Exploring factors of successful transition to elementary school among children with autism spectrum disorder in Japan: a focus group study.

Introduction: Children with autism spectrum disorder (ASD) face numerous challenges in transitioning to elementary school, which can cause confusion for the children and concern among their parents. Aims: This study aimed to identify the process of school transition from kindergarten to elementary school for children with autism spectrum disorder in Japan, by evaluating the effectiveness of a school transition program. Methods: A focus group interview was conducted with seven parents who participated in a transition program. They were asked about communication with the teachers, support obtained from the school, and their experiences after their children entered elementary school. After the group interview was recorded and transcribed, the data were analyzed using inductive content analysis to determine the parents' experiences of the school transition process. Findings: Six main themes emerged from the focus group interview: acquisition of prerequisite skills, adjustment in dealing with children with ASD, communication between school and home, communication between peers and children with autism spectrum disorder, collaboration with special needs education teachers, and the principal's understanding of special needs education. Conclusion: These findings provide an overview of the challenges and possible solutions to support school transitions for children with autism spectrum disorder in inclusive educational environments.

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

Infants' Prefrontal Hemodynamic Responses and Functional Connectivity During Joint Attention in an Interactive-Live Setting.

The present study examined cerebral hemodynamic responses and functional connectivity during joint attention either initiated by infants (Initiating Joint Attention, IJA condition) or by their partner (Responding to Joint Attention, RJA condition). To capture responses to natural social cues in infants aged 7-12 months using functional near-infrared spectroscopy (fNIRS), we employed an interactive-live paradigm for IJA and RJA. During the measurement, an adult sat facing an infant, and objects, such as small stuffed animals, paired with sound toys were presented to the right or left side of the screen. In the RJA condition, the adult gazed at the infants' eyes and then to the objects to encourage the infants to follow the adult's gaze. On the other hand, in the IJA condition, the adult followed the infant's gaze as it shifted to the presented object. Our results indicate that the concentration of oxy-Hb in the bilateral ventral prefrontal region had significantly decreased, then followed by an increase in the right dorsal prefrontal region in the RJA. In addition, a selective activation in the bilateral dorsal prefrontal region was seen in the IJA condition. Moreover, the infants exhibited increased functional connectivity especially within the right ventral prefrontal region during RJA condition when compared with IJA conditions. These findings suggest that RJA and IJA recruit specific brain networks localized in the prefrontal cortex of infants.

Modeling Training of Child's Echoic Conversational Response for Students with Autism Spectrum Disorder: To Be a Good Listener.

Students with autism spectrum disorder (ASD) often have difficulties in responding to conversation with verbal language. These students often repeat what they hear, and their echoic behavior has a potentially communicative function. We define the echoic behavior when an individual repeats a peer's topic word with appropriate prosody within 3 s as the child's echoic conversational response. In this study, we examined the acquisition of the child's echoic conversational response skills and whether these skills could provide and generalize natural conversation for 4 students with ASD. During the training, students were instructed to imitate the topic word that the experimenter had used in the latest conversation. Students learned the child's echoic conversational response skills and improved their conversation skills. They even showed a slight generalization for nontraining materials through trainings and improvements in responding with new verbal responses. These findings suggested that expanding speakers' repertoires for students with ASD might facilitate improvement of natural conversation skills.

Sentence Reading Comprehension by Means of Training in Segment-Unit Reading for Japanese Children with Intellectual Disabilities.

Children with intellectual disabilities (ID) often have difficulty in sentence reading and comprehension. Previous studies have shown that training in segment-unit reading (SUR) facilitates the acquisition of sentence reading comprehension skills for Japanese students with ID. However, it remains unknown whether SUR training is also effective for individuals unable to read sentences and can generalize to untrained sentences. In this study, we examined the improvement and generalization of sentence reading accuracy and comprehension for two children with ID through SUR training with listening comprehensible sentences. During training, the segments were sequentially presented in their correct spatial locations, and participants read them aloud. After the training, participants' reading accuracy and comprehension improved for both trained and untrained sentences. The results suggest that presenting the components of stimuli sequentially in their correct spatial locations is key to facilitating the development of sentence reading accuracy and comprehension for individuals with ID.

Social interaction facilitates word learning in preverbal infants: Word-object mapping and word segmentation.

In natural settings, infants learn spoken language with the aid of a caregiver who explicitly provides social signals. Although previous studies have demonstrated that young infants are sensitive to these signals that facilitate language development, the impact of real-life interactions on early word segmentation and word-object mapping remains elusive. We tested whether infants aged 5-6 months and 9-10 months could segment a word from continuous speech and acquire a word-object relation in an ecologically valid setting. In Experiment 1, infants were exposed to a live tutor, while in Experiment 2, another group of infants were exposed to a televised tutor. Results indicate that both younger and older infants were capable of segmenting a word and learning a word-object association only when the stimuli were derived from a live tutor in a natural manner, suggesting that real-life interaction enhances the learning of spoken words in preverbal infants.

Contingent imitation increases verbal interaction in children with autism spectrum disorders.

Several studies have suggested that contingent adult imitation increase nonverbal communication, such as attention and proximity to adults, in children with autism spectrum disorders. However, few studies have shown the effect of contingent imitation on verbal communication. This study examined whether children with autism were able to promote verbal interaction such as vocal imitation, vocalization, and vocal turn-taking via contingent imitation. We used an alternating treatment design composed of the conditions of contingent imitation and control for six children with autism (aged 33-63 months). For contingent imitation condition, adults imitated children's vocalization immediately. For control condition, adults did not imitate but gave a vocal response immediately. Results showed that in contingent imitation condition, all children increased the number of vocal imitations and vocal turn-takings compared with control condition. The number of vocalizations increased in both condition for all children. Overall, it is suggested that all children promote verbal interaction via contingent imitation.

"Mom called me!" Behavioral and prefrontal responses of infants to self-names spoken by their mothers.

Development of a sense of self is a fundamental process needed for human social interaction. Although functional neuroimaging studies have revealed the importance of medial prefrontal cortex (mPFC) in self-referencing, how this function develops in infancy remains poorly understood. To determine the cerebral basis underlying processing of self-related stimuli, we used behavioral measures and functional multi-channel near-infrared spectroscopy (fNIRS) to measure prefrontal cortical responses in 6-month-old infants hearing their own names. We also investigated the influence of a mother's voice on name perception in infants - an ability that plays a crucial role in the recognition of social signals. Experiment 1 measured the behavioral preferences of infants for their own names and for other names, spoken either by their mothers or by strangers. Results showed that infants significantly preferred their own name to other names, regardless of speaker type. Experiment 2 examined hemodynamic responses to the same four conditions in the prefrontal cortex. Compared with other names, hearing their own names, especially when spoken by their mother, elicited greater activity in the infant's dorsal mPFC. Furthermore, the magnitude of the cerebral response correlated with the degree of behavioral preference only when involving their mother's voice. These findings suggest that, particularly in the context of their mothers' voice, the dorsal mPFC of infants is already sensitive to social signals related to self at 6 months. At the same time, familiarity and affection related processing are also discussed as possible factors modulating dorsal mPFC activation at this age.

Motor cortex-evoked activity in reciprocal muscles is modulated by reward probability.

Horizontal intracortical projections for agonist and antagonist muscles exist in the primary motor cortex (M1), and reward may induce a reinforcement of transmission efficiency of intracortical circuits. We investigated reward-induced change in M1 excitability for agonist and antagonist muscles. Participants were 8 healthy volunteers. Probabilistic reward tasks comprised 3 conditions of 30 trials each: 30 trials contained 10% reward, 30 trials contained 50% reward, and 30 trials contained 90% reward. Each trial began with a cue (red fixation cross), followed by blue circle for 1 s. The subjects were instructed to perform wrist flexion and press a button with the dorsal aspect of middle finger phalanx as quickly as possible in response to disappearance of the blue circle without looking at their hand or the button. Two seconds after the button press, reward/non-reward stimulus was randomly presented for 2-s duration. The reward stimulus was a picture of Japanese 10-yen coin, and each subject received monetary reward at the end of experiment. Subjects were not informed of the reward probabilities. We delivered transcranial magnetic stimulation of the left M1 at the midpoint between center of gravities of agonist flexor carpi radialis (FCR) and antagonist extensor carpi radialis (ECR) muscles at 2 s after the red fixation cross and 1 s after the reward/non-reward stimuli. Relative motor evoked potential (MEP) amplitudes at 2 s after the red fixation cross were significantly higher for 10% reward probability than for 90% reward probability, whereas relative MEP amplitudes at 1 s after reward/non-reward stimuli were significantly higher for 90% reward probability than for 10% and 50% reward probabilities. These results implied that reward could affect the horizontal intracortical projections in M1 for agonist and antagonist muscles, and M1 excitability including the reward-related circuit before and after reward stimulus could be differently altered by reward probability.

Stimulus pairing training for Kanji reading skills in students with developmental disabilities.

Japanese students with developmental disabilities often exhibit difficulties in reading, particularly in Kanji (ideogram) reading, and in acquiring the equivalence relations between pictures, written words, and sounds. Previous research suggested that one student with autism could acquire Kanji reading along with equivalence relations through stimulus pairing training. However, maintenance rates tended to be very low, possibly due to the lack of picture stimuli. In this study, we examined the acquisition and maintenance of Kanji reading skills through stimulus pairing training using corresponding pictures for six students with developmental disabilities. We prepared stimulus pairs consisting of picture stimuli that the students could name along with a corresponding Kanji character that they could not read. All students successfully acquired and maintained the Kanji reading skills through this procedure. These findings suggest that the nameability of picture stimuli in stimulus pairing training may facilitate the acquisition and maintenance of equivalence relations for reading.

Predicting recovery of cognitive function soon after stroke: differential modeling of logarithmic and linear regression.

Cognitive disorders in the acute stage of stroke are common and are important independent predictors of adverse outcome in the long term. Despite the impact of cognitive disorders on both patients and their families, it is still difficult to predict the extent or duration of cognitive impairments. The objective of the present study was, therefore, to provide data on predicting the recovery of cognitive function soon after stroke by differential modeling with logarithmic and linear regression. This study included two rounds of data collection comprising 57 stroke patients enrolled in the first round for the purpose of identifying the time course of cognitive recovery in the early-phase group data, and 43 stroke patients in the second round for the purpose of ensuring that the correlation of the early-phase group data applied to the prediction of each individual's degree of cognitive recovery. In the first round, Mini-Mental State Examination (MMSE) scores were assessed 3 times during hospitalization, and the scores were regressed on the logarithm and linear of time. In the second round, calculations of MMSE scores were made for the first two scoring times after admission to tailor the structures of logarithmic and linear regression formulae to fit an individual's degree of functional recovery. The time course of early-phase recovery for cognitive functions resembled both logarithmic and linear functions. However, MMSE scores sampled at two baseline points based on logarithmic regression modeling could estimate prediction of cognitive recovery more accurately than could linear regression modeling (logarithmic modeling, R(2) = 0.676, P<0.0001; linear regression modeling, R(2) = 0.598, P<0.0001). Logarithmic modeling based on MMSE scores could accurately predict the recovery of cognitive function soon after the occurrence of stroke. This logarithmic modeling with mathematical procedures is simple enough to be adopted in daily clinical practice.

Reciprocal changes in input-output curves of motor evoked potentials while learning motor skills.

Reciprocal inhibition of antagonist muscles is crucial for motor skill learning in humans. However, the changes in reciprocal inhibition function during the motor learning process are unknown. The aim of this study was to systematically observe the changes in reciprocal inhibition function. We investigated the optimal coil position for simultaneously eliciting motor evoked potentials (MEPs) of reciprocal muscles, and the reciprocal changes in input-output (IO) curves during motor skill training. From ten healthy volunteers, the IO curves of MEPs were measured for the midpoint between the center of gravity (CoG) of the extensor carpi radialis (ECR) and the flexor carpi radialis (FCR) muscles, for the CoG of ECR, and for the FCR muscles using transcranial magnetic stimulation (TMS). In addition, the IO curves of the ECR and the FCR muscles were measured before and after the motor skill training of rapid wrist extension. The IO curves measured at the midpoint between the CoGs of the ECR and the FCR muscles and the CoG of each muscle were homogenous. However, after training to perform rapid wrist extension, the IO curve of the agonist (ECR) muscle was increased, while the antagonist (FCR) muscle was decreased. The present findings validate the IO curves simultaneously measured for reciprocal muscles, and suggest that motor skill training could induce reciprocal change in corticospinal excitability.

Cerebral responses to infant-directed speech and the effect of talker familiarity.

A number of behavioral studies suggest that infant-directed speech (IDS) plays a more important role in facilitating both: a) speech perception, and b) adult-infant social interactions than does adult-directed speech (ADS), and hence that IDS contributes to subsequent social and language development. However neural substrates that may underlie these IDS functions have not been examined. The present study examined cerebral hemodynamic responses to IDS in 48 infants (4-13 months of age) using near-infrared spectroscopy (NIRS). Japanese sentences uttered by the infants' own mothers and by unfamiliar mothers were used to record activations in temporal and frontal area separately. Increased activations were observed predominantly in infants' left and right temporal areas when they listened to IDS rather than to ADS when both involved voices of their own and unfamiliar mothers. In contrast, significantly greater activations were observed in the frontal area when infants listened to IDS produced by their own mothers, not when IDS arose from unfamiliar mothers. Furthermore, the present results indicate that responses to IDS do vary as a function of the infant's age and the talker familiarity. These findings suggest a differential function for frontal and temporal areas in processing infant-directed speech by the different speakers.

Comparative analysis of human SRC-family kinase substrate specificity in vitro.

Src family kinases (SFKs) are the earliest known family of tyrosine kinases and are widely thought to play essential roles in cellular signal transduction. Although numerous functional analyses have been performed, no study has analyzed the specificity of all SFKs on an equal platform. To gain a better understanding of SFK phosphorylation, we designed a high-throughput in vitro kinase assay on the subproteome scale using surface plasmon resonance. We reacted each of the 11 human SFKs with 519 substrate proteins, and significant phosphorylation was detected in 33.6% (1921) of the total 5709 kinase-substrate combinations. A large number of novel phosphorylations were included among them. Many substrates were shown to be phosphorylated by multiple SFKs, which might reflect functional complementarity of SFKs. Clustering analysis of phosphorylation results grouped substrates into 10 categories, while the similarity of SFK catalytic specificity exhibited no significant correlation with that of amino acid sequences. In silico predictions of SRC-specific phosphorylation sites were not consistent with experimental results, implying some unknown SRC recognition modes. In an attempt to find biologically meaningful novel substrates, phosphorylation data were integrated with annotation data. The extensive in vitro data obtained in this study would provide valuable clues for further understanding SFK-mediated signal transduction.

Identification and functional analyses of 11,769 full-length human cDNAs focused on alternative splicing.

We analyzed diversity of mRNA produced as a result of alternative splicing in order to evaluate gene function. First, we predicted the number of human genes transcribed into protein-coding mRNAs by using the sequence information of full-length cDNAs and 5'-ESTs and obtained 23 241 of such human genes. Next, using these genes, we analyzed the mRNA diversity and consequently sequenced and identified 11 769 human full-length cDNAs whose predicted open reading frames were different from other known full-length cDNAs. Especially, 30% of the cDNAs we identified contained variation in the transcription start site (TSS). Our analysis, which particularly focused on multiple variable first exons (FEVs) formed due to the alternative utilization of TSSs, led to the identification of 261 FEVs expressed in the tissue-specific manner. Quantification of the expression profiles of 13 genes by real-time PCR analysis further confirmed the tissue-specific expression of FEVs, e.g. OXR1 had specific TSS in brain and tumor tissues, and so on. Finally, based on the results of our mRNA diversity analysis, we have created the FLJ Human cDNA Database. From our result, it has been understood mechanisms that one gene produces suitable protein-coding transcripts responding to the situation and the environment.

Cerebral laterality for phonemic and prosodic cue decoding in children with autism.

This study examined the cerebral functional lateralization, from a phonological perspective, in children with autism spectrum disorder (ASD) and typically developing children (TDC). With near infrared spectroscopy, we measured auditory evoked-responses in the temporal areas to phonemic and prosodic contrasts in word contexts. The results of TDC showed stronger left-dominant and right-dominant responses to phonemic and prosodic differences, respectively. Furthermore, although ASD children displayed similar tendencies, the functional asymmetry for phonemic changes was relatively weak, suggesting less-specialized left-brain functions. The typical asymmetry for the prosodic condition was further discussed in terms of acoustic-physical perceptual ability of ASD children. The study revealed differential neural recruitment in decoding phonetic cues between ASD children and TDC and verified the applicability of near infrared spectroscopy as a suitable neuroimaging method for children with developmental disorders.

Human Gene and Protein Database (HGPD): a novel database presenting a large quantity of experiment-based results in human proteomics.

Completion of human genome sequencing has greatly accelerated functional genomic research. Full-length cDNA clones are essential experimental tools for functional analysis of human genes. In one of the projects of the New Energy and Industrial Technology Development Organization (NEDO) in Japan, the full-length human cDNA sequencing project (FLJ project), nucleotide sequences of approximately 30 000 human cDNA clones have been analyzed. The Gateway system is a versatile framework to construct a variety of expression clones for various experiments. We have constructed 33 275 human Gateway entry clones from full-length cDNAs, representing to our knowledge the largest collection in the world. Utilizing these clones with a highly efficient cell-free protein synthesis system based on wheat germ extract, we have systematically and comprehensively produced and analyzed human proteins in vitro. Sequence information for both amino acids and nucleotides of open reading frames of cDNAs cloned into Gateway entry clones and in vitro expression data using those clones can be retrieved from the Human Gene and Protein Database (HGPD, http://www.HGPD.jp). HGPD is a unique database that stores the information of a set of human Gateway entry clones and protein expression data and helps the user to search the Gateway entry clones.

Human protein factory for converting the transcriptome into an in vitro-expressed proteome,.

Appropriate resources and expression technology necessary for human proteomics on a whole-proteome scale are being developed. We prepared a foundation for simple and efficient production of human proteins using the versatile Gateway vector system. We generated 33,275 human Gateway entry clones for protein synthesis, developed mRNA expression protocols for them and improved the wheat germ cell-free protein synthesis system. We applied this protein expression system to the in vitro expression of 13,364 human proteins and assessed their biological activity in two functional categories. Of the 75 tested phosphatases, 58 (77%) showed biological activity. Several cytokines containing disulfide bonds were produced in an active form in a nonreducing wheat germ cell-free expression system. We also manufactured protein microarrays by direct printing of unpurified in vitro-synthesized proteins and demonstrated their utility. Our 'human protein factory' infrastructure includes the resources and expression technology for in vitro proteome research.

Functional training for initiating joint attention in children with autism.

The present study aimed to examine the controlling variables for initiating joint attention (IJA) in three children with autism. During the baseline, target objects were presented in a location where the child could see them, but the adult could not, and the emergence of IJA was assessed. Children with autism showed some IJA skills during the baseline, but none initiated pointing. In training, the motivating operation for IJA was manipulated by using each child's preferred materials as targets of joint attention. It was found that more frequent and functional joint attention behaviors were emitted following training. The present study suggests that difficulties in IJA in children with autism could be partly explained by restricted interests in children with autism.

Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.