Single-strand DNA breaks in Ig class switch recombination that depend on UNG but not AID

B lymphocytes switch from secreting IgM to secreting IgG, IgA or IgE through a DNA recombination, class switch recombination (CSR), whose mechanism is incompletely understood. CSR is thought to be triggered by activation-induced deaminase (AID), which is believed to deaminate cytosines to uracil in single-strand regions of switch region DNA. Subsequent excision of uracils by uracil DNA glycosylase (UNG) (product of the UNG gene) generates abasic sites, which are targeted for DNA cleavage, producing DNA breaks that are critical intermediates in CSR. Consistent with this model, CSR-related double-strand breaks (DSBs)--detected by ligation-mediated PCR (LMPCR)--have been reported to be dramatically reduced in B cells from either AID(-/-) or UNG(-/-) mice. Here we examine single-strand breaks (SSBs) using LMPCR and report, surprisingly, that CSR-related anti-sense strand breaks in Sgamma regions are dependent only on UNG, and not AID, suggesting participation of a cytosine deaminase other than AID. This conclusion is supported by the sequences at these DNA breaks, which show a bias for a consensus sequence different from that reported for AID. The SSBs appear to be part of the normal CSR pathway since in B cells in which CSR is blocked by deletion of Smu, the content of Sgamma SSBs is elevated as though the breaks resolve inefficiently owing to the lack of a recombination partner for completing mu-to-gamma CSR. These results suggest a narrower role for AID in CSR than previously recognized and prompt a search for a putative alternative cytosine deaminase participating in CSR.     

Memory processes in reading disability subtypes

The purpose of this study was to evaluate immediate verbal memory processes in specific reading disability subtypes. We examined three subgroups of reading disabled children, having (a) language disorder, (b) visuoperceptual disorder, or (c) memory disorder. A total of 75 children were studied (n = 25 in each subgroup), and the three groups did not differ in either age or IQ. The children's ability to retain sequences of color names in memory was assessed using the Color Span Test, which consists of four subtests that involve different stimulus and response combinations (visual‐visual, visual‐verbal, verbal‐visual, and verbal‐verbal). Specific memory profiles were identified for each of the three reading disability subtypes, and these patterns varied depending on the mode of stimulus presentation or response. Only the memory disorder group performed poorly across all modalities. The findings suggest that it is possible to identify preferred memory strategies that may have implications for selecting the type of reading instruction most appropriate for subgroups of reading disabled children.     

阅读障碍回归差异诊断法初探

本研究利用标准化阅读测验及韦氏智力测验，对北京市区３２０名四、五年级学生进行阅读及智力测定，建立了阅读成绩和智商间的回归方程，确定了相应于某一智商预期阅读成绩的计算方法及相应于此智商９５％儿童阅读成绩所在范围，初步建立了该年龄组阅读障碍的回归差异诊断法。     

The neurotrophic properties of progranulin depend on the granulin E domain but do not require sortilin binding

Progranulin (PGRN) is a growth factor involved in wound healing, inflammation, tumor growth, and neurodegeneration. Mutations in the gene encoding PGRN give rise to shortage of PGRN and cause familial frontotemporal lobar degeneration. PGRN exerts neurotrophic functions and binding of PGRN to the membrane receptor sortilin (SORT1) mediates the endocytosis of PGRN. SORT1-mediated uptake plays an important role in the regulation of extracellular PGRN levels. We studied the role of SORT1 in PGRN-mediated neuroprotection in vitro and in vivo. The survival-enhancing effect of PGRN seemed to be dependent on the granulin E (GRN E) domain. Pharmacologic inhibition of the GRN E–SORT1 interaction or deletion of the SORT1 binding site of GRN E did not abolish its neurotrophic function. In addition, the in vivo phenotype of PGRN knockdown in zebrafish embryos was not phenocopied by SORT1 knockdown. These results suggest that GRN E mediates the neurotrophic properties of PGRN and that binding to SORT1 is not required for this effect.     

Ampulla of vater cancers: T-stage and histological subtype but not Dpc4 expression predict prognosis

Loss of immunohistochemical expression of Dpc4 occurs in about 50% of pancreatic ductal cancers and its loss correlates with DPC4/Smad4 gene inactivation. Dpc4 expression was also lost in 6 of 16 (37%) ampulla of Vater cancers (AVCs) previously analyzed. Furthermore, chromosomal losses involving 18q, where DPC4 is located, have been observed in 34% of AVCs and are associated with decreased survival. To evaluate the possibility that expression of Dpc4 may be correlated with survival, we analyzed 89 AVCs for inactivation of DPC4 by immunohistochemical staining. Thirty-seven cases showed no expression of Dpc4 (41%). Multivariate survival analysis was performed including age, sex, tumor size, histological subtype (intestinal or pancreatobiliary), grade of differentiation, T-stage, lymph-node metastases and Dpc4 status. T-stage and histological subtype were selected as independent prognostic factors, while Dpc4 immunostaining was not significantly associated with any clinicopathological variable, including histological subtype. Although Dpc4 expression is of no clinical relevance, its involvement in AVC gives additional weight to the hypothesis that, among all pancreatic exocrine and endocrine tumors, only AVC and common ductal adenocarcinomas have similar molecular fingerprints. Moreover, comparison of the frequencies of allelic loss on chromosomal arm 18q and the loss of Dpc4 expression (34% and 41%, respectively) is highly suggestive that DPC4 is the major target of these losses.     

Handedness and reading disability: a developmental study.

124 normal children were followed from age 5 to 9. Manual laterality status continues to consolidate between these ages and reveals itself unrelated to reading level.     

Podokinetic after-rotation does not depend on sensory conflict

Humans who have been stepping for 10 min or more about their vertical axis on a counterrotating platform while fixating on a stationary visual scene continue to circle in the same direction when they attempt, thereafter, to step on firm ground in darkness without turning (”podokinetic after-rotation”: PKAR). In the present report, we investigate whether PKAR is due to: (1) a sensory reinterpretation triggered by the conflict between the visual signal of stationarity and the somatosensory message of feet-on-platform rotation, or (2) an adaptation of the somatosensory afferents to prolonged unilateral stimulation irrespective of visual stimulation. Subjects (Ss) circled for 10 min about their vertical axis on an either stationary or counterrotating platform while they were either in darkness, or exposed to an optokinetic stimulus, or to a ”head-fixed” stationary pattern. Thereafter, Ss first stood motionless in darkness for 30 s, allowing vestibular after-effects to decay, and then tried (still without vision) to step in place on the stationary platform without turning while their body rotation was recorded by a potentiometer coupled to the head. All conditions involving podomotor activity without concomitant optokinetic stimulation evoked similar PKAR. With optokinetic stimulation, PKAR became larger, apparently because it was summed with an optokinetically induced after-rotation (oPKAR). This oPKAR could be demonstrated in isolation when Ss were passively rotated in front of the OKN-pattern instead of actively circling. PKAR could not be ”dumped”; it reappeared after 30 s of straight stepping under visual control. We suggest that PKAR is caused by adaptation of the somatosensory channel and not by a sensory conflict. Received: 16 April 1999 / Accepted: 30 June 1999     

Phonetic recalibration does not depend on working memory

Listeners use lipread information to adjust the phonetic boundary between two speech categories (phonetic recalibration, Bertelson et al. 2003). Here, we examined phonetic recalibration while listeners were engaged in a visuospatial or verbal memory working memory task under different memory load conditions. Phonetic recalibration was—like selective speech adaptation—not affected by a concurrent verbal or visuospatial memory task. This result indicates that phonetic recalibration is a low-level process not critically depending on processes used in verbal- or visuospatial working memory.     

Early development of neurophysiological processes involved in normal reading and reading disability: a magnetic source imaging study

This longitudinal study examined the development of the brain mechanism involved in phonological decoding in beginning readers using magnetic source imaging. Kindergarten students were assigned to 2 groups: those who showed mastery of skills that are important predictors of proficient reading (low-risk group) and those who initially did not show mastery but later benefited from systematic reading instruction and developed average-range reading skills at the end of Grade 1 (high-risk responders). Spatiotemporal profiles of brain activity were obtained during performance of letter-sound and pseudoword naming tasks before and after Grade 1 instruction. With few exceptions, low-risk children showed early development of brain activation profiles that are typical of older skilled readers. Provided that temporoparietal and visual association areas were recruited into the brain mechanism that supported reading, the majority of high-risk responder children benefited from systematic reading instruction and developed adequate reading abilities.     

Representational momentum in spatial hearing does not depend on eye movements

The perceived final position of a moving object usually seems to be displaced in the direction of motion. This displacement effect, termed representational momentum, has been reported for both visual and acoustic targets. This study investigated whether representational momentum in the auditory modality depends on oculomotor behavior during target presentation. In a dark anechoic environment, subjects localized the final position of a horizontally moving acoustic target (continuous noise) by using a hand pointer. Subjects were instructed to pursue the acoustic target with their eyes, to maintain central gaze direction, or to fixate a central visual fixation point. Forward displacements of the perceived final target position occurred irrespective of the eye-movement condition. This result is not consistent with previous findings in the visual modality indicating a reduction of forward displacement for continuously moving targets with fixation. It is suggested that factors other than oculomotor behavior are the source of representational momentum in spatial hearing.     

EBNA-1 sequence variation in Danish and Chinese EBV-associated tumours: evidence for geographical polymorphism but not for tumour-specific subtype restriction

The Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 is consistently expressed in EBV-associated tumours. Recently, EBNA-1 carboxy (C)-terminal sequence variants have been described based on the amino acid signature at codon 487, and designated prototype (P)-ala (identical to prototype B95.8 strain), P-thr, variant (V)-val, V-leu, and V-pro. These studies suggest that certain EBNA-1 variants show selective cell tropism and may be preferentially associated with different EBV-positive malignancies; for example, in contrast to P-ala subtypes, V-val appeared to be restricted to the oral compartment and to be associated with undifferentiated nasopharyngeal carcinoma (NPC). To test the hypothesis that V-val subtypes are restricted in distribution, EBNA-1 variants were investigated in NPC and throat washings (TWs) from a low (Denmark) and a high (China) NPC risk area. For comparison, cases of Hodgkin's disease (HD) were also studied. V-val was found to be the dominant EBNA-1 subtype, not only in Chinese TWs and NPC biopsies, but also in Chinese HD. Furthermore, V-val was not detected in any of the Danish NPC biopsies or TW samples. These findings show that V-val is not associated with NPC, nor is it restricted to the oral compartment, but rather that it represents a dominant Asian EBNA-1 subtype, both in EBV-associated malignancies and in the general population.     

Noradrenaline-induced feeding responses in the rat do not depend on food characteristics

The noradrenergic system of the hypothalamic paraventricular nuclei (PVN) has been associated with feeding, but whether it controls feeding in a way that is relevant to energy balance is still unclear. Rats were maintained on a high energy, carbohydrate-rich diet (HC) or a low energy, carbohydrate-free, protein-rich diet (LP) until their daily energy intakes equalized. When injected with noradrenaline (NA) into the PVN, they ingested the same amounts of both diets so that the animals on the LP diet consumed only half the total energy of those on the HC diet. Continuous delivery of NA into the PVN via a microdialysis probe induced chewing on non-nutritive pieces of corks. The same chewing pattern could again be elicited by the subsequent NA deliveries. It is concluded that the nutritional value of a diet is irrelevant to the NA feeding response. The failure of NA administration to increase rat feeding in terms of energy intake, combined with its ability to stimulate chewing, suggests that the primary role of the NA system of the PVN may not be controlling the carbohydrate and energy intake, but rather gating behavioral responses that under appropriate circumstances may lead to ingestion.     

ADHD subtype differences in motivational responsivity but not inhibitory control: evidence from a reward-based variation of the stop signal paradigm.

In this study we examined prepotent motor inhibition and responsiveness to reward using a variation of the stop signal reaction time (SSRT) task in clinic- and community-recruited children ages 7 to 12 with attention-deficit/hyperactivity disorder-inattentive type (ADHD-I), ADHD-combined type (ADHD-C), and non-ADHD controls. Contrary to theoretical expectations, we found evidence for inhibitory weaknesses in ADHD-I. We also found evidence that although children with ADHD-I were able to improve their inhibitory control given reward-based motivation, the improvement depended on the order of reward conditions. Results suggest that the 2 primary subtypes of ADHD share similar neuropsychological weaknesses in inhibitory control but that there are subtype differences in response to success and failure that contribute to a child's ultimate level of performance.     

Stability of rhythmic visuo-motor tracking does not depend on relative velocity

It is well established that the in-phase pattern of bimanual coordination (i.e. a relative phase of 0°) is more stable than the antiphase pattern (i.e., a relative phase of 180°), and that a spontaneous transition from antiphase to in-phase typically occurs as the movement frequency is gradually increased. On the basis of results from relative phase perception experiments, Bingham (Proceedings of the 23rd annual conference of the cognitive science society. Laurence Erlbaum Associates, Mahwah, pp 75–79, 2001; Ecol Psychol 16:45–53, 2004; Advances in psychology 135: time-to-contact. Elsevier, Amsterdam, pp 421–442, 2004) proposed a dynamical model that consists of two phase driven oscillators coupled via the perceived relative phase, the resolution of which is determined by relative velocity. In the present study, we specifically test behavioral predictions from this last assumption during a unimanual visuo-motor tracking task. Different conditions of amplitudes and frequencies were designed to manipulate selectively relative phase and relative velocity. While the known effect of phase and frequency were observed, relative phase variability was not affected by the different conditions of relative velocity. As such, Bingham’s model assumption that instability in relative phase coordination is brought about by relative velocity that affects the resolution of the perceived relative phase has been invalidated for the case of rhythmic unimanual visuo-motor tracking. Although this does not rule out the view that relative phase production is constrained by relative phase perception, the mechanism that would be responsible for this phenomenon still has to be established.     

Oculomotor plasticity during vestibular compensation does not depend on cerebellar LTD

Vestibular paradigms are widely used for investigating mechanisms underlying cerebellar motor learning. These include adaptation of the vestibuloocular reflex (VOR) after visual-vestibular mismatch training and vestibular compensation after unilateral damage to the vestibular apparatus. To date, various studies have shown that VOR adaptation may be supported by long-term depression (LTD) at the parallel fiber to Purkinje cell synapse. Yet it is unknown to what extent vestibular compensation may depend on this cellular process. Here we investigated adaptive gain changes in the VOR and optokinetic reflex during vestibular compensation in transgenic mice in which LTD is specifically blocked in Purkinje cells via expression of a peptide inhibitor of protein kinase C (L7-PKCi mutants). The results demonstrate that neither the strength nor the time course of vestibular compensation are affected by the absence of LTD. In contrast, analysis of vestibular compensation in spontaneous mutants that lack a functional olivo-cerebellar circuit (lurchers) shows that this form of motor learning is severely impaired. We conclude that oculomotor plasticity during vestibular compensation depends critically on intact cerebellar circuitry but not on the occurrence of cerebellar LTD.     

Pheromonal release of suckling in rabbits does not depend on the vomeronasal organ

Newborn rabbits are completely dependent on a pheromone present on the mother's belly for the release of the highly stereotyped nipple-search behavior and for nipple attachment. Surgical removal of the vomeronasal organ had no effect on pups' ability to respond to the pheromone when tested on a lactating female, nor on their ability to obtain milk in the normal nursing situation. Lesioned pups could also learn to associate the odor of citral with nipple-search behavior when nursed by a citral-scented doe. In contrast, irrigating the nasal mucosa with ZnSO4 completely eliminated responsiveness both to the pheromone and to the conditioned odor of citral. This is of particular interest given the important role attributed to the accessory olfactory system in pheromonal perception. However, it might be necessary to distinguish between pheromones associated with suckling and therefore peculiar to mammals, and other pheromones.     

Lateralization in normal 6-year-olds as related to later reading disability

The differentiation of lateral preference in hand, eye, ear, and foot was measured in 110 normal Grade 1 children and reading achievement was tested 3 and 5 years later. No support was found for the widely held belief that delays in early lateralization underlie subsequent reading impairment. Paradoxically, boys with serious reading disability showed a strong degree of early lateral concordance. Male, impaired readers displayed a tendency when they were in Grade 1 to be either uniformly right- or left-preferring across all 4 sensory-motor modalities. The results contradict the popular notion that lateral usage emerges from an undifferentiated state in the direction of greater degrees of specialization. Lateralization may be an expression of reflex constraints bound initially to the infant's tonic-neck posture, with later development less reflex-patterned during the acquisition of more sophisticated information-processing strategies. Such an interpretation implies a progressive discontinuity between lateral usage and neuro-maturational processes. Alternatively, the results can be accounted for by (1) a new maturational delay model in which maturation-dependent lateralization proceeds in graduated stages from a highly specialized beginning toward greater levels of neuromotor integration; or (2) a model that maintains the notion of emergent lateralization but in which delays in the lateralization process are actually beneficial to later performance.     

Differentiation of endothelial cells in avian embryos does not depend on gastrulation.

Unincubated quail eggs were treated with Cytochalasin B. By this means, gastrulation of the blastodiscs was inhibited. Fragments of these blastodiscs were grafted into wings buds of chick embryos, and the differentiation fate of graft-derived cells was studied. Results show that only endothelial cells differentiate from the grafts. They were even found outside the graft site in vessels made up of a chimeric endothelium. It can be concluded that determination, differentiation and migration of endothelial cells does not depend on gastrulation.