基因组叠加生物型的基因表达特征

采用聚丙烯酰胺梯度凝胶电泳及特异性组织化学染色技术分析了鲤、鲫及其基因组叠加的不同组合个体的红细胞ＳＯＤ、ＥＳＴ和血红蛋白的电泳图谱。结果表明不同基因组合及不同倍性的个体间存在由基因组差异导致的生化多态性,为不同倍性的鱼类的同工酶（ＳＯＤ）表达存在基因剂量效应提供了依据,证实了不同组合的ＳＯＤ亚基间有协同表达、累积作用。研究表明每个基因有其独特的调控机制,因而在杂种三倍体内三分之一的基因组亦能够表     

Parametric Model of Combination Therapy for Non-Hodgkin Lymphoma

The development and clinical testing of drug combinations for the treatment of Non-Hodgkin Lymphoma (NHL) and other cancers has recently shown great promise. However, determining the optimum combination and its associated dosages for maximum efficacy and minimum side effects is still a challenge. This paper describes a parametric analysis of the dynamics of malignant B-cells and the effects of an anti-sense oligonucleotide targeted to BCL-2 (as-bcl-2), anti-CD-20 (rituximab) and their combination, for a SCID mouse human lymphoma xenograft model of NHL. Our parametric model is straightforward. Several mechanisms of malignant B-cell birth and death in the nodal micro-environment are simulated. Cell death is accelerated by hypoxia and starvation induced by tumor scale, by modification of anti-apoptosis with as-bcl-2, and by direct kill effects of rituximab (cell kill by cytotoxic immune cells is not included, due to the absence of an immune system in the corresponding experiments). We show that the cell population dynamics in the control animals are primarily determined by K*, the ratio of rate constants for malignant cell death, K_d, and cell birth, K_b. Tumor growth with independent treatments is reproduced by the model, and is used to predict their effect when administered in combination. Malignant cell lifetimes are derived to provide a quantitative comparison of the efficacy of these treatments. Future experimental and clinical applications of the model are discussed.     

Seed treatments to lengthen the sugar-beet growing period

Although washing, thiram soaking, advancing and combinations of these treatments increased the rate of emergence of sugar-beet seed, some combinations, particularly those involving ethyl mercuric phosphate steeps and advancing, interacted negatively and greatly reduced total seedling emergence and shoot weight without affecting the rate of emergence. This may have happened because each treatment is, to some extent, fulfilling the function of other treatments and if together the treatments go too far, mercury enters the embryo and damages it. Therefore, proposed seed treatments need careful testing in combination with other existing treatments.     

不同剂量和比例的性信息素对亚洲玉米螟雄蛾的行为作用(英文)

在风洞中观察了亚洲玉米螟雄蛾对不同剂量不同比例的二组份及三组份的人工合成性信息素（１４：ｏＡｃ, Ｅ－１２－１４： ｏＡｃ和 Ｚ－１２－１４：ｏＡｃ）的行为反应。 Ｚ－１２－１４： ｏＡｃ＋Ｅ－１２－１４： ｏＡｃ 二组份诱芯中以比例为３７．５％Ｅ到６２．５％Ｅ之间的诱芯效果最好,有７１％－７８％的雄蛾到达诱芯。三组份诱芯中以工４：Ａｃ： Ｚ－１２－１４： ｏＡｃ： Ｅ－１２－１４： ｏＡｃ＝１： ５： ４的效果最好,雄蛾到达诱芯的百分率（７１％）与二组份诱芯相比无显著差异。但是剂量反应实验显示三组份诱芯的有效剂量范围比二组份诱芯宽,二组分诱芯及三组份诱芯在风洞试验中的最佳剂量范围分别为 １００ｎｇ到 １０００ｎｇ和 １００ ｎｇ到 １０ ０００ｎｇ。低剂量的情况下三组份的诱芯效果要好于二组份诱芯。三组份诱芯对于低到 １ｎｇ的剂量仍能引起 １０％的雄蛾到达诱芯,而在此剂量下二组份诱芯不能引起定向及其以后的各步行为反应。     

Effect of varying proportions of the alcohol component on sex pheromone blend discrimination in male Oriental fruit moths

ABSTRACT. The flight response of individual male Oriental fruit moths, Grapholitha molesta (Busck), was observed in a sustained-flight tunnel to 100 blend–dosage combinations of the three sex pheromone components: (Z)- and (E)-8-dodecenyl acetate and (Z)-8-dodecen-l-ol (1, 3, 10, 30 and 100 μg of Z8-12: AC with, 2, 6, 10, 20% E and, 0, 3, 10, 30 or100% OH alcohol added). Complete flights to the source were observed only to blend combinations containing all three components. Males exhibited highest response levels to two dosages (3 and 10μg) of the natural 6% E blend and these levels were relatively unaffected by changes in the proportion of Z8-12: OH. Certain treatments surrounding the peak area also elicited high response levels compared to the 6% E treatments, but these were strongly dependent on the proportion of OH in the blend. Hierarchical cluster analysis was utilized to compare and group treatments that elicited similar levels of response over the entire flight sequence and to derive an area of blend-dosage combinations within the matrix tested that elicited peak levels of attraction. Analysis of the response patterns for suboptimal treatments adjacent to the area of optimal attraction showed that response specificity was controlled by two major effects on flight behaviour, one occurring early in the flight sequence affecting male orientation to the odour plume, and the other occurring later in the sequence as an arrestment of upwind flight. These effects were strongly influenced by changes in the OH component and the E isomer, with the latter playing the critical role in effecting flight behaviour. Temporal analysis of the flight response to treatments within the optimal area showed that whereas the % OH did not significantly affect the magnitude of response, increasing the level of Z8-12: OH in the blend did significantly increase the duration of each phase of the behavioural sequence. Considering both the magnitude and temporal aspects of male response, optimal attraction in male OFM was best characterized by a small area of treatments around the peak 6% E blends that contained 10% OH. Finally, field tests showed a high degree of correlation between trends in response with changing proportion of Z8-12: OH as observed in the flight tunnel. Peak dosages were generally higher in the field, however, compared to those in the flight tunnel.     

Mutagenesis in CAENORHABDITIS ELEGANS. II. a Spectrum of Mutational Events Induced with 1500 R of γ-RADIATION

We previously established a gamma-ray dose-response curve for recessive lethal events (lethals) captured over the eT1 balancer. In this paper we analyze the nature of lethal events produced, with a frequency of 0.04 per eT1 region, at a dose of 1500 r. To do so, we developed a protocol that, in the absence of cytogenetics, allows balanced lethals to be analyzed for associated chromosomal rearrangements. A set of 35 lethal strains was chosen for the analysis. Although the dosage was relatively low, a large number of multiple-break events were observed. The fraction of lethals associated with rearrangements was found to be 0.76. Currently most X- and gamma-ray dosages used for mutagenesis in C. elegans are 6000-8000 r. From our data we conservatively estimated that 43% of rearrangements induced with 8000 r would be accompanied by additional chromosome breaks in the genome. With 1500 r the value was 5%. The 35 lethals studied were derived from 875 screened F1's. Among these lethals there were (1) at least two unc-36 duplications, (2) at least four translocations, (3) at least six deficiencies of chromosome V (these delete about 90% of the unc-60 to unc-42 region) and (4) several unanalyzed rearrangements. Thus, it is possible to recover desired rearrangements at reasonable rates with a dose of only 1500 r. We suggest that the levels of ionizing radiation employed in most published C. elegans studies are excessive and efforts should be made to use reduced levels in the future.     

Optimization of pheromone dosage for gypsy moth mating disruption

The effect of aerial applications of the pheromone disparlure at varying dosages on mating disruption in low‐density gypsy moth, Lymantria dispar (L.) (Lepidoptera: Lymantriidae), populations was determined in field plots in Virginia, USA during 2000 and 2002. Six dosages [0.15, 0.75, 3, 15, 37.5, and 75 g active ingredient (AI)/ha] of disparlure were tested during the 2‐year study. A strongly positive dose–response relationship was observed between pheromone dosages and mating disruption, as measured by the reduction in male moth capture in pheromone‐baited traps and mating successes of females. Dosages of pheromone 15 g AI/ha (15, 37.5, and 75 g AI/ha) reduced the mating success of females by >99% and significantly reduced male moth catches in pheromone‐baited traps compared to untreated plots. Pheromone dosages <15 g AI/ha also reduced trap catch, but to a lesser extent than dosages 15 g AI/ha. Furthermore, the effectiveness of the lower dosage treatments (0.15, 0.75, and 3 g AI/ha) declined over time, so that by the end of the study, male moth catches in traps were significantly lower in plots treated with pheromone dosages 15 g AI/ha. The dosage of 75 g AI/ha was initially replaced by a dosage of 37.5 g AI/ha in the USDA Forest Service Slow‐the‐Spread (STS) of the Gypsy Moth management program, but the program is currently making the transition to a dosage of 15 g AI/ha. These changes in applied dosages have resulted in a reduction in the cost of gypsy moth mating disruption treatments.     

In vitro biofilm models to study dental caries: a systematic review

The aim of this systematic review is to characterize and discuss key methodological aspects of in vitro biofilm models for caries-related research and to verify the reproducibility and dose-response of models considering the response to anti-caries and/or antimicrobial substances. Inclusion criteria were divided into Part I (PI): an in vitro biofilm model that produces a cariogenic biofilm and/or caries-like lesions and allows pH fluctuations; and Part II (PII): models showing an effect of anti-caries and/or antimicrobial substances. Within PI, 72.9% consisted of dynamic biofilm models, while 27.1% consisted of batch models. Within PII, 75.5% corresponded to dynamic models, whereas 24.5% corresponded to batch models. Respectively, 20.4 and 14.3% of the studies reported dose-response validations and reproducibility, and 32.7% were classified as having a high risk of bias. Several in vitro biofilm models are available for caries-related research; however, most models lack validation by dose-response and reproducibility experiments for each proposed protocol.     

Drug, dosage, activity, studies of antimalarials by physical methods--II

Studies pertaining to drug-DNA interactions in treating a disease efficiently have taken an important place in recent times. Murthy and colleagues were active in correlating the drug activity, with physical parameters like refractivity, susceptibility, molecular electron ionization cross-section and the dosage. The molecular polarizability, diamagnetic susceptibility and molecular electron ionization cross section Q have been evaluated. An analysis of Q in the light of the data available on plasma protein binding, bio availability, Log P and half-Life show semblance of regular dependence of Q on them and hence an effort is made to bring this dependence into a regular mathematical relationship. The dosage of each drug is calculated. A critical look at the results arrived on Q and dosages reveal that a highly active drug with large Q need to be monitored in very small quantities and any minute increase in dosage is resulting in unwanted toxic effects and vice versa. The algebraic formulae enable one to calculate the dosages theoretically from the value of Q and other parameters and the calculated dosage through the formulae agreed favorably well with suggested dosages. For example, in primaquine phosphate, the calculated dosage is 30 mg per day against the suggested practical dosage of 26.3 mg per day. A similar observation is made in mepacrine with theoretical dosage of 60 mg per day as against the suggested practical dosage of 100 mg per day. In short, the molecular structure followed by refraction and susceptibility measurements and Q will throw light on dosage, toxicity of a drug. Thus the present investigations pave way for a new direction of approach for study of drug activity without recourse to techniques involving highly expensive instrumentation and highly theoretical approaches involving quantum mechanical methods.     

Influences of endogenous dopamine on carotid body discharge and ventilation

Ventilatory and carotid body responses to hypoxia have been related to the endogenous release of dopamine by use of the antagonist drug haloperidol. The published studies have produced conflicting data for ventilation. However, antagonist drugs can act at multiple anatomical sites, on multiple pharmacological receptors, often at different dosages, and have nonspecific actions at high dosage. For these reasons, we have undertaken a systematic study of haloperidol dose-response curves with particular emphasis on the lowest possible concentrations of drug. In five cats anesthetized with pentobarbital sodium (30-35 mg/kg), single- or few-fiber afferent recordings of the carotid body showed that haloperidol increased the discharge during both basal and asphyxic conditions, the increments being proportional to haloperidol dosage (0.1-1,000 micrograms/kg). Increments of ventilation were also produced, these increments increasing only over the lower range of dosage; at the highest haloperidol dosage, the dose response showed a tendency to plateau or inflect downward, suggesting the appearance of an opposing inhibitory mechanism.     

Two-drug combinations of memory enhancers: effect of dose ratio upon potency and therapeutic window, in mice

Two-drug combinations have been reported to enhance retention more effectively than when either drug was administered alone at the same dose. Some combinations of cholinergic drugs enhance retention even though the total drug dosage is reduced by as much as 97% compared to the dose needed to improve retention when the same drugs are administered singly. The choice of dose ratio is usually arbitrary or based on empirical results. The present study systematically varied the ratio of two drugs in a combination and at the same time varied the dosage of each drug. The drug combinations were administered to mice immediately after training on T-maze footshock avoidance task. Retention was tested one week later. Three two-drug combinations were selected for presentation because they differed considerably as to (a) the lowest effective total dose that improved memory-retention, (b) the optimal ratio that improved retention and (c) the width of the therapeutic window. The effect of a drug combination on retention was found to be dependent on the particular drugs in the combination, the ratio and the dose administered.     

Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages

We need to find ways of enhancing the potency of existing antibiotics, and, with this in mind, we begin with an unusual question: how low can antibiotic dosages be and yet bacterial clearance still be observed? Seeking to optimise the simultaneous use of two antibiotics, we use the minimal dose at which clearance is observed in an in vitro experimental model of antibiotic treatment as a criterion to distinguish the best and worst treatments of a bacterium, Escherichia coli. Our aim is to compare a combination treatment consisting of two synergistic antibiotics to so-called sequential treatments in which the choice of antibiotic to administer can change with each round of treatment. Using mathematical predictions validated by the E. coli treatment model, we show that clearance of the bacterium can be achieved using sequential treatments at antibiotic dosages so low that the equivalent two-drug combination treatments are ineffective. Seeking to treat the bacterium in testing circumstances, we purposefully study an E. coli strain that has a multidrug pump encoded in its chromosome that effluxes both antibiotics. Genomic amplifications that increase the number of pumps expressed per cell can cause the failure of high-dose combination treatments, yet, as we show, sequentially treated populations can still collapse. However, dual resistance due to the pump means that the antibiotics must be carefully deployed and not all sublethal sequential treatments succeed. A screen of 136 96-h-long sequential treatments determined five of these that could clear the bacterium at sublethal dosages in all replicate populations, even though none had done so by 24 h. These successes can be attributed to a collateral sensitivity whereby cross-resistance due to the duplicated pump proves insufficient to stop a reduction in E. coli growth rate following drug exchanges, a reduction that proves large enough for appropriately chosen drug switches to clear the bacterium.     

Interactions between a commercial preparation of Bacillus thuringiensis and β-exotoxin in the fall armyworm,Spodoptera frugiperda

A commercial preparation of Bacillus thuringiensis (Dipel) and its β-exotoxin were assayed alone and in combination against neonate (3- to 6-hr-old) fall armyworm, Spodoptera frugiperda, larvae using a microdroplet technique. Positive dosage-mortality response curves were determined for each agent. Combination bioassays were then conducted using dosages based on these curves. Presence or absence of interactions was determined by comparing mortality levels from the combination assays with expected mortality levels using single degree of freedom χ² tests. Synergism occurred in 14 of 18 combinations of B. thuringiensis and β-exotoxin tested. Four combinations, all of which contained low individual dosages, exhibited additivity of effects. Maximum deviation of observed from expected mortality occurred at the combination of LC₃₀ for B. thuringiensis plus LC₃₀ for β-exotoxin (observed = 100%, expected = 51%). The data suggested that both agents were contributing to the synergism in this system, but that B. thuringiensis was a slightly stronger synergist than β-exotoxin.     

Evaluation of dosages and routes of administration of tramadol analgesia in rats using hot-plate and tail-flick tests

Tramadol is an opioid-like analgesic with relatively mild side effects. Because it is inexpensive and is not classified as a controlled substance by the US federal government, the authors wanted to evaluate its applicability as a practical and effective analgesic in male Sprague Dawley rats. They measured the efficacy of four dosages (4, 12.5, 25 or 50 mg tramadol per kg body weight) and three routes of administration (per os (p.o.) in a flavored gelatin cube, subcutaneous (s.c.) or intraperitoneal (i.p.)) using the hot-plate test and the tail-flick test, which were carried out 1 week apart. Rats that were dosed p.o. were given flavored gelatin cubes without tramadol on the 2 d before testing to help them become acclimated to the gelatin, in an effort to increase the likelihood that they would consume the gelatin on the testing day. Results from the hot-plate and tail-flick tests for rats that were given tramadol p.o. were similar before and after administration, regardless of tramadol dosage, suggesting that this route of administration was not effective. The s.c. route of administration was effective at dosages of 25 mg and 50 mg tramadol per kg body weight, although these dosages also resulted in sedation and skin lesions. The i.p. route of administration was also effective at dosages of 12.5 mg, 25 mg and 50 mg tramadol per kg body weight, though sedation was observed at dosages of 25 mg and 50 mg per kg body weight. Intraperitoneal administration of 12.5 mg tramadol per kg body weight had no notable side effects, and the authors plan to further study this dosage and route of administration in a rodent surgical model of pain.     

Preparation of ethylene gas and comparison of ethylene responses induced by ethylene,ACC, and ethephon

Ethylene is a gaseous plant hormone used in many physiological studies examining its role in plant growth and development. However, ethylene gas may not be conveniently available to many laboratories for occasional use, and therefore several chemicals can be used as replacements. Here we report that the kinetics of the ethylene response induced by ethylene and two widely-used ethylene replacements are different. ACC failed to efficiently replace prolonged ethylene treatments, while the decomposition products of ethephon may cause non-specific responses and the efficiency of ethephon conversion to ethylene was relatively low. A cost-effective method to prepare ethylene gas was developed. Analyzed by gas chromatography, the chemically produced ethylene exhibited an identical chromatogram to that from the commercial source. Our synthetic ethylene gave the same dose-response curve in Arabidopsis as gaseous ethylene. Our study shows that the use of the ethylene gas is essential to experiments that are sensitive to treatment duration and dosage. When ACC and ethephon are used as replacements, caution should be taken in the experimental design. For laboratories that do not have an ethylene tank, ethylene gas can be easily prepared by a chemical approach without further purification.     

Individual and combined effects of dosages of azoxystrobin and epoxiconazole in wheat

The effects of single fungicide applications on Mycosphaerella graminicola (septoria leaf blotch) control and winter wheat yield were evaluated in field trials conducted in central Belgium between 2000 and 2004. Individual applications of 25, 50, 75 and 100% of the manufacturer's recommended dose rates of azoxystrobin and epoxiconazole, and all the combinations of these treatments, were made at GS 39 in 2001 to 2004 and at GS 59 in 2000. Disease assessments were made at growth stage 75, some 7-8 weeks after the last applications. Between 2000 and 2003, no significant difference was observed for disease control between the products when applied alone. With regard to the dose responses, the differences between the recommended dose rates and the 50% reduced dosages were not important. In 2004, azoxystrobin was less effective than epoxiconazole. This was probably the result of strobilurin-resistant isolates of M. graminicola reaching an occurrence of 32% before fungicide application. The combination of different dosages of azoxystrobin and epoxiconazole revealed that there was very little synergy between these products when applied in a single application. The combinations of these products were better than individual applications only when high dosages of both compounds were used.     

Apparent synergism between radiation and the carcinogen 1,2-dimethylhydrazine in the induction of colonic tumors in rats

We have evaluated the interaction of radiation and 1,2-dimethylhydrazine (DMH) with respect to colon carcinogenesis in the Fischer 344 rat and have demonstrated the utility of this model for future more detailed mechanistic studies. In initial experiments, single doses of abdomen-only radiation (9 Gy) or DMH (150 mg/kg) were employed alone or in combination. Radiation was administered 3.5 days prior to the DMH. At 8 months post-treatment, the incidence of DMH-induced colon tumors was doubled by prior radiation exposure. When the protocol was repeated employing a DMH dose of 135 mg/kg with a 6-month observation period, the incidence of tumors induced by DMH alone was reduced, but the combination of radiation plus DMH still resulted in an augmentation of tumor incidence. When the protocol of radiation plus DMH was repeated three times at monthly intervals, a 15-fold increase in tumor incidence (from 5 to 74%) was observed at 6 months post-treatment. This finding demonstrates an apparent synergy between the radiation and the chemical carcinogen. Throughout these studies, the appearance of carcinomas was associated with preexisting colonic lymphoid nodules. The reproducibility of tumor induction as well as range of tumor incidence generated by variations in this system may be adequately sensitive to examine the combination of much lower doses of radiation and/or chemical carcinogen. The relationship between existing lymphoid aggregates which alter local epithelial cell kinetics and which are associated with fenestrations in the basement membrane, and the development of colon cancer in congruent sites may assist in defining dose-response curves for combined agents as well as providing a system for evaluating the mechanisms underlying their interactions.     

DESIGN: computerized optimization of experimental design for estimating Kd and Bmax in ligand binding experiments. II. Simultaneous analysis of homologous and heterologous competition curves and analysis blocking and of "multiligand" dose-response surfaces

We have developed a computer program, DESIGN, for optimization of ligand binding experiments to minimize the "average" uncertainty in all unknown parameters. An earlier report [G. E. Rovati, D. Rodbard, and P. J. Munson (1988) Anal. Biochem. 174, 636-649] described the application of this program to experiments involving a single homologous or heterologous dose-response curve. We now present several advanced features of the program DESIGN, including simultaneous optimization of two or more binding competition curves optimization of a "multiligand" experiment. Multiligand designs are those which use combinations of two (or more) ligands in each reaction tube. Such designs are an important and natural extension of the popular method of "blocking experiments" where an additional ligand is used to suppress one or more classes of sites. Extending the idea of a dose-response curve, the most general multiligand design would result in a "dose-response surface". One can now optimize the design not only for a single binding curve, but also for families of curves and for binding surfaces. The examples presented in this report further demonstrate the power and utility of the program DESIGN and the nature of D-optimal designs in the context of more complex binding experiments. We illustrate D-optimal designs involving one radioligand and two unlabeled ligands; we consider one example of homogeneous and several examples of heterogeneous binding sites. Further, to demonstrate the virtues of the dose-response surface experiment, we have compared the optimal surface design to the equivalent design restricted to traditional dose-response curves. The use of DESIGN in conjunction with multiligand experiments can improve the efficiency of estimation of the binding parameters, potentially resulting in reduction of the number of observations needed to obtain a desired degree of precision in representative cases.