Telomere identity crisis(بحران هویت)

Telomere identity crisis

 

Bridget L. Baumgartner1,2 and Vicki Lundblad1,3

1Salk Institute for Biological Research, La Jolla, California 92037, USA; 2Interdepartmental Program in Cell and Molecular

Biology, Baylor College of Medicine, Houston, Texas 77030, USA Cells are designed to be intolerant of breaks in DNA, yet it is critical that cells do not identify the ends of linear chromosomes, called telomeres, as damaged DNA ends. Telomeres therefore must somehow prevent the recognition and subsequent repair of chromosome ends as double-strand breaks (DSBs), although how this is achieved is poorly understood. Chromosomal breaks can occur as a result of ionizing radiation, DNA replication across nicked DNA, or as intermediates of recombination. Whether these breaks are induced by the cell—for example, due to V(D)J recombination during lymphocyte development—or arise as a consequence of spontaneous damage, it is imperative that such lesions be repaired in order to prevent genomic rearrangements or even outright chromosome loss (Bassing and Alt 2004). The cell avoids such deleterious consequences by mounting a response, called the DNA damage checkpoint,

which pauses the cell cycle, thereby permitting the efficient recruitment of a highly conserved set of proteins to the break (Zhou and Elledge 2000; Nyberg et al. 2002). In the budding yeast Saccharomyces cerevisiae, this process has been studied extensively using an experimental system that allows the creation of a single DSB at high frequency at a defined site, through the action of a sequence-specific endonuclease, HO (Rudin and Haber 1988). The DNA damage checkpoint is alerted to the presence of the HO-generated break by recruitment of sensor proteins, such as Tel1/ATM and Mec1/ATR, to the site of damage (Lisby et al. 2004; Garber et al. 2005). These kinases activate downstream effector proteins, Rad53/CHK2, Rad9, and Dun1, which in turn facilitate the activation of repair proteins. Repair of DSBs requires the recognition of these broken ends by the Ku70/80 heterodimer and the Mre11–Rad50–Xrs2 complex (MRX, or MRN in humans). The cell then has a choice between two pathways for DNA repair. If DSBs are repaired through the nonhomologous end-joining pathway (NHEJ), DNA ligase 4 is brought in to seal the two ends together. If the repair is accomplished by homologous recombination, the DSB is first processed by an exonuclease

to reveal a single-stranded 3_ overhang, which subsequently initiates recombination with homologous sequences present in the genome. Functional DNA damage checkpoints also act to inhibit cell cycle progression in the presence of damaged DNA. Even a single DSB is sufficient to cause the cell cycle to arrest until repair is completed (Sandell and Zakian 1993), thereby ensuring

that cells do not progress through mitosis until the integrity of the genome has been restored. Despite the presence of a highly efficient machine for the recognition of DSBs, the ends of linear chromosomes are natural DNA termini that must somehow be masked from triggering the DNA damage checkpoint and subsequent repair events. This unique property of telomeres is owed to the sequence and structure of the telomere DNA itself, as well as to the proteins that localize to chromosome ends (Blackburn 2001; Smogorzewska and de Lange 2004). In most eukaryotes, telomeres are composed of tandem G-rich repeats that terminate with a 3_ singlestranded overhang of the G-rich strand, often referred to as a G-tail. Disruption of this G-tail structure, due to

either loss of the G-tail itself or exposure of the C-strand to nucleolytic attack, is a lethal event for the cell. Thus, cells have developed a dynamic protein assembly that

maintains a telomere “cap.” In budding yeast, this cap depends in part on the essential single-strand telomerebinding protein Cdc13, along with several Cdc13-interacting factors. Loss of the Cdc13 complex exposes yeast telomeres to massive resection of the C-strand, with the

resulting 20–30-kb region of exposed single-stranded DNA provoking arrest of the cell cycle (Weinert et al. 1994; Garvik et al. 1995; Booth et al. 2001). A second protein, Rap1, which is bound to duplex telomeric repeats, may aid in protection of the other strand of the telomere, the G-strand overhang: Depleting cells of Rap1 causes telomere fusions that are mediated through the NHEJ pathway (Pardo and Marcand 2005). Mammalian cells also possess a mechanism to protect the vulnerable G-tail, which similarly relies on a duplex telomere DNA-binding factor called TRF2. In TRF2-deficient

cells, the integrity of the terminal G-strand overhang is disrupted, resulting in high frequencies of end-to-end fusions (van Steensel et al. 1998; Celli and de Lange 2005). This TRF2-mediated telomere capping activity may be aided by the ability of telomeres to fold into a looped structure, called the t-loop, wherein the 3_ overhang invades the duplex region of telomere repeats (Griffith et al. 1999). Not unexpectedly, normal telomeres rarely interact with DSBs. However, loss of telomere repeats can lead to “repair” of chromosome ends, through either recombination (Lundblad and Blackburn 1993; Bryan et al. 1995) or end-to-end fusions (Smogorzewska et al. 2002). The latter situation creates dicentric chromosomes, which are unstable in dividing cells. Dysfunctional telomeres can be created experimentally, through genetic manipulation of telomere-associated components or by altering the sequence of the telomere repeats themselves. Human cells, in which telomerase expression has been

down-regulated, can also accumulate eroded telomeres as a consequence of continual cell division. In both cases, critically shortened telomeres trigger a damage response that prevents the cells from dividing in the absence of intact chromosome ends. Cells can, however, escape this block to proliferation (albeit at very low frequencies) and continue to divide in the absence of functional

telomeres, but at a price: Such “escapees” display massive levels of chromosomal rearrangements, illustrating the importance of telomeres for genome stability. Given all this, it is tempting to assume that telomeres prevent components of DNA damage-responsive pathways from interacting with the ends of chromosomes. However, the situation is more complicated, as many of the genes required for DNA repair are also necessary for normal telomere maintenance (Maser and DePinho 2004). The intertwining of DSB repair and telomere maintenance extends to pathways involved in signaling damage, as well as to those responsible for the actual repair of damage. For example, the members of the NHEJ pathway are intimately involved in telomere maintenance. This is paradoxical considering it is the NHEJ pathway that causes the fusion of chromosomes when telomeres become dysfunctional, and yet, the components of this pathway affect multiple facets of telomere metabolism. In yeast, the Ku heterodimer exhibits a robust association with telomeres and is required for capping, modulation of subtelomeric gene expression, and even telomere length regulation as the result of a direct interaction with the telomerase holoenzyme (Bertuch and Lundblad 2003). Likewise, deletion of any of the MRX subunits leads to telomere shortening (Boulton and Jackson 1998), possibly because telomere-specific proteins such as Cdc13 fail to be recruited to telomeres in the absence of MRX function (Diede and Gottschling 2001; Takata et al. 2005)...

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Eye movement theory

Eye movement theory
Eye movement would generally entail low-level functions, though it necessarily involves high-level functions as well. Whenever one views a figure, the fixation point jumps around from one interesting feature to another. The trajectory of this rapid eye movement is distorted or changed in some way under, for instance, the influences of neighboring features, and this causes the illusion. However, it is easy to show that geometrical illusion does not necessarily need eye movement. If you are presented an illusory figure for a fraction of a second, you will still see the illusion. In such a short time, eye movement is not possible. It is also true that in a short presentation the magnitude of the illusion is generally larger than in a long presentation. Therefore, the eye movement theory is not perfect. An excellent counter argument is that we do not need physical eye movement but only the preparation for the eye movement in the brain to get an illusion.

 

 

 

EMDR - Eye Movement Desensitization and Reprocessing

Eye Movement Desensitization and Reprocessing (EMDR)remains acontroversial treatment technique despite the fact that it was developed by Francine Shapiro in 1987. It was initially used to treat trauma survivors, but it is now also used with phobias and other problems.

The treatment is fairly complex and includes elements from several different schools of therapy. There are eight stages to the treatment technique, and they draw from different approaches and orientations.

The most unusual part of the treatment involves the therapist waving his or her fingers back and forth in front of the client's eyes, and the client tracking the movements while focusing on a traumatic event. The act of tracking while concentrating seems to allow a different level of processing to occur. The client is often able to review the event more calmly or more completely than before.

EMDR also includes a strong cognitive-behavioral component. Clients are asked to come up with a negative belief about themselves which resulted from the trauma, and asked "What would you rather believe about yourself?" At various points the client rates their level of emotions and the extent to which they believe this new belief.

How does it work? That's one of the mysteries. Shapiro proposes an "accelerated information processing theory" mechanism. In earlier writings she speculated on the relationship between the eye movements and the eye movements in REM sleep. Another interesting theory has been presented online in the paper "An Orienting Reflex/External Inhibition Model of EMDR and Thought Field Therapy" by Nathan R. Denny, Ph.D. Denny speculates that both EMDR and "Thought Field Therapy" work by a common mechanism. He states that the eye movements elicit the orienting reflex, and that this reflex is incompatible with the fight-or-flight response.

I asked Dr. Shapiro about this theory in her online forum An EMDR Discussion with Francine Shapiro. This forum on Behavior Online is a fascinating opportunity to discuss these issues with the psychologist who developed the technique. A portion of her reply:

The inhibition of a fight or flight mechanism is intriguing. However, as I stipulated in the text, hypotheses regarding potential effects of the eye movements alone are insufficient to account for the wide range of treatment effects. For that one has to look at an interaction of the all the various procedural elements. (Shapiro, 1997)

Suzanne Hurst and Natasha Milkewicz have written a review of the research in a paper entitled Eye Movement Desensitization and Reprocessing - A Controversial Treatment Technique. They conclude that EMDR deserves further research because of the surprisingly positive results from a number of studies. In their review they note that Shapiro has been criticized for insisting that all EMDR training be done by herself and a select group of people that she has trained. Her organization thus stands to profit from all of the training.

Some of the criticism has been muted since she published Eye Movement Desensitization and Reprocessing : Basic Principles, Protocols, and Procedures in 1995. This book explains the technique in detail so that researchers can fully examine it. Clinicians are still encouraged to receive training in this complex procedure.

I've been trained in EMDR and I use it at times in my practice. I have seen it work extremely well to relieve trauma symptoms in a short period of time, but it does not seem to work for everyone. We need more research and study to determine who this treatment works best for.

Visual-motor transformations for smooth pursuit eye movements

 

When a small, smoothly moving object appears, primates are able to generate a smooth eye movement having a velocity nearly equal to the velocity of the target. The basic anatomical circuit for pursuit is known -- from retina to motoneuron. We are trying to understand how visual inputs related to moving targets are converted by the brain to commands for motor action. In the past 5 years, we have discovered that pursuit is a complex voluntary motor behavior that comprises many components. These include: the representation of target motion with respect to the eye, primarily in extrastriate area MT (Lisberger & Movshon 1999; Osborne et al 2004); pooling of the population response in MT to acquire good estimates of the direction and speed of target motion (Churchland & Lisberger 2001; Gardner et al 2004); an on-line volume control that regulates how strongly visual inputs are transmitted to the motor system (Tanaka & Lisberger 2001); the ability to choose targets based on a spatial window of motor attention under the control of orienting, saccadic eye movements (Gardner & Lisberger 2002); learning based on the recent history of target motions (Chou & Lisberger 2004; Medina & Lisberger 2005); and cerebellar compensation for the physical properties of the eye and orbit.

Our work is currently focusing on two main concepts.

1) We are using theoretical approaches to exploit the variation in natural pursuit behavior and neural responses. Our goal is to correlate the variation in neural and motor behavior as a way of understanding how different groups of neurons contribute to pursuit behavior. Recent unpublished results have revealed that the variation in pursuit behavior can be understood in terms of errors in estimates of the direction, speed, and time of onset of target motion. The coordinate system of the variations implies pursuit operates at the precision to sensory coding, and that motor noise may arise primarily from sensory representations. By relating variations in sensory representation to variations in motor behavior, we will understand how neurons pool the sensory population response to generate eye movements.

2) We are using a combination of precise measurements of eye movement, electrical stimulation, and neural recordings to evaluate the neural basis for modulation of the strength of visual transmission to the motor system. We have evidence that the neural mechanism of this "gain" modulation is related to learning, target choice, and motor attention. Our goal is to identify the neural loci and mechanisms of gain modulation, learning, and target choice.

Toward a Neurophysiologically-based Theory of Eye Movement Control During Reading

Toward a Neurophysiologically-based Theory of Eye Movement Control During Reading

 

        Yang & McConkie (Vision Research, in press) describe the beginnings of a theory of eye movement control during reading, based on a neurophysiological framework of eye movement control proposed by Findlay & Walker (1999, Brain & Behavior Science).  This paper will develop the theory more fully, describing, in terms of activation and inhibition within the oculomotor system, the normal operation of eye movement control during reading, possible ways in which eye behavior is modified in response to task and stimulus characteristics, and how the system responds to processing difficulties.  The paper will describe how certain puzzling observations can be explained within this theory (i.e., the many saccades that are uninfluenced by current stimulus characteristics, lack of a relation between fixation duration and whether a word is skipped, relatively flat hazard curve for longer fixation durations).  It will also point out issues that arise within the frame of reference of this type of theory, such as the time course of the onset and dissipation of saccade inhibition when processing difficulties are encountered, and how activation and inhibition influence saccade length and direction.

CAN EYE MOVEMENTS CURE MENTAL AILMENTS?

CAN EYE MOVEMENTS CURE MENTAL AILMENTS?

Gerald M. Rosen, PhD and Jeffrey Lohr, PhD

The null hypothesis, which assumes that no difference exists until a statistically significant effect is demonstrated, is the keystone of scientific testing.   Nevertheless, the field of psychology recently has seen the null hypothesis turned upside down in the promotion of Eye Movement Desensitization and Reprocessing (EMDR), a popular new psychotherapeutic procedure now proposed as a treatment for a wide range of problems including Post-Traumatic Stress Disorder, self-esteem issues, and achieving "peak performance."  Television documentaries have attested to the power of EMDR, presentations on the procedure are being given at some of the most prestigious psychiatric centers in the nation, and EMDR's "discoverer," Francine Shapiro, was given the 1994 Scientific Achievement Award by the California State Psychological Association. (Shapiro's has a doctorate degree from unaccredited Professional School for Psychological Studies, San Diego, a now-defunct "authorized" school that was authorized by the State of California. "Authorized" is the lowest level assigned to proprietary schools in California, followed by "approved" and "accredited.")

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Eye Movements

Eye Movements

 

The role of the eye movement component in the EMDR process awaits empirical validation.  However, the confused reporting of eye movement research has led some writers to the premature conclusion that eye movements do not contribute to the effects of EMDR.  In reality, the role of eye movements (and alternative dual-attention stimuli) in the EMDR process remains a matter for more adequate empirical testing.

Inaccurate or incomplete reviews of some of the early single-subject design data have been misleading and misinterpreted in subsequent scientific literature.  For example, Herbert et al. (2000a, 2000b), Rosen, Lohr, et al. (1998), and Rosen, McNally, et al. (1998a, 1998b) all cite Lohr et al. (1998) in their conclusion that eye movement "adds nothing to the traditional imaginal exposure component" of EMDR (McNally, 1999b, p. 619).  Remember, however, that the "traditional imaginal exposure component" of EMDR claimed by McNally (1999b) was demonstrated above not to be traditional at all, either in theory or by procedures used in the exposure treatment they reported.  But more importantly, the citation of Lohr et al. (1998) brings additional problems to the body of review literature due to the incomplete reporting of data from previous studies. 
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eye movement desensitization and reprocessing (EMDR)

....what is new in EMDR does not appear to be helpful, and what is helpful is what we already know about relaxation, education, and psychotherapy.*

Although the research regarding the necessity of the eye movement component is currently inconclusive, EMDR is a psychological treatment for PTSD which has received considerable empirical validation (Carlson et al., 1998; Marcus et al., 1997; Rothbaum, 1997; Scheck et al., 1998; Wilson et al., 1995). However, in spite of the empirical validation, confusion still exists in the literature regarding EMDR. Some of the confusion is theoretical and due to the current lack of empirical validation of Shapiro’s (1991b, 1995) information processing model and the continued inability of other models (e.g., exposure) to convincingly explain EMDR methods and effects.*

EMDR is a therapeutic technique in which the patient moves his or her eyes back and forth, hither and thither, while concentrating on "the problem." The therapist waves a stick or light in front of the patient and the patient is supposed to follow the moving stick or light with his or her eyes. The therapy was discovered by therapist Dr. Francine Shapiro while on a walk in the park. (Her doctorate was earned at the now defunct and never accredited Professional School of Psychological Studies. Her undergraduate degree is in English literature.*) It is claimed that EMDR can "help" with “phobias, generalized anxiety,

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Visual field recovery after vision restoration therapy (VRT) is independent of eye movements: an eye

Institute of Medical Psychology, Otto-von-Guericke-University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany. [e-mail]

AIM: It has been argued that patients with visual field defects compensate for their deficit by making more frequent eye movements toward the hemianopic field and that visual field enlargements found after vision restoration therapy (VRT) may be an artefact of such eye movements. In order to determine if this was correct, we recorded eye movements in hemianopic subjects before and after VRT. METHODS: Visual fields were measured in subjects with homonymous visual field defects (n=15) caused by trauma, cerebral ischemia or haemorrhage (lesion age >6 months). Visual field charts were plotted using both high-resolution perimetry (HRP) and conventional perimetry before and after a 3-month period of VRT, with eye movements being recorded with a 2D-eye tracker. This permitted quantification of eye positions and measurements of deviation from fixation.

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Chapter 10 Fixational eye movements and motion perception.

• Murakami I.

Department of Life Sciences, University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan.

Small eye movements are necessary for maintained visibility of the static scene, but at the same time they randomly oscillate the retinal image, so the visual system must compensate for such motions to yield the stable visual world. According to the theory of visual stabilization based on retinal motion signals, objects are perceived to move only if their retinal images make spatially differential motions with respect to some baseline movement probably due to eye movements. Motion illusions favoring this theory are demonstrated, and psychophysical as well as brain-imaging studies on the illusions are reviewed. It is argued that perceptual stability is established through interactions between motion-energy detection at an early stage and spatial differentiation of motion at a later stage. As such, image oscillations originating in fixational eye movements go unnoticed perceptually, and it is also shown that image oscillations are, though unnoticed, working as a limiting factor of motion detection. Finally, the functional importance of non-differential, global motion signals are discussed in relation to visual stability during large-scale eye movements as well as heading estimation.

eye movement

• Geisler WS,
• Perry JS,
• Najemnik J.

Center for Perceptual Systems and Department of Psychology, University of Texas at Austin, Austin, TX 78712, USA. [e-mail]

Two of the factors limiting progress in understanding the mechanisms of visual search are the difficulty of controlling and manipulating the retinal stimulus when the eyes are free to move and the lack of an ideal observer theory for fixation selection during search. Recently, we developed a method to precisely control retinal stimulation with gaze-contingent displays (J. S. Perry & W. S. Geisler, 2002), and we derived a theory of optimal eye movements in visual search (J. Najemnik & W. S. Geisler, 2005). Here, we report a parametric study of visual search for sine-wave targets added to spatial noise backgrounds that have spectral characteristics similar to natural images (the amplitude spectrum of the noise falls inversely with spatial frequency). Search time, search accuracy, and eye fixations were measured as a function of target spatial frequency, 1/f noise contrast, and the resolution falloff of the display from the point of fixation. The results are systematic and similar for the two observers. We find that many aspects of search performance and eye movement pattern are similar to those of an ideal searcher that has the same falloff in resolution with retinal eccentricity as the human visual system.

The pursuit theory of motion parallax.

• Nawrot M,
• Joyce L.

Center for Visual Neuroscience, Department of Psychology, North Dakota State University, Fargo, North Dakota, USA.

Although motion parallax is closely associated with observer head movement, the underlying neural mechanism appears to rely on a pursuit-like eye movement signal to disambiguate perceived depth sign from the ambiguous retinal motion information [Naji, J. J., & Freeman, T. C. A. (2004). Perceiving depth order during pursuit eye movement. Vision Research, 44, 3025-3034; Nawrot, M. (2003). Eye movements provide the extra-retinal signal required for the perception of depth from motion parallax. Vision Research, 43, 1553-1562]. Here, we outline the evidence for a pursuit signal in motion parallax and propose a simple neural network model for how the pursuit theory of motion parallax might function within the visual system. The first experiment demonstrates the crucial role that an extra-retinal pursuit signal plays in the unambiguous perception of depth from motion parallax. The second experiment demonstrates that identical head movements can generate opposite depth percepts, and even ambiguous percepts, when the pursuit signal is altered. The pursuit theory of motion parallax provides a parsimonious explanation for all of these observations.