Some cognitive effects of frontal-lobe lesions in man

The study of patients undergoing unilateral frontal-lobe excisions for the relief of focal epilepsy has revealed specific cognitive disorders that appear against a background of normal functioning on many intellectual, perceptual and memory tasks. Lesions that invade the frontal eye field cause subtle impairments of voluntary oculomotor control, which reveal themselves as an inability to suppress an initial glance at a potentially distracting stimulus. After frontal lobectomy in either hemisphere, deficits are found quite consistently on motor-differentiation tasks (Konorski 1972) in which the subject must learn to produce different responses to different, randomly presented, environmental signals. More directly related to the concept of planning are those sequential tasks in which the subject is free to choose his own order of responding, but must not make the same response twice. Here the left frontal lobe plays the major role, a finding consistent with the notion of left-hemisphere dominance for the programming of voluntary actions. In contrast, the right frontal lobe appears to be more critically involved in monitoring the temporal sequence of externally ordered events, although the verbal or non-verbal nature of the stimuli remains a relevant factor.     

Stochastic amplification of fluctuations in cortical up-States

Cortical neurons are bistable; as a consequence their local field potentials can fluctuate between quiescent and active states, generating slow [Formula: see text] Hz oscillations which are widely known as transitions between Up and Down States. Despite a large number of studies on Up-Down transitions, deciphering its nature, mechanisms and function are still today challenging tasks. In this paper we focus on recent experimental evidence, showing that a class of spontaneous oscillations can emerge within the Up states. In particular, a non-trivial peak around [Formula: see text] Hz appears in their associated power-spectra, what produces an enhancement of the activity power for higher frequencies (in the [Formula: see text] Hz band). Moreover, this rhythm within Ups seems to be an emergent or collective phenomenon given that individual neurons do not lock to it as they remain mostly unsynchronized. Remarkably, similar oscillations (and the concomitant peak in the spectrum) do not appear in the Down states. Here we shed light on these findings by using different computational models for the dynamics of cortical networks in presence of different levels of physiological complexity. Our conclusion, supported by both theory and simulations, is that the collective phenomenon of "stochastic amplification of fluctuations" - previously described in other contexts such as Ecology and Epidemiology - explains in an elegant and parsimonious manner, beyond model-dependent details, this extra-rhythm emerging only in the Up states but not in the Downs.     

Nonlinearities make a difference: comparison of two common Hill-type models with real muscle

Compared to complex structural Huxley-type models, Hill-type models phenomenologically describe muscle contraction using only few state variables. The Hill-type models dominate in the ever expanding field of musculoskeletal simulations for simplicity and low computational cost. Reasonable parameters are required to gain insight into mechanics of movement. The two most common Hill-type muscle models used contain three components. The series elastic component is connected in series to the contractile component. A parallel elastic component is either connected in parallel to both the contractile and the series elastic component (model [CC+SEC]), or is connected in parallel only with the contractile component (model [CC]). As soon as at least one of the components exhibits substantial nonlinearities, as, e.g., the contractile component by the ability to turn on and off, the two models are mechanically different. We tested which model ([CC+SEC] or [CC]) represents the cat soleus better. Ramp experiments consisting of an isometric and an isokinetic part were performed with an in situ cat soleus preparation using supramaximal nerve stimulation. Hill-type models containing force–length and force–velocity relationship, excitation–contraction coupling and series and parallel elastic force–elongation relations were fitted to the data. To test which model might represent the muscle better, the obtained parameters were compared with experimentally determined parameters. Determined in situations with negligible passive force, the force–velocity relation and the series elastic component relation are independent of the chosen model. In contrast to model [CC+SEC], these relations predicted by model [CC] were in accordance with experimental relations. In conclusion model [CC] seemed to better represent the cat soleus contraction dynamics and should be preferred in the nonlinear regression of muscle parameters and in musculoskeletal modeling.     

Individual differences in behaviour and their statistical consequences

Some elementary points concerning the statistical consequences of individual differences in behaviour are discussed. Various ways are suggested of taking individual differences into account when designing experiments. True individual differences are represented by the within-group variability that remains after the effects of measurement error have been excluded. Thus, mere variability in data does not necessarily demonstrate that true individual differences are present. Individual differences have two important effects. First, statistical power is reduced, which means that true effects are more difficult to detect. Second, statements about groups may be untrue for all individuals in the group and, conversely, group characteristics may be difficult to infer from measurements of individuals. Some simple tactics for coping with individual differences in experimental data are outlined: (1) obtaining repeated outcome scores for each subject; (2) obtaining a baseline score for each subject prior to the experimental treatment; (3) a combination of 1 and 2; and (4) using a longitudinal design, i.e. obtaining a series of scores across time for each subject. Each of these tactics also has the merit of providing additional information about the nature of the response to the treatment. A fifth tactic is to increase the sample size. Finally, some possible disadvantages of a sixth tactic, that of matching experimental and control subjects, are pointed out.     

Molecular genetic analysis of Down syndrome

Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer’s disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.     

Inhibitory Control,but Not Prolonged Object-Related Experience Appears to Affect Physical Problem-Solving Performance of Pet Dogs

Human infants develop an understanding of their physical environment through playful interactions with objects. Similar processes may influence also the performance of non-human animals in physical problem-solving tasks, but to date there is little empirical data to evaluate this hypothesis. In addition or alternatively to prior experiences, inhibitory control has been suggested as a factor underlying the considerable individual differences in performance reported for many species. Here we report a study in which we manipulated the extent of object-related experience for a cohort of dogs (Canis familiaris) of the breed Border Collie over a period of 18 months, and assessed their level of inhibitory control, prior to testing them in a series of four physical problem-solving tasks. We found no evidence that differences in object-related experience explain variability in performance in these tasks. It thus appears that dogs do not transfer knowledge about physical rules from one physical problem-solving task to another, but rather approach each task as a novel problem. Our results, however, suggest that individual performance in these tasks is influenced in a complex way by the subject’s level of inhibitory control. Depending on the task, inhibitory control had a positive or a negative effect on performance and different aspects of inhibitory control turned out to be the best predictors of individual performance in the different tasks. Therefore, studying the interplay between inhibitory control and problem-solving performance will make an important contribution to our understanding of individual and species differences in physical problem-solving performance.     

The Mobility of The Coordinates of a Subjective Semantic Space As a Manifestation of Categorical Set

The perception and objective semantic interpretation of an object depend on categorical set. Categorical set is the readiness of the subject to interact with objects of a specified category. A multitude of experimental evidence confirms the existence of categorical set. This evidence can be divided into three groups: (a) data indicating that perception depends on experimental instructions; (b) data indicating that perception depends on the category to which the preceding stimulation belongs; and, finally, (c) data indicating that perception depends on individual differences in motivation, which are a priori with regard to the experiment. The reasons for the appearance of sets vary; but in the end they all lead to one and the same result: the evocation of diverse expectations (hypotheses) in different subjects in the same situation, or in the same subject at different moments in time (Bruner, 1977).     

Sharing Research Data and Intellectual Property Law: A Primer

Sharing research data by depositing it in connection with a published article or otherwise making data publicly available sometimes raises intellectual property questions in the minds of depositing researchers, their employers, their funders, and other researchers who seek to reuse research data. In this context or in the drafting of data management plans, common questions are (1) what are the legal rights in data; (2) who has these rights; and (3) how does one with these rights use them to share data in a way that permits or encourages productive downstream uses? Leaving to the side privacy and national security laws that regulate sharing certain types of data, this Perspective explains how to work through the general intellectual property and contractual issues for all research data.For the researcher seeking to use another’s data, this Perspective offers some good news and some not as good news. The good news is that if a source of data—the researcher or repository—gives permission to reuse the data and one’s intended use fits within the scope of the permission, one need not be overly concerned with the details of the discussion that follows because the permission provides the legal basis for data reuse. For example, if one seeks data from the European Bioinformatics Institute, one will find that the terms of use state that “[t]he public databases of EMBL-EBI [The European Molecular Biology Laboratory-The European Bioinformatics Institute] are freely available by any individual and for any purpose” [1]. This would appear to give any individual academic researcher permission to copy and reuse the data at will. It leaves open a question about whether an employee acting on behalf of his or her employer (is s/he acting as “an individual”?) is equally granted this permission.There is, however, a catch. The EBI’s terms also warn the user that some third parties may claim intellectual property or other legal rights on the original data, and it is up to the researcher not to infringe these rights. This kind of legal uncertainty interferes with the productive reuse of research data. It can be avoided if the repository requires depositors to grant permission to downstream users or to give up any intellectual property rights they may have in the data. Alternatively, the final section of this Perspective describes means by which repositories can make it easy for depositors to signal the scope of the permission they grant to downstream users.In the absence of clear permission, mapping how intellectual property law does—and does not—apply to research data may be of use. In my view, the law makes all of this far more complicated than it need be. For those seeking to pick and choose which reuses of another’s data may be permitted by law, regrettably, the answers to the above questions are more context dependent than many would like.This is so for two reasons. First, the source of all intellectual property rights is national law. Certain international treaties harmonize intellectual property owners’ rights but leave the users’ rights to vary by country. Second, certain countries have added protection beyond what the treaties require. Specifically, the members of the European Union, candidate countries in Eastern Europe, Mexico [2], and South Korea have created a specialized database right that applies to certain databases created or maintained within their borders. These laws regulate uses of these databases only within their borders.     

Transit times through the cycle phases of jejunal crypt cells of the mouse. Analysis in terms of the mean values and the variances.

Mean transit times as well as variances of the transit times through the individual phases of the cell cycle have been determined for the crypt epithelial cells of the jejunum of the mouse. To achieve this the fraction of labelled mitoses (FLM) technique has been modified by double labelling with [3H] and [14C]thymidine. Mice were given a first injection of [3H]thymidine, and 2 hr later a second injection of [14C]thymidine. This produces a narrow subpopulation of purely 3H-labelled cells at the beginning of G2-phase and a corresponding subpopulation of purely 14C-labelled cells at the beginning of the S-phase. When these two subpopulations progress through the cell cycle, one obtains FLM waves of purely 3H- and purely 14C-labelled mitoses. These waves have considerably better resolution than the conventional FLM-curves. From the temporal positions of the observed maxima the mean transit times of the cells through the individual phases of the cycle can be determined. Moreover one obtains from the width of the individual waves the variances of the transit times through the individual phases. It has been found, that the variances of the transit times through successive phases are additive. This indicates that the transit times of cells through successive phases are independently distributed. This statistical independence is an implicit assumption in most of the models applied to the analysis of FLM curves, however there had previously been no experimental support of this assumption. A further result is, that the variance of the transit time through any phase of the cycle is proportional to the mean transit time. This implies that the progress of the crypt epithelial cells is subject to an equal degree of randomness in the various phases of the cycle.     

The nature of the memory trace and its neurocomputational implications

The brain processes underlying cognitive tasks must be very robust. Disruptions such as the destruction of large numbers of neurons, or the impact of alcohol and lack of sleep do not have negative effects except when they occur in an extreme form. This robustness implies that the parameters determining the functioning of networks of individual neurons must have large ranges or there must exist stabilizing mechanisms that keep the functioning of a network within narrow bounds. The simulation of a minimal neuronal architecture necessary to study cognitive tasks is described, which consists of a loop of three cell-assemblies. A crucial factor in this architecture is the critical threshold of a cell-assembly. When activated at a level above the critical threshold, the activation in a cell-assembly is subject to autonomous growth, which leads to an oscillation in the loop. When activated below the critical threshold, excitation gradually extinguishes. In order to circumvent the large parameter space of spiking neurons, a rate-dependent model of neuronal firing was chosen. The resulting parameter space of 12 parameters was explored by means of a genetic algorithm. The ranges of the parameters for which the architecture produced the required oscillations and extinctions, turned out to be relatively narrow. These ranges remained narrow when a stabilizing mechanism, controlling the total amount of activation, was introduced. The architecture thus shows chaotic behaviour. Given the overall stability of the operation of the brain, it can be concluded that there must exist other mechanisms that make the network robust. Three candidate mechanisms are discussed: synaptic scaling, synaptic homeostasis, and the synchronization of neural spikes.     

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: Development of a potent and CNS penetrant [3.1.0]-based lead

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclinical model of schizophrenia (prepulse inhibition).     

Cosine analysis of heart beat data of children in a stressful situation

The EKG of twenty-four children (mean age = = 5.7 years) was individually and continuously recorded in a dental situation. Measures of cardiac activity (heart rate [HR] and heart rate variability [HRV]) were computed by means of a CDC 1,700 and an IBM 360 computer. Histograms of heart rate (HR) and heart rate variability (HRV) measures were generated. -Successive cosine fits were fitted for each 70 beats within an interval for each individual and these cosine fits were also presented in a histogram which represented a frequency analysis of cyclic functions within individuals. Within and between subject correlations were also computed for all measures. Sinus arrhythmia seemed to account for less of the variance than a yet unexplained cosine fit function having a lower limit of 18.6 seconds in this child population. In this population many measures of HRV seem to be negatively correlated with HR.     

Criteria of Intellectual Development in Children

The psychodiagnosis of child intellectual development has become a timely problem in connection with our country's school reform [1]. Now that school-entry age has been lowered to six years, procedures for diagnosing level of intellectual development, to determine whether children are ready for school, must be developed and applied routinely. This, in turn, requires the development of scientifically sound criteria of intellectual development, based on modern psychological concepts of the development of intelligence in ontogeny.     

Analysis of benzo[a]pyrene deactivation mechanisms in rats

The experimental data on the effects of a widespread carcinogen, benzo[a]pyrene (BP), on individual reactions of rats were treated using mathematical-statistical methods. The individual reactions were analyzed in dependence of doses and modes of administration (single or chronic). The analysis revealed a statistically significant correlation between life span and urinary content of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (7,8-BP) in rats treated with BP. The calculated regression equations revealed that the individual sensitivity to carcinogen in case of the BP single administration to rats is mainly determined by efficiency of excretion of the BP active forms out of the organism, whereas after chronic BP administration it is determined by mechanisms of enzymatic deactivation of BP.     

The Difference Between Selection and Drift: A Reply to Millstein

Millstein [Bio. Philos. 17 (2002) 33] correctly identies a serious problem with the view that natural selection and random drift are not conceptually distinct. She offers a solution to this problem purely in terms of differences between the processes of selection and drift. I show that this solution does not work, that it leaves the vast majority of real biological cases uncategorized. However, I do think there is a solution to the problem she raises, and I offer it here. My solution depends on solving the biological analogue of the reference class problem in probability theory and on the reality of individual fitnesses.     

启发式思考题对医学本科分子生物学实验教学的促进作用

目的:通过自行设计的启发式思考题,让问题式学习伴随医学生分子生物学实验教学全程,利用实验课的教学互动环节发挥学生学习的主观能动性。方法:借鉴启发式教学经验和问题式教学方法,在实验的平时考核中增加了启发式思考题,针对教学内容设置拓展性问题,以开卷回答的方式引导学生通过自学寻找操作实践及其理论基础中潜在的知识内涵和科学规律。结果:思考题的引入在强化学生自主学习,锻炼思考和解决问题能力的同时也显示出了良好的区分度。思考题成绩以及以此为基础的平时成绩与实验理论考核成绩之间显示出了显著的相关性。结论:贯穿于实验课教学活动中的启发式思考题在拓展思维、提升学生自主学习能力的同时促进了实验课的教学效果。     

黄酮碳苷类化合物ESIMS-MS裂解规律初探

本研究通过ESIMS-MS技术分析一系列黄酮化合物的裂解情况,探讨黄酮碳苷类化合物ESIMS-MS的裂解规律。结果表明,六碳黄酮碳苷ESIMS-MS的子离子谱图中出现[M-H-60]-、[M-H-90]-和[M-H-120]-的离子碎片;五碳黄酮碳苷ESIMS-MS的子离子谱图中只能产生脱去60和90质量单位的碎片峰。该研究表明黄酮碳苷类化合物ESIMS-MS裂解具有一定的规律性,并有助于发现微量黄酮碳苷类成分。     

SENSORY ANALYSIS PROCEDURES AND VIEWPOINTS: INTELLECTUAL HISTORY,CURRENT DEBATES,FUTURE OUTLOOKS1

This paper presents the intellectual history of product testing (sensory analysis). It traces the history from two separate streams; the expert (and expert panelist), and the empiricist (sociologist, followed by experimental psychologist). Sensory analysis in the last decade of the 20th century is host to many of the same intellectual arguments in these two fields as were current a half century ago, or longer, in psychology. What has been absent is a set of worldviews and organizing principles around which the field can grow and mature more rapidly. The paper presents three major organizing subject areas for sensory analysis: individual differences (sensory segmentation), sensory-instrumental analysis (reverse engineering), and cognitive approaches (mixed modeling and optimization of physical and conceptual variables). These three subject areas and their organizing principles provide sensory analysis with a vision of future research and application that accord with the scientific heritage and extend current procedures.     

Delineation of the Role of Astroglial GABA Transporters in Seizure Control

Studies of GABA transport in neurons and astrocytes have provided evidence that termination of GABA as neurotransmitter is brought about primarily by active transport into the presynaptic, GABAergic nerve endings. There is, however, a considerable transport capacity in the astrocytes surrounding the synaptic terminals, a transport which may limit the availability of transmitter GABA leading to a higher probability of seizure activity governed by the balance of excitatory and inhibitory neurotransmission. Based on this it was hypothesized that selective inhibition of astrocytic GABA transport might prevent such seizure activity. A series of GABA analogs of restricted conformation were synthesized and in a number of collaborative investigations between Prof. Steve White at the University of Utah and medicinal chemists and pharmacologists at the School of Pharmacy and the University of Copenhagen, Denmark, GABA analogs with exactly this pharmacological property were identified. The most important analogs identified were N-methyl-exo-THPO (N-methyl-3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole) and its lipophilic analog EF-1502 ((RS)-4-[N-[1,1-bis(3-methyl-2-thienyl)but-1-en-4-yl]-N-methylamino]-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) both of which turned out to be potent anticonvulsants in animal models of epilepsy.