit significant response in patients, particularly for dimeric antibody agonists that require secondary cross-linking via Fcγ receptors expressed on immune cells to achieve optimal clustering of DR5. To overcome this limitation, a novel multivalent Nanobody approach was taken with the goal of generating a significantly more potent DR5 agonist. In the present study, we show that trivalent DR5 targeting Nanobodies mimic the activity of natural ligand, and furthermore, increasing the valency of domains to tetramer and pentamer markedly increased potency of cell killing on tumor cells, with pentamers being more potent than tetramers in vitro. Increased potency was attributed to faster kinetics of death-inducing signaling complex assembly and caspase-8 and caspase-3 activation. In vivo, multivalent Nanobody molecules elicited superior anti-tumor activity compared to a conventional DR5 agonist antibody, including the ability to induce tumor regression in an insensitive patient-derived primary pancreatic tumor model. Furthermore, complete responses to Nanobody treatment were obtained in up to 50% of patient-derived primary pancreatic and colon tumor models, suggesting that multivalent DR5 Nanobodies may represent a significant new therapeutic modality for targeting death receptor signaling.     

Membrane Potential and Catecholamine Secretion by Bovine Adrenal Chromaffin Cells: Use of Tetraphenylphosphonium Distribution and Carbocyanine Dye Fluorescence

Changes in plasma membrane potential of isolated bovine adrenal chromaffin cells were measured independently by two chemical probe methods and related to corresponding effects on catecholamine secretion. The lipophilic cation tetraphenylphosphonium (TPP+) and the carbocyanine dye 3,3'-dipropylthiadicarbocyanine [DiS-C3-(5)] were used. The necessity of evaluating the subcellular distribution of TPP+ among cytoplasmic, mitochondrial, secretory granule, and bound compartments was demonstrated and the resting plasma membrane potential determined to be -55 mV. The relationship between membrane potential and catecholamine secretion was determined in response to variations in extracellular K+ and to the presence of several secretagogues including cholinergic receptor ligands, veratridine, and ionophores for Na+ and K+. The dependence of potential on K+ concentration fit the Goldman constant field equation with a Na/K permeability ratio of 0.1. The dependence of both K+- and veratridine-evoked catecholamine secretion on membrane potential exhibited a potential threshold of about -40 mV before a significant rise in secretion occurred. This is likely related to the threshold for opening of voltage-sensitive Ca2+ channels. Acetylcholine and nicotine evoked a large secretory response without a sufficiently sustained depolarization to be detectable by the relatively slow potential sensitive chemical probes. Decamethonium induced a detectable depolarization of the chromaffin cells. Veratridine and gramicidin evoked both membrane depolarization and catecholamine release. By contrast the K ionophore valinomycin evoked significant levels of secretion without any depolarization. This is consistent with its utilization of an intracellular source of Ca2+ and the independence of its measured secretory response on extracellular Ca2+.     

Coupling of the polyamine and iron metabolism pathways in the regulation of proliferation: Mechanistic links to alterations in key polyamine biosynthetic and catabolic enzymes

Many biological processes result from the coupling of metabolic pathways. Considering this, proliferation depends on adequate iron and polyamines, and although iron-depletion impairs proliferation, the metabolic link between iron and polyamine metabolism has never been thoroughly investigated. This is important to decipher, as many disease states demonstrate co-dysregulation of iron and polyamine metabolism. Herein, for the first time, we demonstrate that cellular iron levels robustly regulate 13 polyamine pathway proteins. Seven of these were regulated in a conserved manner by iron-depletion across different cell-types, with four proteins being down-regulated (i.e., acireductone dioxygenase 1 [ADI1], methionine adenosyltransferase 2α [MAT2α], Antizyme and polyamine oxidase [PAOX]) and three proteins being up-regulated (i.e., S-adenosyl methionine decarboxylase [AMD1], Antizyme inhibitor 1 [AZIN1] and spermidine/spermine-N¹-acetyltransferase 1 [SAT1]). Depletion of iron also markedly decreased polyamine pools (i.e., spermidine and/or spermine, but not putrescine). Accordingly, iron-depletion also decreased S-adenosylmethionine that is essential for spermidine/spermine biosynthesis. Iron-depletion additionally reduced ³H-spermidine uptake in direct agreement with the lowered levels of the polyamine importer, SLC22A16. Regarding mechanism, the “reprogramming” of polyamine metabolism by iron-depletion is consistent with the down-regulation of ADI1 and MAT2α, and the up-regulation of SAT1. Moreover, changes in ADI1 (biosynthetic) and SAT1 (catabolic) partially depended on the iron-regulated changes in c-Myc and/or p53. The ability of iron chelators to inhibit proliferation was rescuable by putrescine and spermidine, and under some conditions by spermine. Collectively, iron and polyamine metabolism are intimately coupled, which has significant ramifications for understanding the integrated role of iron and polyamine metabolism in proliferation.