Realism about mental disorders is a perennial area of dispute, but the controversy burns especially intensely for Attention Deficit Hyperactivity Disorder. In this dissertation, I clarify what is at issue in these debates, surveying how realists have typically argued for mental disorder realism: the definitional debate about health and illness. I argue that the realist need not be committed to the terms of the definitional debate and recommend that a better approach is to show that mental disorders are natural kinds. (...) While there are many accounts of kind-hood on offer, I adopt Richard Boyd’s homeostatic property cluster theory of kinds, which I interpret through the philosophy of neuroscience literature on mechanisms. In sum, I conclude that if ADHD is a natural kind – and thus real – then individuals diagnosed with the disorder should be sufficiently similar with respect to an underlying cognitive neurobiological mechanism. To determine whether ADHD individuals are similar in this way, I consider the question through Russell Barkley’s Executive Function Model of ADHD. Relying primarily on the cognitive neurobiological research, I argue that there is now reasonable evidence to conclude that the DSM classification of ADHD corresponds not to a single natural kind, but several. Thus, ADHD is thus real. (shrink)

This study surveyed investors to determine the extent to which they preferred ethical behavior to profits and their interest in having information about corporate ethical behavior reported in the corporate annual report. First, investors were asked to determine what penalties should be assessed against employees who engage in profitable, but unethical, behavior. Second, investors were asked about their interest in using the annual report to disclose the ethical performance of the corporation and company officials. Finally, investors were asked if they (...) felt that ethics reports should be audited.The survey results indicate that many shareholders (42%) do not expect a high level of ethical behavior from corporate employees or officers. There is a significant amount of interest in disclosure of ethical issues (72%) and unwillingness to trust management to provide unbiased reports of ethical behavior. If such reports are included with the financial statements, 32 percent of the investors surveyed would prefer to have them audited to provide independent verification. (shrink)

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an anti‐tumourigenic mechanism. We describe how (...) hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. (shrink)

Chromosomes are not only carriers of the genetic material, but also actively regulate the assembly of complex intracellular architectures. During mitosis, chromosome‐induced microtubule polymerisation ensures spindle assembly in cells without centrosomes and plays a supportive role in centrosome‐containing cells. Chromosomal signals also mediate post‐mitotic nuclear envelope (NE) re‐formation. Recent studies using novel approaches to manipulate histones in oocytes, where functions can be analysed in the absence of transcription, have established that nucleosomes, but not DNA alone, mediate the chromosomal regulation (...) of spindle assembly and NE formation. Both processes require the generation of RanGTP by RCC1 recruited to nucleosomes but nucleosomes also acquire cell cycle stage specific regulators, Aurora B in mitosis and ELYS, the initiator of nuclear pore complex assembly, at mitotic exit. Here, we review the mechanisms by which nucleosomes control assembly and functions of the spindle and the NE, and discuss their implications for genome maintenance. (shrink)

This paper offers a reconstruction of Xenocrates’ theory of indivisibles which would not commit him to the idea of ‘jerky motion’ criticized by Aristotle in Physica VI, yet would perfectly square with Plato’s Timaeus, the basis of Xenocrates’ canon. Relying on Alexander’s, Porphyry’s, and Themistius’s accounts of his theory, as well on a detailed analysis of De lineis insecabilibus, I suggest that Xenocrates’ minima, contrary to what Aristotle implies, are not to be understood as more or less stable particulars, like (...) tiny chunks of matter, moving about or leaping in physical space from point A to point B. Yet Xenocrates’ minima do remain ‘physical’ and ‘corporeal’ in a more Platonic sense of these words, not presupposing any kind of leaping, jumping, or jerking. This explains why Xenocrates associated the sensible realm with one of the three Fates, namely Clotho. (shrink)

The position of the spindle determines the position of the cleavage plane, and is thus crucial for cell division. Although spindle positioning has been extensively studied, the underlying forces ultimately responsible for moving the spindle remain poorly understood. A recent pioneering study by Garzon‐Coral et al. uses magnetic tweezers to perform the first direct measurements of the forces involved in positioning the mitotic spindle. Combining this with molecular perturbations and geometrical effects, they use their data to (...) argue that the forces that keep the spindle in its proper position for cell division arise from astral microtubules growing and pushing against the cell's cortex. Here, we review these ground‐breaking experiments, the various biomechanical models for spindle positioning that they seek to differentiate, and discuss new questions raised by these measurements. (shrink)

Sleep spindles are frequently studied for their relationship with state and trait cognitive variables, and they are thought to play an important role in sleep-related memory consolidation. Due to their frequent occurrence in NREM sleep, the detection of sleep spindles is only feasible using automatic algorithms, of which a large number is available. We compared subject averages of the spindle parameters computed by a fixed frequency (11-13 Hz for slow spindles, 13-15 Hz for fast spindles) automatic detection algorithm and (...) the individual adjustment method (IAM), which uses individual frequency bands for sleep spindle detection. Fast spindle duration and amplitude are strongly correlated in the two algorithms, but there is little overlap in fast spindle density and slow spindle parameters in general. The agreement between fixed and manually determined sleep spindle frequencies is limited, especially in case of slow spindles. This is the most likely reason for the poor agreement between the two detection methods in case of slow spindle parameters. Our results suggest that while various algorithms may reliably detect fast spindles, a more sophisticated algorithm primed to individual spindle frequencies is necessary for the detection of slow spindles as well as individual variations in the number of spindles in general. (shrink)

Although alterations in Ras signalling are found in about 30% of human cancers, the transforming activity of oncogenic Ras is not fully understood. In a recent paper, a putative Ras1 effector in S. pombe, named Scd1, was reported to localize to mitotic apindies. Scd1 physically associates with Moe1, a factor that may contribute to the inherent inatability of microtubules (MTs) and appears to be needed for proper apindle function. Altered MT dynamics within the spindle are likely to affect (...) class='Hi'>spindle assembly and chromosome capture, processes that need to be delicately controlled if cells are to guard against genome instability adn transformation. BloEssays 23: 307‐310,2001.©2001 John Willey & Sons, Inc. (shrink)

Asymmetric cell division generates cell diversity and contributes to cellular aging and rejuvenation. Here, we review the molecular mechanisms enabling budding yeast to recognize spindle pole bodies (SPB, centrosome equivalent) based on their age, and guide their non‐random mitotic segregation: SPB inheritance requires the distinction of old from new SPBs and is regulated by the SPB‐inheritance network (SPIN) and the mitotic exit network (MEN). The SPIN marks the pre‐existing SPB as old and the MEN recognizes these marks translating them (...) into spindle orientation. We next revisit other molecules and structures that partition depending on their age rather than their abundance at mitosis as, for example, DNA, centrosomes, mitochondria, and histones in yeast and other systems. The recurrence of this differential behavior suggests a functional significance for numerous cell types, which we then discuss. We conclude that non‐random segregation may facilitate asymmetric cell fate determination and thereby indirectly aging and rejuvenation. (shrink)

Localized mRNA translation is a biological process that allows mRNA to be translated on‐site, which is proposed to provide fine control in protein regulation, both spatially and temporally within a cell. We recently reported that Vasa, an RNA‐helicase, is a promising factor that appears to regulate this process on the spindle during the embryonic development of the sea urchin, yet the detailed roles and functional mechanisms of Vasa in this process are still largely unknown. In this review article, to (...) elucidate these remaining questions, we first summarize the prior knowledge and our recent findings in the area of Vasa research and further discuss how Vasa may function in localized mRNA translation, contributing to efficient protein regulation during rapid embryogenesis and cancer cell regulation. (shrink)

At anaphase chromosomes move to the spindle poles (anaphase A) and the spindle poles move apart (anaphase B). In vitro studies using isolated diatom spindles demonstrate that the primary mechano‐chemical event responsible for spindle elongation is the sliding apart of half‐spindle microtubules. Further, these forces are generated within the zone of microtubule overlap in the spindle midzone.

Tissues are shaped and patterned by mechanical and chemical processes. A key mechanical process is the positioning of the mitotic spindle, which determines the size and location of the daughter cells within the tissue. Recent force and position-fluctuation measurements indicate that pushing forces, mediated by the polymerization of astral microtubules against­ the cell cortex, maintain the mitotic spindle at the cell center in Caenorhabditis elegans embryos. The magnitude of the centering forces suggests that the physical limit on the (...) accuracy and precision of this centering mechanism is determined by the number of pushing microtubules rather than by thermally driven fluctuations. In cells that divide asymmetrically, anti-centering, pulling forces generated by cortically located dyneins, in conjunction with microtubule depolymerization, oppose the pushing forces to drive spindle displacements away from the center. Thus, a balance of centering pushing forces and anti-centering pulling forces localize the mitotic spindles within dividing C. elegans cells. We discuss microtubule-based mechanisms of the mitotic spindle positioning, a key mechanical process that shapes and patterns tissues. The magnitude of the centering forces indicates that the physical limit on the accuracy and precision of centering is set by the number of contributing microtubules rather than by thermally driven fluctuations. (shrink)

Mitotic spindles constitute the machinery responsible for equidistribution of the genetic material into each daughter cell during cell division. They are transient and hence quite labile structures, changing their morphology even while performing their function. Biochemical, immunological and genetic analyses of mitotic cells have allowed us to identify a variety of molecules that are recruited to form the spindle at the onset of mitosis. Evaluation of the roles of these molecules in both the formation and in the dynamics of (...) spindle microtubules should be important for understanding the molecular basis of mitosis and its regulation. We have recently identified a novel mitosis‐specific microtubule‐associated protein (MAP) using a monoclonal antibody probe raised against the mitotic spindles isolated from cultured mammalian cells. This 95/105 kDa antigen represents a unique component of the spindle distinct from any of the other MAPs reported so far. Antibody microinjection resulted in mitotic inhibition in a stage‐specific and dosedependent manner, indicating that the protein is an essential spindle component. (shrink)

This paper examines whether there are moral differences between the mitochondrial replacement techniques that have been recently developed in order to help women afflicted by mitochondrial DNA diseases to have genetically related children absent such conditions: maternal spindle transfer and pronuclear transfer. Firstly, it examines whether there is a moral difference between MST and PNT in terms of the divide between somatic interventions and germline interventions. Secondly, it considers whether PNT and MST are morally distinct under a therapy/creation optic. (...) Finally, it investigates whether there is a moral difference between MST and PNT from a human embryo destruction point of view. I conclude, contra recent arguments, that regarding the first two points there is no moral differences between PNT and MST; and that regarding the third one MST is morally preferable to PNT, but only if we hold a gradualist account of the moral value of human embryos where zygotes have slight moral value. (shrink)

News about the first baby born after a mitochondrial replacement technique (MRT; specifically maternal spindle transfer) broke on September 27, 2016 and, in a matter of hours, went global. Of special interest was the fact that the mitochondrial replacement procedure happened in Mexico. One of the scientists behind this world first was quoted as having said that he and his team went to Mexico to carry out the procedure because, in Mexico, there are no rules. In this paper, we (...) explore Mexico's rule of law in relation to mitochondrial replacement techniques and show that, in fact, certain instances of MRTs are prohibited at the federal level and others are prohibited at the state level. According to our interpretation of the law, the scientists behind this first successful MRT procedure broke federal regulations regarding assisted fertilization research. (shrink)

The neuromodulatory effects of brain stimulation therapies notably involving repetitive transcranial magnetic stimulation on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to (...) investigate cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex. All-night polysomnography data was acquired at four time points: Adaptation, Baseline, Post-1, and Post-2. Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II–IV at four electrode sites: F3, F4, P3, and P4. Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation. (shrink)

The mitotic spindle contains the machinery responsible for sister chromatid segregation. It is composed of a complex and dynamic array of microtubules, which are nucleated from the spindle poles. Studies of yeast spindle functions by molecular genetic analysis and by in vitro functional analysis have identified proteins that are mitosis‐specific and present at very low concentrations in the cell, and have revealed the molecular bases of several processes required for the formation and functioning of the mitotic (...) class='Hi'>spindle. Here I review the current knowledge of the processes that are common to most eukaryotes: microtubule nucleation at the spindle poles, bipolar spindle assembly, maintenance of the spindle structure, chromosome attachment to the spindle and chromosome separation on the spindle. (shrink)

In the discussions leading up to the enactment of the UK Human Fertilisation and Embryology Regulations 2015, it was repeatedly emphasised, by many commentators, that maternal spindle transfer and pronuclear transfer did not give rise to children who could be considered as having three or more parents. This was because it was argued that only the genetic material found in the chromosomes should be considered as the determining factor for the formation of parent–child relationships and the resulting kinship identities. (...) In this present study, however, this assertion will be questioned in the light of different kinds and different understandings of kinship identities. It will also be suggested that any person who is partly responsible for the very existence of a child, through any means, may qualify as a causal parent — a parent whom the resulting child may want to identify. As a result, a positive response should be given to a request from a person born from MST and PNT concerning identifying information for all the individuals responsible for bringing him or her into existence. In the light of this, the article will conclude that it is regrettable that the UK government enacted binding legislation making sure that children, born through MST and PNT, will never be able to contact the egg donors and, in the case of PNT, the sperm donors. This reflects a very limited understanding of who parents really are and may give rise to serious long-term psychological distress in the prospective children. (shrink)

This commentary implicates the neostriatum in the production of the EEG sleep spindle and in the processing of motor procedural learning in sleep. Whether the sleep spindle may implement not only the consolidation-based enhancement of procedural learning, but also its initial consolidation, is considered; as is the fit between (1) corticostriatal anatomy and physiology, and (2) the physical properties of the sleep spindle.

The assembly of a bipolar spindle is essential for the accurate segregation of replicated chromosomes during cell division. Do chromosomes rely solely on other cellular components to regulate the assembly of the bipolar spindle or are they masters of their own fate? In the Zhang and Nicklas(1) study reviewed here, micromanipulation techniques and video microscopy were used to demonstrate the different roles that chromosome arms, kinetochores and centrosomes play in bipolar spindle assembly.

Marsilio Ficino (1433–99) was greatly intrigued by the questions on free will raised by the myth of Er in Plato’s Republic. By focusing on his Argumentum in Platonis Respublicam, this article discusses Ficino’s interpretation of the myth in light of his view on the faculties of the soul—intellect, reason, the imagination, and the vegetative power—and of how they become subject to providence or fate. Moreover, it will situate Ficino’s discussion of the myth within his understanding of the universe as an (...) interconnected organism in which different levels of life are perfectly attuned with one another. (shrink)

The human spindle and kinetochore associated complex is required for proper mitotic progression. Extensive studies have demonstrated its important functions in both stable kinetochore-microtubule interactions and spindle checkpoint silencing. We suggest a model to explain how various Ska functions might be fulfilled by distinct pools of Ska at kinetochores. The Ndc80-loop pool of Ska is recruited by the Ndc80 loop, or together with some of its flanking sequences, and the recruitment is also dependent on Cdk1-mediated Ska3 phosphorylation. This (...) pool seems to play a more important role in silencing the spindle checkpoint than stabilizing kinetochore-microtubule interactions. In contrast, the Ndc80-N-terminus pool of Ska is recruited by the N-terminal domains of Ndc80 and appears to be more important for stabilizing kinetochore-microtubule interactions. Here, we review and discuss the evidence that supports this model and suggest further experiments to test the functioning mechanisms of the Ska complex. The human spindle and kinetochore associated complex plays essential functions in proper mitotic progression by promoting stable kinetochore-microtubule interactions and spindle checkpoint silencing. We propose that “distinct pools” of Ska—the Ndc80-loop and Ndc80-N-terminus pools—might fulfill these various functions. (shrink)

Beta‐catenin is a multifunctional protein with critical roles in cell‐cell adhesion, Wnt‐signaling and the centrosome cycle. Whereas the roles of β‐catenin in cell‐cell adhesion and Wnt‐signaling have been studied extensively, the mechanism(s) involving β‐catenin in centrosome functions are poorly understood. β‐Catenin localizes to centrosomes and promotes mitotic progression. NIMA‐related protein kinase 2 (Nek2), which stimulates centrosome separation, binds to and phosphorylates β‐catenin. β‐Catenin interacting proteins involved in Wnt signaling such as adenomatous polyposis coli, Axin, and GSK3β, are also localized at (...) centrosomes and play roles in promoting mitotic progression. Additionally, proteins associated with cell‐cell adhesion sites, such as dynein, regulate mitotic spindle positioning. These roles of proteins at the cell cortex and Wnt signaling that involve β‐catenin indicate a cross‐talk between different sub‐cellular sites in the cell at mitosis, and that different pools of β‐catenin may co‐ordinate centrosome functions and cell cycle progression. (shrink)

The relationship between kinetochores and nuclear pore complexes (NPCs) is intimate but poorly understood. Several NPC components and associated proteins are relocated to mitotic kinetochores to assist in different activities that ensure faithful chromosome segregation. Such is the case of the Mad1‐c‐Mad2 complex, the catalytic core of the spindle assembly checkpoint (SAC), a surveillance pathway that delays anaphase until all kinetochores are attached to spindle microtubules. Mad1‐c‐Mad2 is recruited to discrete domains of unattached kinetochores from where it promotes (...) the rate‐limiting step in the assembly of anaphase‐inhibitory complexes. SAC proficiency further requires Mad1‐c‐Mad2 to be anchored at NPCs during interphase. However, the mechanistic relevance of this arrangement for SAC function remains ill‐defined. Recent studies uncover the molecular underpinnings that coordinate the release of Mad1‐c‐Mad2 from NPCs with its prompt recruitment to kinetochores. Here, current knowledge on Mad1‐c‐Mad2 function and spatiotemporal regulation is reviewed and the critical questions that remain unanswered are highlighted. (shrink)

Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers stress tolerance, (...) and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment. PTEN is a guardian of the genome. However, the role of PTEN in guarding the genome has not been revealed until recently. PTEN controls multiple fundamental processes of genomic transmission. By physically interacting with key molecules in DNA replication, DNA repair/decatenation, and chromosome segregation during the cell cycle, PTEN maintains genomicintegrity and fitness. (shrink)