Efficacy and Mechanism of Action of Marine Alkaloid 3,10-Dibromofascaplysin in Drug-Resistant Prostate Cancer Cells

Efficacy and mechanism of action of marine alkaloid 3,10-dibromofascaplysin (DBF) were investigated in human prostate cancer (PCa) cells harboring different levels of drug resistance. Anticancer activity was observed across all cell lines examined without signs of cross-resistance to androgen receptor targeting agents (ARTA) or taxane based chemotherapy. Kinome analysis followed by functional investigation identified JNK1/2 to be one of the molecular targets of DBF in 22Rv1 cells. In contrast, no activation of p38 and ERK1/2 MAPKs was observed. Inhibition of the drug-induced JNK1/2 activation or of the basal p38 activity resulted in increased cytotoxicity of DBF, whereas an active ERK1/2 was identified to be important for anticancer activity of the alkaloid. Synergistic effects of DBF were observed in combination with PARP-inhibitor olaparib most likely due to the induction of ROS production by the marine alkaloid. In addition, DBF intensified effects of platinum-based drugs cisplatin and carboplatin, and taxane derivatives docetaxel and cabazitaxel. Finally, DBF inhibited AR-signaling and resensitized AR-V7-positive 22Rv1 prostate cancer cells to enzalutamide, presumably due to AR-V7 down-regulation. These findings propose DBF to be a promising novel drug candidate for the treatment of human PCa regardless of resistance to standard therapy.     

Identification of seed protein and oil related QTL in 944 RILs from a diallel of early-maturing European soybean

Soybean[Glycine max(L.)Merr.]is a global protein source and is currently expanding in Central and Northern Europe.Protein and oil content are two important quality traits that have been studied in different germplasm,however,their genetic architecture in earlymaturing European soybean has not been investigated yet.In this study,we therefore performed QTL mapping for both traits using 944 recombinant inbred lines derived from eight families from a half-diallel crossing design.We identified five QTL for each trait,with the QTL on chromosomes 8,15,and 20 being identified for both protein content and oil content.The known major QTL on chromosome 20 was detected in four families whereas the other QTL were only found in single families.Further analyses revealed the QTL to have pleiotropic but inverse effects on both traits.The effect of the major QTL was comparable between families,illustrating that it is largely independent from the genetic background.Collectively,our results illustrate the quantitative nature of protein and oil content in early European soybean.Marker-assisted selection for the QTL is possible,but the inverse effect on protein and oil content should be kept in mind.     

Study of Structure–Activity Relationships of the Marine Alkaloid Fascaplysin and Its Derivatives as Potent Anticancer Agents

Marine alkaloid fascaplysin and its derivatives are known to exhibit promising anticancer properties in vitro and in vivo. However, toxicity of these molecules to non-cancer cells was identified as a main limitation for their clinical use. Here, for the very first time, we synthesized a library of fascaplysin derivatives covering all possible substituent introduction sites, i.e., cycles A, C and E of the 12H-pyrido[1-2-a:3,4-b’]diindole system. Their selectivity towards human prostate cancer versus non-cancer cells, as well as the effects on cellular metabolism, membrane integrity, cell cycle progression, apoptosis induction and their ability to intercalate into DNA were investigated. A pronounced selectivity for cancer cells was observed for the family of di- and trisubstituted halogen derivatives (modification of cycles A and E), while a modification of cycle C resulted in a stronger activity in therapy-resistant PC-3 cells. Among others, 3,10-dibromofascaplysin exhibited the highest selectivity, presumably due to the cytostatic effects executed via the targeting of cellular metabolism. Moreover, an introduction of radical substituents at C-9, C-10 or C-10 plus C-3 resulted in a notable reduction in DNA intercalating activity and improved selectivity. Taken together, our research contributes to understanding the structure–activity relationships of fascaplysin alkaloids and defines further directions of the structural optimization.     

Impact of agricultural subsidies on biodiversity at the landscape level

Agricultural management is a major factor driving the change of faunal richness in anthropogenic landscapes. Thus, there is an urgent need to develop tools that allow decision-makers to understand better intended and unintended effects of agricultural policy measures on biodiversity. Here we demonstrate the potential of such a tool by combining a socio-economic model with the biodiversity model GEPARD to forecast the response of bird and carabid species richness to two scenarios of agricultural subsidies: (1) subsidies based on production levels and prices and (2) direct income support that is independent of production levels. We focussed on farmland of the Lahn-Dill area, Germany, as an example of European regions with low intensity farming. GEPARD predicts faunal richness and is based on multi-scaled resource-selection functions. Under both scenarios the area of predicted losses in species richness of birds and carabids was larger than the area of predicted gains in species richness. However, the area with predicted losses of avian richness was smaller under the direct income support scenario than under the production-based subsidy scenario, whereas the area with predicted losses of carabid species richness was smaller under the production-based subsidy scenario than under the direct income support. Yet locally, richness gains of up to four species were predicted for carabids under both scenarios. We conclude that the sometimes contrasting and heterogeneous responses of birds and carabids at different localities suggest the need for spatially targeted subsidy schemes. With the help of the GIS-based approach presented in this study, prediction maps on potential changes in local and regional species richness can be easily generated.     

天然生长促进剂在畜禽饲料中的应用前景

天然生长促进剂之所以能促进动物的生长,主要是因为它们能够促进肠道有益菌的生长,这样就能够保护宿主动物免受病原菌的侵害,并能缓解动物遭受的应激。     

TEMPOROMANDIBULAR JOINT MORPHOLOGY IN CAVALIER KING CHARLES SPANIELS

Temporomandibular joint dysplasia has been reported in several breeds of dog. Three Cavalier King Charles Spaniel (CKCS) skulls were examined and radiographed during the course of a separate study and all demonstrated changes consistent with bilateral temporomandibular joint dysplasia. Subsequently, skull radiographs from all CKCS dogs examined at the University of Glasgow Veterinary School between 1991 and 2001 were reviewed (n = 26). Only two of these dogs were radiographed specifically for investigation of the temporomandibular joint, although varying degrees of dysplasia were identified in all dogs where the joints were adequately visualized (n = 20). The head of four CKCS cadavers was also radiographed, and similar changes were found. This finding suggests that temporomandibular joint dysplasia is a widespread asymptomatic condition in the CKCS and should be regarded as a normal morphologic variation rather than a pathologic anomaly. Subtle changes are best seen on lateral oblique radiographs, although marked changes are also visible on dorsoventral views. The rotational angle or angle of articulation of each of the dysplastic mandibular condyles was measured and was related to the severity of the dysplastic changes. However, there was overlap between the values calculated for these abnormal joints and normal ones in other breeds, suggesting this measurement was of limited significance and the shape of the components of the temporomandibular joint are more relevant when assessing this joint for the presence of dysplastic changes.     

A new dissection technique for approach to right-sided intrahepatic portosystemic shunts: anatomic study and use in three dogs

OBJECTIVE : To determine the feasibility of indirect suture passage around the right portal vein for attenuation of right-sided intrahepatic portosystemic shunts (IHPSS). STUDY DESIGN : Anatomic study of cadavers and prospective evaluation of clinical cases. ANIMALS : Nine canine cadavers (median weight, 20.5 kg) and 6 client-owned dogs suspected of having right-sided IHPSS. METHODS : Silicone casts of the caudal vena cava and pre- and intrahepatic portal veins were made in fresh canine cadavers. A suture was passed dorsal to the portal vein above and below its bifurcation and pulled laterally so that it surrounded the right portal vein. The number and size of portal and caudal vena cava branches that interfered with the suture passage were recorded. Intra- and postoperative complications were evaluated in 3 dogs with right-sided IHPSS and 3 dogs suspected of having right-sided IHPSS that had right portal vein dissection and occlusion using this technique. RESULTS : Suture passage and placement around the right portal vein were easily accomplished in all 9 specimens. A 1 mm branch from the dorsal surface of the right portal vein was included in the encircling ligature in 4 specimens. The dissection technique was used successfully in 3 dogs with right-sided IHPSS and 2 other clinical cases. The portal branch to the papillary process of the caudate lobe interfered with suture placement in 1 dog with a central IHPSS. CONCLUSIONS : Indirect suture passage for ligation of the right portal vein can be successfully performed in normal dogs and dogs with congenital portosystemic shunts. CLINICAL RELEVANCE : Hemorrhage, vascular trauma, and surgery time may be reduced using this technique for attenuation of right-sided IHPSS.     

Effects of doxapram HCl on laryngeal function of normal dogs and dogs with naturally occurring laryngeal paralysis

OBJECTIVES: To compare the effects of IV doxapram on glottic size and arytenoid motion in normal dogs and in dogs with laryngeal paralysis. STUDY DESIGN: Prospective experimental and clinical trials. ANIMALS: Six healthy dogs weighing 24.5 +/- 3.9 kg and six dogs weighing 27.4 +/- 11.5 kg suspected of having laryngeal paralysis. METHODS: Dogs were pre-medicated with acepromazine and butorphanol, and a light plane of anesthesia was induced with isoflurane by mask. Videoendoscopic examination of laryngeal function was recorded before (baseline) and after IV doxapram administration. Normalized glottal gap area (NGGA) at maximal inspiration and expiration, and percentage change in height, width, area, and NGGA were calculated with measurements from digitized images of the glottal gap. RESULTS: Active arytenoid motion was present in all normal dogs at baseline. After doxapram administration, depth of respiration appeared greater, but arytenoid motion, as measured by percentage change in NGGA, and in area and width, did not significantly increase in normal dogs. No arytenoid motion was detected in dogs with laryngeal paralysis at baseline; however, rima glottidis NGGA of dogs with laryngeal paralysis was greater at inspiration and expiration than normal dogs. After doxapram administration, dogs with laryngeal paralysis developed paradoxical arytenoid motion and significant, negative percentage change in area (-61%) and NGGA (-145%) because of inward collapse of the arytenoids during inspiration. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of doxapram during laryngeal examination is useful for differentiating normal dogs from dogs with laryngeal paralysis. Dogs with laryngeal paralysis may suffer extreme glottic constriction with vigorous respirations, and may require intubation during examination.     

Anchorage of mature conifers: resistive turning moment, root-soil plate geometry and root growth orientation

Eighty-four mature Norway spruce (Picea abies L. Karst), silver fir (Abies alba Mill) and Scots pine (Pinus sylvestris L.) trees were winched over to determine the maximum resistive turning moment (M(a)) of the root-soil system, the root-soil plate geometry, the azimuthal orientation of root growth, and the occurrence of root rot. The calculation of M(a), based on digital image tracking of stem deflection, accounted not only for the force application and its changing geometry, but also for the weight of the overhanging tree, representing up to 42% of M(a). Root rot reduced M(a) significantly and was detected in 25% of the Norway spruce and 5% of the silver fir trees. Excluding trees with root rot, differences in M(a) between species were small and insignificant. About 75% of the variance in M(a) could be explained by one of the four variables--tree mass, stem mass, stem diameter at breast height squared times tree height, and stem diameter at breast height squared. Among the seven allometric variables assessed above ground, stem diameter at breast height best described the root-soil plate dimensions, but the correlations were weak and the differences between species were insignificant. The shape of the root-soil plate was well described by a depth-dependent taper model with an elliptical cross section. Roots displayed a preferred azimuthal orientation of growth in the axis of prevailing winds, and the direction of frequent weak winds matched the orientation of growth better than that of rare strong winds. The lack of difference in anchorage parameters among species probably reflects the similar belowground growth conditions of the mature trees.     

Occurrence of rift valley fever in cattle in Ijara district,Kenya

Ijara district in Kenya was one of the hotspots of rift valley fever (RVF) during the 2006/2007 outbreak which led to human and animal deaths causing huge economic and public health losses. The main constraint in the control and prevention of RVF is inadequate knowledge on its occurrence during the interepidemic period. This study was aimed at understanding the occurrence of RVF in cattle in Ijara to enable the development of improved community-based disease surveillance, prediction, control and prevention.