Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer

In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.     

The role of signal and motivational links of a conditioned reflex in the initiation of instrumental movements in dogs

Alimentary instrumental conditioned reflex (CR) was elaborated in dogs to light flashes (I series), electrostimulation (ES) of the hippocampus (II series) and the hypothalamus (III series). Nonreinforced ES of the hypothalamus, amygdala, hippocampus and septum reproduced pressings on the pedal to the least extent in the I series (17-40% of trials), increasing in the II-nd one up to 40-87% during stimulation of the lateral hypothalamus, medial amygdala and contralateral hippocampus. In the III-rd series the number of pressings increased statistically significantly in comparison with the I-st series for most structures. Probably, besides the artificial increase of motivation during ES of the limbic structures which took place in all series, in the II-nd and III-rd series significance for movement reproduction was acquired by CR generalization appearing due to close interconnection of the structures. In this phenomenon connections (evaluated by the EPs) from the tested structures to the initially signal one are important.     

Analysis of cedar pollen time series: no evidence of low-dimensional chaotic behavior

Much of the current interest in pollen time series analysis is motivated by the possibility that pollen series arise from low-dimensional chaotic systems. If this is the case, short-range prediction using nonlinear modeling is justified and would produce high-quality forecasts that could be useful in providing pollen alerts to allergy sufferers. To date, contradictory reports about the characterization of the dynamics of pollen series can be found in the literature. Pollen series have been alternatively described as featuring and not featuring deterministic chaotic behavior. We showed that the choice of test for detection of deterministic chaos in pollen series is difficult because pollen series exhibit power spectra. This is a characteristic that is also produced by colored noise series, which mimic deterministic chaos in most tests. We proposed to apply the Ikeguchi–Aihara test to properly detect the presence of deterministic chaos in pollen series. We examined the dynamics of cedar (Cryptomeria japonica) hourly pollen series by means of the Ikeguchi–Aihara test and concluded that these pollen series cannot be described as low-dimensional deterministic chaos. Therefore, the application of low-dimensional chaotic deterministic models to the prediction of short-range pollen concentration will not result in high-accuracy pollen forecasts even though these models may provide useful forecasts for certain applications. We believe that our conclusion can be generalized to pollen series from other wind-pollinated plant species, as wind speed, the forcing parameter of the pollen emission and transport, is best described as a nondeterministic series that originates in the high dimensionality of the atmosphere.     

Effect of rifampicin on development of tolerance to analgesic actions.

Two series of experiments were performed. In the first series the reaction times of mice were determined using the hotplate technique. In the second series of experiments the reactions of rats were determined using the electric footshock technique. In both series of experiments morphine was observed to alter the responses, and chronic morphine administration resulted in tolerance to these actions of morphine. In both series of experiments, tolerance, defined by these same criteria, was inhibited by the concurrent administration of rifampicin.     

Endurance vs. strength training: comparison of cardiac structures using normal predicted values

The importance of metabolic feedback regulation vs. feedforward regulation of hepatic glucose production (HGP) during exercise was investigated in rats by infusing glucose intravenously from the onset of running. Glucose infusion equaled the average exercise-induced increase from basal to steady state in HGP found in saline-infused control rats. Rats were studied at two work loads, running at 21 (series I) or 18 m/min (series II) for 35 min. Glucose turnover was measured by means of an intravenous [3H]glucose infusion. HGP was suppressed by glucose infusion corresponding to the infused amount of glucose in both series, except for late in exercise in series I, where HGP plus infused glucose tended to exceed HGP in saline-infused rats (P less than 0.10). Muscle glycogenolysis and fat metabolism were similar in both groups in the two series. Plasma glucose was never elevated, whereas insulin was, in glucose- vs. saline-infused rats of both series. Plasma catecholamines were lower in glucose- compared with saline-infused rats in series II. In conclusion, HGP is very sensitive to metabolic feedback inhibition at low exercise intensities. Feedforward control of HGP may play a role at higher work loads (series I). Exogenously supplied glucose, in moderate amounts, may replace HGP specifically without concomitant changes in mobilization of other substrates.     

An optical determination of the series resistance in Loligo

The resistance in series with the membrane capacitance in the giant axon of the squid Loligo pealei was measured using potentiometric probes that exhibit absorbance changes proportional to the voltage across the plasma membrane proper. The method relies upon the fact that a voltage drop across the series resistance produces a deviation in the true transmembrane voltage from that imposed by a voltage clamp. Optical measurement of the true transmembrane potential, together with electrical measurement of the ionic current, permits the immediate determination of the series resistance by Ohm's law. An alternative method monitored the amount of electronic series resistance compensation required to force the optical signal to match the shape of the reference potential. The value of the series resistance measured in artificial seawater was 3.78 +/- 0.95 omega X cm2. The estimated value of the contribution of the Schwann cell layer to the series resistance was 2.57 +/- 0.89 omega X cm2.     

Early classification of multivariate temporal observations by extraction of interpretable shapelets

ABSTRACT: BACKGROUND: Early classification of time series is beneficial for biomedical informatics problems suchincluding, but not limited to, disease change detection. Early classification can be oftremendous help by identifying the onset of a disease before it has time to fully take hold. Inaddition, extracting patterns from the original time series helps domain experts to gaininsights into the classification results. This problem has been studied recently using timeseries segments called shapelets. In this paper, we present a method, which we callMultivariate Shapelets Detection (MSD), that allows for early and patient-specificclassification of multivariate time series. The method extracts time series patterns, calledmultivariate shapelets, from all dimensions of the time series that distinctly manifest thetarget class locally. The time series were classified by searching for the earliest closestpatterns. RESULTS: The proposed early classification method for multivariate time series has been evaluated oneight gene expression datasets from viral infection and drug response studies in humans. Inour experiments, the MSD method outperformed the baseline methods, achieving highlyaccurate classification by using as little as 40%-64% of the time series. The obtained resultsprovide evidence that using conventional classification methods on short time series is notas accurate as using the proposed methods specialized for early classification. CONCLUSION: For the early classification task, we proposed a method called Multivariate ShapeletsDetection (MSD), which extracts patterns from all dimensions of the time series. Weshowed that the MSD method can classify the time series early by using as little as40%-64% of the time series' length.     

Human assessment of time intervals depending on the manner of their representation

On 42 subject three experimental series were carried out: in the first (12 persons) and second (24 persons) series the presented interval was limited by two short clicks, in the third series (6 persons)--by electrocutaneous stimuli. Duration of the stimuli was 1 ms. There were three regimes of work in the first and third series: the intervals successively increased from 100 to 500 ms with a step of 100 ms (1), decreased from 5000 to 100 ms (2) or varied in a random order (3). In the second series only the regime 3 was applied. In all series the method of temporal intervals reproduction was used. The means of the reproduction varied: in the second and third series the interval was reproduced by button pressing according to the presented duration: in the first series the end of the interval was marked by a short button push, and the beginning was the moment of the second stimulus presentation. With the first means a considerable overreproduction was observed of the presented duration at all intervals and all regimes. At the second and third series a phasic character of the reproduction duration was noted: up to 1000 ms the interval mostly was overestimated, over 2000 ms--it was significantly underestimated. It is suggested that as the estimation of the temporal interval implies some motor reaction, the afferent flow of signals from the active muscles can change the value of the reproduced duration. In the first series, the subjects probably do not take into account the time necessary for the realized signal perception.     

Polycyclic nitrogen heterocycles as potential thymidine phosphorylase inhibitors: synthesis,biological evaluation,and molecular docking study

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.     

Changes in evoked potentials during systematic exposure to a series of similar signals with variable intersignal intervals]

Series of clicks, standard by the number of stimuli and greatly varying by the length of interstimuli intervals in each series, were systematically presented to dogs without reinforcement. Evoked potentiale (EP) in the cortical auditory zone were recorded. It has been found that a typical U-shaped distribution of amplitude values of averaged EP is elaborated in the series in the course of repeated presentations; a maximal amplitude is observed in response to the first and last clicks, and a minimal, in the middle of the series. Such a regularity was previously found for the action of standard series with a constant interstimuli interval. It is assumed that an estimation may take place in the dog CNS of the number of signals used in a series, whose mechanism is not necessarily based on the time factor. The ability to estimate the number of signals in the series may be regarded as an elementary model of counting in the dogs' CNS.     

Alterative and repair processes in lymph nodes under the direct and mediated effects of radiation]

Under study were the popliteal lymph nodes of rats at different times after total irradiation of animals (the 1st series), total irradiation with screening the left node (the 2nd series) and local screening of other parts of the body (the 3rd series). X-ray irradiation in all experiments was performed under standard conditions in dosage of 800 r. The amount of mitoses (MC 0/00) in light centers and cortical substance was counted in addition to histological alterations. In shielded lymph nodes (2nd series) mediate effects of irradiation were observed characterized by a decrease of the MK amount and massive death of lymphocytes in later terms than after direct effects (1st series). In irradiated nodes (3rd series) the reparative process was more rapid than in the first series due to migration of lymphocytes from non-irradiated parts of the body. The mediate effect of radiation results also in increased amount of plasma cells in lymphatic nodes of animals subjected to total irradiation (1st and 2nd series). It is suggested by the absence of such increase of amount of plasma cells in locally irradiated lymphatic nodes when screening other parts of the body (3rd series). availability of individual distinctions in the character of the lymphoid tissue response to effects of ionizing radiation puts a question of division of experimental animals at least into 2 subgroups which have different indices of proliferative processes.     

A Subsequent Fit of Time Series and Amplitude Histogram of Patch-Clamp Records Reveals Rate Constants up to 1 per Microsecond

Fast gating in time series of patch-clamp current demands powerful tools to reveal the rate constants of the adequate Hidden Markov model. Here, two approaches are presented to improve the temporal resolution of the direct fit of the time series. First, the prediction algorithm is extended to include intermediate currents between the nominal levels as caused by the anti-aliasing filter. This approach can reveal rate constants that are about 4 times higher than the corner frequency of the anti-aliasing filter. However, this approach is restricted to time series with very low noise. Second, the direct fit of the time series is combined with a beta fit, i.e., a fit of the deviations of the amplitude histogram from the Gaussian distribution. Since the “theoretical” amplitude histograms for higher-order Bessel filters cannot be calculated by analytical tools, they are generated from simulated time series. In a first approach, a simultaneous fit of the time series and of the Beta fit is tested. This simultaneous fit, however, inherits the drawbacks of both approaches, not the benefits. More successful is a subsequent fit: The fit of the time series yields a set of rate constants. The subsequent Beta fit uses the slow rate constants of the fit of the time series as fixed parameters and the optimization algorithm is restricted to the fast ones. The efficiency of this approach is illustrated by means of time series obtained from simulation and from the dominant K⁺ channel in Chara. This shows that temporal resolution can reach the microsecond range.     

Social dominance and female reproductive behaviour in rhesus monkeys (Macaca mulatta)

The relationship between dominance rank and female sexual behaviour was examined in rheusus monkeys (Macaca mulatta) living in a social group. High-ranking females engaged in copulatory series as frequently as lower-ranking females. Furthermore, lower-ranking females copulated with as many available males as did high-ranking females. Social rank did appear to influence the pattern of sexual activity exhibited, in that copulatory series were more often initiated by the higher-ranking animal of the mating pair. Copulatory series involving high-ranking females were characterized by more mounts by males and were longer in duration. Higher-ranking animals interfered more often with copulatory series involving other animals, but such interference was not effective in preventing completion of the series. These data indicate that any reproductive advantage conferred to high-ranking females is not the result of sexual competition in social-living rhesus monkeys.     

Le revêtement cutané des raies (Chondrichthyes,Elasmobranchii, Batoidea). II. Morphologie et arrangement des tubercules cutanés

The dermal covering of most batoid fish is constituted by dermal denticles and by different series of tubercles or thorns. The repartition and the morphological variations of these structures can provide complementary information about the taxonomy of skates and rays. The variations in these dermal structures within Pristiforms, Rajiforms and Myliobatiforms have been studied, taking into consideration the number of tubercles, their location and their arrangement in different series. Following Hubbs and Ishiyama [30], two new terms and 15 new series are indicated. The characteristics of the arrangement and of the morphology of these structures can separate the Rajiforms, having spiny tubercles or thorns, from the Myliobatiformes, bearing lanceolate or heart-shaped tubercles. The main taxinomic characters found are: guitar fish characterized by two scapular series, one well-developed rostral series and tubercles with an anterolateral ornamentation (relief). Within this group, Rhinidae and Rhynchobatidae are set apart by the morphology of their tubercles (devoid of any anterolateral ornamentation), by the absence of a middorsal caudal series and by the presence of an outer supraspiracular series. Platyrhina and Platyrhinoidis are distinguishable by the absence of anterolateral relief and by the presence of anterolateral, lateral and parallel series. Rajoids are characterized by thorns, only one scapular series and sometimes a nucho-scapular triangle, malar and alar thorns in adults, and well-developed parallel and lateral series. Myliobatiforms are devoid of rostral, orbito-spiracular, malar, alar, anterolateral, parallel and lateral series but a caudal sting is present in most species. Sawfish are almost entirely devoid of tubercules, except for rostral ‘teeth’. The morphology and arrangement of the rostral teeth can differenciate the two genera within this family.     

天目山柳杉树轮δ13C年序列差异

对天目山3株柳杉树轮δ¹³C年序列分别进行了测定,分析了柳杉树轮δ¹³C年序列变化的异同及其原因.结果表明,在1837～1982年的共同时段,3个树轮δ¹³C年序列彼此间相关系数为：r₁₂=0.47,r₁₃=0.65,r₂₃=0.52 (n=146),都通过了显著性水平α=0.001的信度检验.用多项式拟合法去除原δ¹³C年序列中的高频变化后,所得3个低频序列间高度正相关;原δ¹³C年序列与拟合序列的差值序列即高频序列间也显著正相关,相关系数均达到0.79～0.99,说明气候因素引起树轮δ¹³C年序列的高频变化及大气CO₂浓度引起的低频变化对不同的柳杉个体是共同的.3株树轮δ¹³C年序列间的差异主要是树木立地处局部环境条件的不同所造成的,但是局部环境条件所引起的树轮δ¹³C年序列间的个性差异对其共性变化影响较小.所以,3个树轮δ¹³C年序列间的个性差异,并不影响树轮δ¹³C年作为气候变化研究代用资料的适宜性及重建历史气候结果的可靠性与一致性.     

Polymerization of oligodeoxythymidylates and oligoriboadenylates catalyzed by T4 polynucleotide ligase and their use as analytical markers in polyacrylamide-gel electrophoresis

A series of polymers of oligodeoxythymidylates has been prepared by the T4 polynucleotide ligase-catalyzed joining of oligodeoxythymidylates in the presence of poly(dA) or poly(rA). A similar series of polymers of oligoriboadenylates was prepared by the enzymatic joining reaction of oligoriboadenylates in the presence of poly(dT). Analysis of the polymer series by polyacrylamide-gel electrophoresis showed that polynucleotides of up to 250 nucleotides in length were present. Chain length of individual oligomers could be determined by internal to external phosphate ratios. The oligodeoxythymidylate and oligoriboadenylate polymers provide a series of specific molecular weight markers for size estimation of single-stranded RNA and DNA in the size range 10–200 nucleotides on denaturing gels containing 7 m urea.     

Dynamics of temporal parameters of sensorimotor reactions in relation to the type of human movement

The study was conducted on nine right-handed male subjects 20-24 year old and consisted of two series. In the first series one warning signal in the form of one of the digits (from 1 to 8) was successively presented to the subjects on the display and then four trigger signals which required either simple pressing of the push button (an arrow with a dot) or its holding during 0.5 s (two arrows) by the right or left hand depending on the arrow direction. The digit corresponded to one variant of signals succession. Each variant was repeated randomly among other variants 15 times. In the second series instead of arrows asterisks were presented. Reaction time and duration of push button holding were recorded. Two regularities were observed: significant decrease of RT in the series of reacting by memory and successive decrease of RT in accordance with the decrease of the number of the remaining signals observed in both series. In the first series RT successively decreased by 35-40 ms, in the second one-by 16-20 ms. It is supposed that the difference in RTs between series characterizes the time of signal structure analysis, while the difference in RTs within one block of signals in the second series-the time of extraction of selected motor program from memory.     

Modelling aerobiological time series. Application to Urticaceae

This paper deals with the characterisation ofaerobiological time series. The seriesdiscussed are annual series of mean dailyconcentration of Urticaceae pollen, obtained bymeans of Hirst traps on six sites of theAerobiological Network of Catalonia (XAC).First, some alternatives for fitting a smoothtrend to one of these series are discussed, andtwo satisfactory methods are presented, aGaussian mixture model (parametric) and theFriedman supersmoother (non-parametric).Dividing daily concentrations by trend values,a series of residuals is obtained. The residualseries can be characterised with simpleconventional time series models, and somecommon patterns emerge from the parameterestimates. The long-term patterns of the pollendynamics can be thus characterised by thetrends, and the short-term behaviour by theresiduals. The Spearman correlation is used inthis paper as a measure of the similarity oftwo series.     

Life stress on the Roman limes in continental Croatia

The purpose of the paper is to analyze and compare the demographic profiles and disease frequencies between a skeletal series from Zmajevac, a settlement on the Danubian limes, and a composite «non-limes» skeletal series consisting of human osteological remains from three large urban settlements to the west of the limes; roman Mursa (modern Osijek), Cibalae (Vinkovci) and Certissia (Štrbinci). To determine if life stresses were different in settlements on the limes the age and sex distribution in Zmajevac was compared to the composite «non-limes» series. All skeletons were also analyzed for the presence of dental pathology, dental enamel hypoplasia, cribra orbitalia, trauma, and physical stress.

Data collected from the skeletal series show that, with the exception of some indicators of physical stress, no significant differences in quality of life is evident. Both series are characterized by an underrepresentation of subadults from the youngest age category and by similar average adult male and female ages at death. In Zmajevac the average ages at death for adult males and females were 40.0 and 39.0 years respectively, in the composite «non-limes» series 37.4 years for both males and females. The frequencies of dental disease, subadult stress indicators, and trauma are similar in both series. The only consistent difference between the two series is noted in the frequencies of skeletal markers of physical stress, in particular the frequencies of vertebral osteoarthritis and Schmorl's defects. Total male and total female vertebral osteoarthritis frequencies in the two series are significantly different, as is the difference in total male frequencies of Schmorl's defects. Young adult males in the Zmajevac series seem to have been experiencing particularly heavy physical strain on the vertebral column. They exhibit significantly higher frequencies of both vertebral osteoarthritis and Schmorl's defects than young adult males from the composite non-limes series.     

Name changes in fungi of microbiological,industrial and medical importance

This is the fourth in a series of reports bringing changes in the names of fungi of microbiological, industrial and medical importance to the attention of workers in these fields. The series is sponsored by the Division of Mycology of the International Union of Microbiological Societies (IUMS) and prepared under the auspices of the International Commission on the Taxonomy of Fungi (ICTF). The first of this series of reports included an introduction to the series explaining the need for name changes.