A novel transport and delivery mechanism underpins the effectiveness of prolyl-m-sarcolysyl-p-fluorophenylalanine (PSF) in a human melanoma xenograft nude-mouse model

The alkylating peptide PSF shows very promising results in vitro on different cancer cells but its efficacy in animals has not been assessed. Here we evaluate the efficacy of PSF in human melanoma-bearing nude mice and examine the underlying mechanism. In melanoma-bearing nude mice, escalating doses of PSF showed dose-dependent responses and reached tumor regression with an optimal dose of 20 mg/kg for 1 month. A comparison of PSF with its free moiety m-sarcolysin and melphalan showed a highly significant advantage of PSF. Furthermore, dose fractionation yielded an even better control of tumor regrowth. In vitro studies unraveled an original delivery mechanism based on the rapid binding of PSF mainly due to red blood cells to form a pro-drug complex and the subsequent release of active metabolites by tumor-associated proteolytic enzymes. Blood kinetics showed one major metabolite partially released over time, while in the presence of melanoma cells three additional metabolites are generated. Interestingly, tumor-shed proteases also induce the production of these metabolites and varying combinations of enzyme inhibitors indicate the involvement of metallo- and other families of proteases in the delivery process. This particular transport and delivery of such an alkylating agent may have several benefits, mainly lowering the drug-free moiety in plasma and at the same time increasing its concentration in protease rich areas such as tumors.     

Immediate Effect of Specific Nostril Manipulating Yoga Breathing Practices on Autonomic and Respiratory Variables

The effect of right, left, and alternate nostril yoga breathing (i.e., RNYB, LNYB, and ANYB, respectively) were compared with breath awareness (BAW) and normal breathing (CTL). Autonomic and respiratory variables were studied in 21 male volunteers with ages between 18 and 45 years and experience in the yoga breathing practices between 3 and 48 months. Subjects were assessed in five experimental sessions on five separate days. The sessions were in fixed possible sequences and subjects were assigned to a sequence randomly. Each session was for 40 min; 30 min for the breathing practice, preceded and followed by 5 min of quiet sitting. Assessments included heart rate variability, skin conductance, finger plethysmogram amplitude, breath rate, and blood pressure. Following RNYB there was a significant increase in systolic, diastolic and mean pressure. In contrast, the systolic and diastolic pressure decreased after ANYB and the systolic and mean pressure were lower after LNYB. Hence, unilateral nostril yoga breathing practices appear to influence the blood pressure in different ways. These effects suggest possible therapeutic applications.     

黄土丘陵沟壑区典型流域径流输沙对土地利用/覆被变化的响应

基于动力水文过程测定技术和景观生态学测度方法,对位于黄土丘陵沟壑区第三副区的甘肃天水罗玉沟流域1986—2004年土地利用/覆被变化对流域径流输沙的影响进行了研究.结果表明：研究期间,罗玉沟流域土地利用/覆被变化对年径流输沙有显著影响,1995—2004年的输沙量比1986—1994年减少约63.0%,且随着年降水量的增多,其减沙效应明显;土地利用/覆被变化对流域径流输沙的影响具有季节性特征,相对于1986—1994年而言,研究区1995—2004年的减沙效应主要集中在5—10月,且月降水越多,后期的月均输沙量较前期减少得越多.降雨和洪峰流量频率分析表明,若具有相同频率分布的雨强,则任一重现期下罗玉沟流域1995—2004年的洪水平均含沙量小于1986—1994年.     

Inhibitory role of neutrophils on influenza virus multiplication in the lungs of mice.

The protective role of neutrophils on intranasal infection of influenza virus was investigated in 3 strains of tumor-bearing mice with neutrophilic leukocytosis. In vitro multiplication of influenza virus was inhibited by neutrophils from both normal and tumor-bearing mice, and the inhibitory effect of neutrophils was augmented by an addition of fMLP to the culture. Pulmonary virus infectivities in the early phase after infection decreased in such ICR and BALB/c mice, and virus elimination in the late phase was accelerated in the ICR mice. However, no decrease in pulmonary virus infectivity was observed in tumor-bearing C57BL/6 mice. Intranasal administration of fMLP into normal and tumor-bearing C57BL/6 mice after infection significantly inhibited the virus propagation in the lungs. The decrease in neutrophil infiltration into the lung in tumor-bearing C57BL/6 mice was confirmed from histological observations of the lung and lung lavage after infection and from analysis of the neutrophil chemotactic activity induced by fMLP. This might be responsible for the high level of pulmonary virus titer in tumor-bearing C57BL/6 mice. Phagocytic activities of alveolar macrophages and productions of neutralizing antibody were suppressed in the 3 strains of tumor-bearing mice. These observations indicated that neutrophils could be significant effector cells as a host defense mechanism against influenza virus infection in vivo, and infiltration and functional activation of neutrophils could play a significant role in virus elimination from the infected site. Furthermore, the inhibition of virus propagation by neutrophils in vitro was almost completely abrogated by an addition of ZnSO4, suggesting that calprotectin could inhibit influenza virus multiplication.     

A possible role for flowering locus T‐encoding genes in interpreting environmental and internal cues affecting olive (Olea europaea L.) flower induction

Olive (Olea europaea L.) inflorescences, formed in lateral buds, flower in spring. However, there is some debate regarding time of flower induction and inflorescence initiation. Olive juvenility and seasonality of flowering were altered by overexpressing genes encoding flowering locus T (FT). OeFT1 and OeFT2 caused early flowering under short days when expressed in Arabidopsis. Expression of OeFT1/2 in olive leaves and OeFT2 in buds increased in winter, while initiation of inflorescences occurred i n late winter. Trees exposed to an artificial warm winter expressed low levels of OeFT1/2 in leaves and did not flower. Olive flower induction thus seems to be mediated by an increase in FT levels in response to cold winters. Olive flowering is dependent on additional internal factors. It was severely reduced in trees that carried a heavy fruit load the previous season (harvested in November) and in trees without fruit to which cold temperatures were artificially applied in summer. Expression analysis suggested that these internal factors work either by reducing the increase in OeFT1/2 expression or through putative flowering repressors such as TFL1. With expected warmer winters, future consumption of olive oil, as part of a healthy Mediterranean diet, should benefit from better understanding these factors.     

Observations of responses to re‐introducing fire in a Basalt Plains grassland after the removal of grazing: Implications for restoration

Natural grasslands in southern Australia commonly exist in altered states. One widespread altered state is grassland pasture dominated by cool‐season (C3) native grasses maintained by ongoing grazing. This study explores the consequences of removing grazing and introducing fire as a conservation management tool for such a site. We examined the abundance of two native and three exotic species, across a mosaic of fire regimes that occurred over a three‐year period: unburnt, summer wild‐fire (>2 years previous), autumn management fire (<1 year previously) and burnt in both fires. Given that one aim of conservation management is to increase native species at the expense of exotics, the impacts of the fires were largely positive. Native grasses were at higher cover levels in the fire‐managed vegetation than in the unburnt vegetation. Of the three exotic species, one was consistently at lower density in the burnt plots compared to the unburnt plots, while the others were lower only in those plots burnt in summer. The results show that the response of a species varies significantly between different fire events, and that the effects of one fire can persist through subsequent fires. Importantly, some of the effects were large, with changes in the density of plants of over 100‐fold. Fire is potentially a cost‐effective tool to assist the ecological restoration of retired grassland pastures at large scales.     

Predictability in community dynamics

The coupling between community composition and climate change spans a gradient from no lags to strong lags. The no‐lag hypothesis is the foundation of many ecophysiological models, correlative species distribution modelling and climate reconstruction approaches. Simple lag hypotheses have become prominent in disequilibrium ecology, proposing that communities track climate change following a fixed function or with a time delay. However, more complex dynamics are possible and may lead to memory effects and alternate unstable states. We develop graphical and analytic methods for assessing these scenarios and show that these dynamics can appear in even simple models. The overall implications are that (1) complex community dynamics may be common and (2) detailed knowledge of past climate change and community states will often be necessary yet sometimes insufficient to make predictions of a community's future state.     

Alternating flow filtration as an alternative to internal spin filter based perfusion process: Impact on productivity and product quality

This article reports the results obtained from comparison of internal spin filter (ISF) and alternating flow filtration (ATF) as cell retention systems, regarding cell growth, volumetric perfusion rate, cell specific perfusion rate and cell productivity in the fermentation process. As expected we were able to reach higher cell densities and to achieve longer runs since ATF systems are known to be less affected by fouling. Volumetric production of the reactor using the ATF system was 50‐70% higher than the production achieved using the ISF due to higher cell density and a two‐fold increase in the perfusion rate. On the other hand, downstream processing performances were evaluated regarding chromatographic steps yields and productivity and quality attributes of the purified materials. Similar results were obtained for all evaluated systems. The fact that we were able to achieve a 2 working volumes (WV)/day perfusion rate using an ATF system as cell retention device allowed us to virtually double the WV of a 25 L reactor. These results constitute valuable data for the optimization of recombinant protein production in perfusion processes since a two‐fold increase in the average production of a manufacturing facility could be easily achieved as long as downstream scale up is possible. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1010–1014, 2017     

Ecological thresholds at the savanna-forest boundary: how plant traits, resources and fire govern the distribution of tropical biomes

Fire shapes the distribution of savanna and forest through complex interactions involving climate, resources and species traits. Based on data from central Brazil, we propose that these interactions are governed by two critical thresholds. The fire-resistance threshold is reached when individual trees have accumulated sufficient bark to avoid stem death, whereas the fire-suppression threshold is reached when an ecosystem has sufficient canopy cover to suppress fire by excluding grasses. Surpassing either threshold is dependent upon long fire-free intervals, which are rare in mesic savanna. On high-resource sites, the thresholds are reached quickly, increasing the probability that savanna switches to forest, whereas low-resource sites are likely to remain as savanna even if fire is infrequent. Species traits influence both thresholds; saplings of savanna trees accumulate bark thickness more quickly than forest trees, and are more likely to become fire resistant during fire-free intervals. Forest trees accumulate leaf area more rapidly than savanna trees, thereby accelerating the transition to forest. Thus, multiple factors interact with fire to determine the distribution of savanna and forest by influencing the time needed to reach these thresholds. Future work should decipher multiple environmental controls over the rates of tree growth and canopy closure in savanna.