A cottonseed oil-enriched diet improves liver and plasma lipid levels in a male mouse model of fatty liver.

A high-fat (HF) diet causes fatty liver, hyperlipidemia, and hypercholesterolemia, and cottonseed oil (CSO) has been shown to improve liver and plasma lipids in human and mouse models. The purpose of this study was to determine the effect of CSO vs. olive oil (OO)-enriched diets on lipid levels in a HF-diet model of fatty liver disease. We placed mice on a HF diet to induce obesity and fatty liver, after which mice were placed on CSO or OO diets, with chow and HF (5.1 kcal/g) groups as control. When CSO- and OO-fed mice were given isocaloric diets with the HF group, there were no differences in body weight, plasma, or hepatic lipids. However, when the CSO and OO diets were reduced in calories (4.0 kcal/g), CSO and OO groups reduced body weight. The CSO group had lower plasma total cholesterol (-56 ± 6%, P < 0.01), free cholesterol (-53 ± 7%, P < 0.01), triglycerides (-61 ± 14%, P < 0.01), and LDL (-42 ± 16%, P = 0.01) vs. HF group whereas the OO diet lowered LDL (-18 ± 12%, P = 0.05) vs. HF. Furthermore, the CSO diet decreased hepatic total cholesterol (-40 ± 12%, P < 0.01), free cholesterol (-23 ± 11%, P = 0.04), and triglycerides (-47 ± 12%, P = 0.02). There were no significant changes in lipogenesis and fatty acid oxidation among the groups. However, the CSO group increased lipid oxidative gene expression in liver and dihydrosterculic acid increased PPARα target genes with in vitro models. Taken together, consuming a reduced calorie diet enriched in CSO reduces liver and plasma lipid profiles in an obese model of fatty liver.

Production of tocotrienols in seeds of cotton (Gossypium hirsutum L.) enhances oxidative stability and offers nutraceutical potential.

Upland cotton (Gossypium hirsutum L.) is an economically important multi-purpose crop cultivated globally for fibre, seed oil and protein. Cottonseed oil also is naturally rich in vitamin E components (collectively known as tocochromanols), with α- and γ-tocopherols comprising nearly all of the vitamin E components. By contrast, cottonseeds have little or no tocotrienols, tocochromanols with a wide range of health benefits. Here, we generated transgenic cotton lines expressing the barley (Hordeum vulgare) homogentisate geranylgeranyl transferase coding sequence under the control of the Brassica napus seed-specific promoter, napin. Transgenic cottonseeds had ~twofold to threefold increases in the accumulation of total vitamin E (tocopherols + tocotrienols), with more than 60% γ-tocotrienol. Matrix assisted laser desorption ionization-mass spectrometry imaging showed that γ-tocotrienol was localized throughout the transgenic embryos. In contrast, the native tocopherols were distributed unequally in both transgenic and non-transgenic embryos. α- Tocopherol was restricted mostly to cotyledon tissues and γ-tocopherol was more enriched in the embryonic axis tissues. Production of tocotrienols in cotton embryos had no negative impact on plant performance or yield of other important seed constituents including fibre, oil and protein. Advanced generations of two transgenic events were field grown, and extracts of transgenic seeds showed increased antioxidant activity relative to extracts from non-transgenic seeds. Furthermore, refined cottonseed oil from the two transgenic events showed 30% improvement in oxidative stability relative to the non-transgenic cottonseed oil. Taken together, these materials may provide new opportunities for cottonseed co-products with enhanced vitamin E profile for improved shelf life and nutrition.

Changing recruitment capacity in global fish stocks.

Marine fish and invertebrates are shifting their regional and global distributions in response to climate change, but it is unclear whether their productivity is being affected as well. Here we tested for time-varying trends in biological productivity parameters across 262 fish stocks of 127 species in 39 large marine ecosystems and high-seas areas (hereafter LMEs). This global meta-analysis revealed widespread changes in the relationship between spawning stock size and the production of juvenile offspring (recruitment), suggesting fundamental biological change in fish stock productivity at early life stages. Across regions, we estimate that average recruitment capacity has declined at a rate approximately equal to 3% of the historical maximum per decade. However, we observed large variability among stocks and regions; for example, highly negative trends in the North Atlantic contrast with more neutral patterns in the North Pacific. The extent of biological change in each LME was significantly related to observed changes in phytoplankton chlorophyll concentration and the intensity of historical overfishing in that ecosystem. We conclude that both environmental changes and chronic overfishing have already affected the productive capacity of many stocks at the recruitment stage of the life cycle. These results provide a baseline for ecosystem-based fisheries management and may help adjust expectations for future food production from the oceans.

Naturally occurring high oleic acid cottonseed oil: identification and functional analysis of a mutant allele of Gossypium barbadense fatty acid desaturase-2.

MAIN CONCLUSION: Some naturally occurring cotton accessions contain commercially attractive seed oil fatty acid profiles. The likely causal factor for a high-oleate trait in pima cotton ( Gossypium barbadense ) accession GB-713 is described here. Vegetable oils are broadly used in the manufacture of many human and animal nutritional products, and in various industrial applications. Along with other well-known edible plant oils from soybean, corn, and canola, cottonseed oil is a valuable commodity. Cottonseed oil is a co-product derived from the processing of cottonseed fiber. In the past, it was used extensively in a variety of food applications. However, cottonseed oil has lost market share in recent years due to less than optimal ratios of the constituent fatty acids found in either traditional or partially hydrogenated oil. Increased awareness of the negative health consequences of dietary trans-fats, along with the public wariness associated with genetically modified organisms has created high demand for naturally occurring oil with high monounsaturate/polyunsaturate ratios. Here, we report the discovery of multiple exotic accessions of pima cotton that contain elevated seed oil oleate content. The genome of one such accession was sequenced, and a mutant candidate fatty acid desaturase-2 (FAD2-1D) gene was identified. The mutant protein produced significantly less linoleic acid in infiltrated Arabidopsis leaf assays, compared to a repaired version of the same enzyme. Identification of this gene provides a valuable resource. Development of markers associated with this mutant locus will be very useful in efforts to breed the high-oleate trait into agronomic fiber accessions of upland cotton.

Initial Clinical Experience: Symmetric-Tip Dialysis Catheter with Helical Flow Characteristics Improves Patient Outcomes.

PURPOSE: To report preliminary clinical experience with a new symmetric-tip dialysis catheter compared with a conventional split-tip catheter. MATERIALS AND METHODS: Over a 5-month period, patients requiring a tunneled catheter for hemodialysis or undergoing exchange of a dysfunctional dialysis catheter at a tertiary academic medical center were retrospectively analyzed. Patients underwent placement of a VectorFlow or Ash Split Cath catheter at the discretion of the inserting interventional radiologist. Patient demographics, catheter patency, mean blood flow rate, and arterial and venous pressures were compared according to catheter type. Catheter failure was analyzed based on clinical and anatomic variables by using a multivariate Cox proportional-hazards model. RESULTS: A total of 33 VectorFlow and 46 Ash Split Cath catheters were placed. Patients in the VectorFlow group had significantly higher body mass index (P = .013) and Charlson Comorbidity Index (P = .049), as well as more non-internal jugular vein placements. At 120 days, 89% of VectorFlow catheters remained functional, compared with 45% of Ash Split Cath catheters (P = .046). The VectorFlow catheter was associated with 16% lower arterial pressures during dialysis (P = .009); mean blood flow rate was equivalent. On multivariate analysis, the risk of catheter failure was 13.3 times higher in the Ash Split Cath group compared with the VectorFlow group (P = .004). Left-sided catheters were also predictive of catheter failure (relative risk = 5.5; P = .02). CONCLUSIONS: The VectorFlow catheter was associated with a significant increase in intervention-free catheter patency compared with the Ash Split Cath catheter, with equivalent flow at lower arterial pressures during dialysis.

Predator decline leads to decreased stability in a coastal fish community.

Fisheries exploitation has caused widespread declines in marine predators. Theory predicts that predator depletion will destabilise lower trophic levels, making natural communities more vulnerable to environmental perturbations. However, empirical evidence has been limited. Using a community matrix model, we empirically assessed trends in the stability of a multispecies coastal fish community over the course of predator depletion. Three indices of community stability (resistance, resilience and reactivity) revealed significantly decreasing stability concurrent with declining predator abundance. The trophically downgraded community exhibited weaker top-down control, leading to predator-release processes in lower trophic levels and increased susceptibility to perturbation. At the community level, our results suggest that high predator abundance acts as a stabilising force to the naturally stochastic and highly autocorrelated dynamics in low trophic species. These findings have important implications for the conservation and management of predators in marine ecosystems and provide empirical support for the theory of predatory control.

Predictive modeling of marine benthic macrofauna and its use to inform spatial monitoring design.

This study undertakes ecological analysis focused on predictive modelling and design for spatial sampling. The approaches are applied to a set of coastal marine benthic macrofaunal observations, and associated environmental data, measured at 48 sites in St Anns Bay, Nova Scotia, Canada. A multivariate generalized least-squares regression was used to establish a predictive relationship between benthic fauna and the environment. Five ecological indices derived from faunal composition (abundance, richness, species number, diversity, AMBI) were treated as a multivariate response, and 10 environmental variables as candidate predictors. The multivariate regression also incorporated the effects of spatial autocorrelation. Predictive relationships were highly significant, and variable selection identified three key environmental predictors (median sediment grain size, porosity, and sulfide). Using these baseline data, we developed a procedure to identify a reduced sampling design for long-term monitoring of benthic faunal health. The procedure is based on a sequential (backward elimination) algorithm to identify the set of sites that contributed most to the overall information. This study provides a general and comprehensive statistical framework for treating environmental monitoring and sampling design. It can be extended beyond the statistical framework used, and applied to a range of ecological applications.

Di(phenylpropylamino)gossypol: a derivative of the dimeric natural product gossypol.

Di(phenylpropylamino)gossypol [systematic name: 2,2'-bis{1,6-dihydroxy-5-isopropyl-8-[(3-phenylpropylamino)methylidene]naphthalen-7-one}, C48H52N2O6, was formed by reaction of the dimeric natural product gossypol with 3-phenylpropylamine. The structure of this compound has its two naphthalene ring systems oriented approximately perpendicular to each other, and the two pendant phenylpropyl groups have different conformations. One of these side groups is considerably disordered at room temperature but less so at 120 K. The enantiomeric molecules form centrosymmetric dimers that are supported by intermolecular hydrogen bonds and by hydrophobic interactions between a pair of naphthalene rings. Two additional hydrogen bonds tie the dimer pairs into layers. Unlike gossypol and many gossypol Schiff base derivatives, the title compound crystallizes without the inclusion of solvent, which appears to occur because of the size and flexibility of its phenylpropyl pendent groups.

A real-time data assimilative forecasting system for animal tracking.

Monitoring technologies now provide real-time animal location information, which opens up the possibility of developing forecasting systems to fuse these data with movement models to predict future trajectories. State-space modeling approaches are well established for retrospective location estimation and behavioral inference through state and parameter estimation. Here we use a state-space model within a comprehensive data assimilative framework for probabilistic animal movement forecasting. Real-time location information is combined with stochastic movement model predictions to provide forecasts of future animal locations and trajectories, as well as estimates of key behavioral parameters. Implementation uses ensemble-based sequential Monte Carlo methods (a particle filter). We first apply the framework to an idealized case using a nondimensional animal movement model based on a continuous-time random walk process. A set of numerical forecasting experiments demonstrates the workflow and key features, such as the online estimation of behavioral parameters using state augmentation, the use of potential functions for habitat preference, and the role of observation error and sampling frequency on forecast skill. For a realistic demonstration, we adapt the framework to short-term forecasting of the endangered southern resident killer whale (SRKW) in the Salish Sea using visual sighting information wherein the potential function reflects historical habitat utilization of SRKW. We successfully estimate whale locations up to 2.5 h in advance with a moderate prediction error (<5 km), providing reasonable lead-in time to mitigate vessel-whale interactions. It is argued that this forecasting framework can be used to synthesize diverse data types and improve animal movement models and behavioral understanding and has the potential to lead to important advances in movement ecology.

EUS-guided liver biopsy using a modified wet heparin suction technique.

Video 1Description of the technique of EUS-guided liver biopsy using a modified wet heparin suction technique.

Estimating behavioral parameters in animal movement models using a state-augmented particle filter.

Data on fine-scale animal movement are being collected worldwide, with the number of species being tagged and the resolution of data rapidly increasing. In this study, a general methodology is proposed to understand the patterns in these high-resolution movement time series that relate to marine animal behavior. The approach is illustrated with dive data from a northern fur seal (Callorhinus ursinus) tagged on the Pribilof Islands, Alaska, USA. We apply a state-space model composed of a movement model and corresponding high-resolution vertical movement data. The central goal is to estimate parameters of this movement model, particularly their variation on appropriate time scales, thereby providing a direct link to behavior. A particle filter with state augmentation is used to jointly estimate the movement parameters and the state. A multiple iterated filter using overlapping data segments is implemented to match the parameter time scale with the behavioral inference. The time variation in the auto-covariance function facilitates identification of a movement model, allows separation of observation and process noise, and provides for validation of results. The analysis yields fitted parameters that show distinct time-evolving changes in fur seal behavior over time, matching well what is observed in the original data set.

6,6'-Dimethoxygossypolone.

6,6'-Dimethoxygossypolone (systematic name: 7,7'-dihydroxy-5,5'-diisopropyl-6,6'-dimethoxy-3,3'-dimethyl-1,1',4,4'-tetraoxo-2,2'-binaphthalene-8,8'-dicarbaldehyde), C(32)H(30)O(10), is a dimeric molecule formed by oxidation of 6,6'-dimethoxygossypol. When crystallized from acetone, 6,6'-dimethoxygossypolone has monoclinic (P2(1)/c) symmetry, and there are two molecules within the asymmetric unit. Of the four independent quinoid rings, three display flattened boat conformations and one displays a flattened chair/half-chair conformation. The angles between the planes of the two bridged naphthoquinone structures are fairly acute, with values of about 68 and 69°. The structure has several intramolecular O-H...O and C-H...O hydrogen bonds and several weak intermolecular C-H...O hydrogen bonds, but no intermolecular O-H...O hydrogen bonds.

Effects of a nursing intervention on quality of life outcomes in post-surgical women with gynecological cancers.

OBJECTIVE: Women with gynecological cancers have reported poor health-related quality of life (QOL), with complex physical and psychological needs post-surgery and during chemotherapy treatment. There are no studies reporting interventions addressing these needs post-hospital discharge in this population. METHODS: Patients were randomized into two groups. The intervention group received 6 months of specialized care by an Advanced Practice Nurse (APN); in addition, women with high distress were evaluated and monitored by a psychiatric consultation-liaison nurse (PCLN). The attention control group was assisted with symptom management by a research assistant. The effects of the 6-month intervention were evaluated using self-report questionnaires at baseline (24-48 h after surgery), 1, 3, and 6 months post- surgery. QOL assessments included the Center for Epidemiological Studies-Depression Scale , the ambiguity subscale of the Mishel Uncertainty in Illness Scale , the Symptom Distress Scale, and the Short-Form Health Survey (SF-12). The sample for the longitudinal analysis included 123 who completed QOL outcome measures across three occasions post-surgery. RESULTS: The APN intervention resulted in significantly less uncertainty than the attention control intervention 6 months after surgery. When the sub-group who received the APN plus PCLN intervention was compared with the total attention control group, the sub-group had significantly less uncertainty, less symptom distress, and better SF-12 mental and physical QOL over time. CONCLUSION: Nurse tailored interventions that target both physical and psychological aspects of QOL in women recovering from cancer surgery and undergoing chemotherapy produce stronger outcomes than interventions that target solely one QOL aspect.

(-)-Gossypol reduces invasiveness in metastatic prostate cancer cells.

BACKGROUND: Acquisition of metastatic ability by prostatic cancer cells is the most lethal aspect of prostatic cancer progression. (-)-Gossypol, a polyphenolic compound present in cottonseeds, possesses anti-proliferative and proapoptotic effects in various cancer cells. MATERIALS AND METHODS: In this study, the differences between MAT-LyLu, rat prostate cancer cells, with a novel isolated subline from metastasized tumors in the lungs of MAT-LyLu-bearing Copenhagen rats (MLL cells) were compared with respect to cell growth and invasion. The effects of (-)-gossypol on cell viability, colony formation, invasive ability and cell migration in MAT-LyLu and MLL cells were also evaluated. RESULTS: Results showed that MLL cells displayed higher growth ability, colony formation and aggressive penetration than those of MAT-LyLu cells. MLL cells possess lower protein expression of Bcl-xL and nm23-H1 than those of MAT-LyLu cells, implying differences in invasive ability. Moreover, (-)-gossypol treatment induced a dose-dependent inhibition of invasive activity and cell viability and reduced Bcl-2 and Bcl-xL proteins but induced nm23-H1 protein in both cell lines. CONCLUSION: These findings illustrated that (-)-gossypol reduced in vitro invasion of both the parental MAT-LyLu cells and the isolated MLL cells, suggesting that (-)-gossypol might serve as a chemotherapeutic and/or chemopreventive agent.

Short-term effects of coping skills training in school-age children with type 1 diabetes.

OBJECTIVE: Little is known about the use of psychosocial interventions in children younger than adolescence with type 1 diabetes (T1D) and their parents. We report preliminary short-term outcomes of a randomized controlled trial of coping skills training (CST) compared with group education (GE) in school-aged children with T1D and their parents. METHODS: One hundred and eleven children (range = 8-12 yr) with T1D for at least 6 months (3.71 +/- 2.91 yr) were randomized to CST (55.6% female (F); 81.5% white (W)) or GE (69.7% F; 90.9% W). Children and parents (n = 87) who completed the intervention, baseline, 1- and 3-month data are included. Children completed measures of self-efficacy, coping, and quality of life; parents completed measures of family functioning (adaptability and cohesion), diabetes-related conflict, parent depression, and parent coping. Metabolic control was assessed with glycosylated hemoglobin A1c. Mixed-model repeated measures anova was used to analyze the data. RESULTS: CST and GE group composition was generally comparable. Children had good psychosocial adaptation and metabolic status. CST parents reported significantly more improvement in family adaptability compared with GE parents, and a trend was seen indicating that CST children showed greater improvement in life satisfaction than GE children. Effect sizes for this short-term follow-up period were small, but group participants were receptive to the intervention and reported positive gains. CONCLUSIONS: In these preliminary results, CST and GE were more similar than different across multiple measure of psychosocial adaptation, although CST showed promising statistical trends for more adaptive family functioning and greater life satisfaction. Longer term follow-up is underway.

HPLC preparation of the chiral forms of 6-methoxy-gossypol and 6,6'-dimethoxy-gossypol.

A concentrated mixture of gossypol, 6-methoxy-gossypol, and 6,6'-dimethoxy-gossypol was extracted from the root bark of St. Vincent Sea Island cotton with acetone. This extract was derivatized with R-(-)-2-amino-1-propanol to form diastereomeric gossypol Schiff's bases. Analytical-scale reverse-phase chromatography of these Schiff's bases produced six peaks, indicating separation of the enantiomeric forms of the three gossypol compounds. The elution order of the peaks was found to vary with the polarity of the mobile phase. The chromatography was scaled to a preparative level and was used to isolate each compound. After hydrolysis of the separated Schiff's bases, the original compounds were recovered by precipitation from solutions of diethyl ether, acetic acid, and water. Fifty injections yielded approximately 500 mg of each methoxy-gossypol enantiomer and 300 mg of each dimethoxy-gossypol enantiomer. Each compound was characterized for carbon and hydrogen content, optical rotation, UV-vis light absorption, and melting point. Standard curves were developed and were used to measure the concentration of each gossypol form in the root bark and dehulled seed of St. Vincent Sea Island cotton. In seed tissue, 48% of the gossypol compounds were methylated, and the (-)-optical form was found to be in a slight excess to the (+)-optical form (53-54%) for all three compounds. In root bark, 71% of the gossypol compounds were methylated, and the (+)-optical form was in excess to the (-)-optical form for all three compounds. However, in this tissue the extent of enantiomeric excess decreased with the degree of methylation, with 77% of the gossypol existing in the (+)-optical form and 59% of the 6,6'-dimethoxy-gossypol existing in the (+)-optical form.

Effect of racemic, (+)- and (-)-gossypol on survival and development of Heliothis virescens larvae.

Gossypol is a constituent of the lysigenous foliar glands of cotton plants and is also found in glands in cottonseed. Gossypol exists as enantiomers because of restricted rotation around the binaphthyl bond. The biological activities of the enantiomers differ. For example, (+)-gossypol can be fed safely to nonruminants such as chickens, but (-)-gossypol cannot. Most commercial cottonseed contain a (+)- to (-)-gossypol ratio of approximately 3:2. Conventional breeding techniques can be used to develop cottonseed that contains >95% (+)-gossypol. Notably, gossypol protects the plant from insect herbivores. Herein, we report the effect of various forms of gossypol on Heliothis virescens (Fabricius) larvae. Three levels (0.16, 0.24, and 0.32%) of racemic, (+)-, and (-)-gossypol were added to artificial rearing diets and were fed to H. virescens larvae. All 0.24 and 0.32% gossypol diets significantly lengthened days-to-pupation and decreased pupal weight compared with the control. Percent survival was significantly less for larvae reared on diets containing 0.24% of all three forms of gossypol as compared with the control diet. (+)-Gossypol was superior or equivalent to racemic gossypol as measured by the three parameters studied. Higher concentrations of all gossypol forms were required to reduce survival and pupal weights and increase days-to-pupation for larvae of H. virescens larvae compared with the concentration needed to affect larvae of Helicoverpa zea (Boddie), which was studied previously. These results indicate that current efforts to breed cotton lines containing mostly (+)-gossypol in seed should not significantly impair the plant's natural defenses against insects.

Quality of life among women after surgery for ovarian cancer.

OBJECTIVES: Difficulties with diagnosis and aggressive, long-term treatment may result in lower quality of life (QOL), including high levels of anxiety, depression, and uncertainty, greater symptom distress, and lower overall QOL among women with ovarian cancer. The purpose of this study was to describe demographic, clinical, and other risk factors associated with compromised QOL among women who have undergone surgery for ovarian malignancies. METHODS: Subjects were recruited to participate in a clinical trial that tested a specialized nursing intervention addressing psychological and physical care among women post-surgical for ovarian cancer. QOL was measured using five standardized self-report measures: the State-Trait Anxiety Scale (SAS), the Center for Epidemiological Studies Depression Scale (CES-D), the Mishel Uncertainty in Illness Scale (MUIS), the Symptom Distress Scale (SDS), and the Short-Form Health Survey (SF-12). Baseline data were collected while women were hospitalized following surgery. RESULTS: The sample (n=145) included women with ovarian cancer (58%) and other cancers metastasized to the ovaries and abdomen (42%). Mean scores on the measures were consistent with or higher than previously reported means for similar populations. Women reporting the lowest QOL were more likely to be younger, more educated, and have early stage disease. SIGNIFICANCE OF RESULTS: Women who have undergone surgery for ovarian malignancies have psychological needs that are often considered secondary to physical needs. Interventions should include routine screening for distress and referral to appropriate psychological and social services, thereby facilitating quality cancer care.

Gossypol inhibits calcineurin phosphatase activity at multiple sites.

Calcineurin, the Ca2+/calmodulin-dependant serine/threonine phosphatase is the target for the immunosuppressant drugs FK506 and cyclosporine-A. These established calcineurin inhibitors each require an immunophilin protein cofactor. Gossypol, a polyphenol produced by the cotton plant, inhibits calcineurin (IC50=15 microM), in a noncompetitive, reversible manner, and is independent of any cofactor. We found that gossypol acts by at least two mechanisms to inhibit calcineurin phosphatase activity. A calmodulin-independent form of calcineurin was less sensitive to inhibition by gossypol than native calcineurin (IC50=41 and 18 microM, respectively) indicating that gossypol may interfere with calmodulin binding. A fluorescence polarization based assay demonstrated that 100 microM gossypol reduced the affinity of calmodulin for calcineurin (from K(d)=2.4 to 250 nM). Inhibition of calcineurin phosphatase activity by gossypol could not be overcome by adding excess calmodulin or by testing the inhibition toward a calmodulin-independent calcineurin indicating that gossypol acts at a site different from the calmodulin-binding site. Gossypol decreased the affinity of calcineurin for immunosuppressant/immunophilin complexes only in the presence of calmodulin, indicating that gossypol blocks the effects of calmodulin binding to calcineurin. In addition, gossypol had a stimulatory effect on native calcineurin in the absence of calmodulin, possibly indicating a calmodulin mimetic effect. Gossypol exists in two enantiomeric forms which are reported to have different potency for cell toxicity. (+) and (-) gossypol had equivalent potency for inhibition of native and calmodulin-independent calcineurin phosphatase activity, and for inhibition of calmodulin binding. The inhibition of calcineurin by gossypol via multiple binding sites without stereo-specificity indicates that gossypol is not a specific calcineurin inhibitor.