Brain markers of subtraction and multiplication skills in childhood: task-based functional connectivity and individualized structural similarity.

Arithmetic, a high-order cognitive ability, show marked individual difference over development. Despite recent advancements in neuroimaging techniques have enabled the identification of brain markers for individual differences in high-order cognitive abilities, it remains largely unknown about the brain markers for arithmetic. This study used a data-driven connectome-based prediction model to identify brain markers of arithmetic skills from arithmetic-state functional connectivity and individualized structural similarity in 132 children aged 8 to 15 years. We found that both subtraction-state functional connectivity and individualized SS successfully predicted subtraction and multiplication skills but multiplication-state functional connectivity failed to predict either skill. Among the four successful prediction models, most predictive connections were located in frontal-parietal, default-mode, and secondary visual networks. Further computational lesion analyses revealed the essential structural role of frontal-parietal network in predicting subtraction and the essential functional roles of secondary visual, language, and ventral multimodal networks in predicting multiplication. Finally, a few shared nodes but largely nonoverlapping functional and structural connections were found to predict subtraction and multiplication skills. Altogether, our findings provide new insights into the brain markers of arithmetic skills in children and highlight the importance of studying different connectivity modalities and different arithmetic domains to advance our understanding of children's arithmetic skills.

Sex differences in large-scale brain network connectivity for mental rotation performance.

Mental rotation has emerged as an important predictor for success in science, technology, engineering, and math fields. Previous studies have shown that males and females perform mental rotation tasks differently. However, how the brain functions to support this difference remains poorly understood. Recent advancements in neuroimaging techniques have enabled the identification of sex differences in large-scale brain network connectivity. Using a classic mental rotation task with functional magnetic resonance imaging, the present study investigated whether there are any sex differences in large-scale brain network connectivity for mental rotation performance. Our results revealed that, relative to females, males exhibited less cross-network interaction (i.e. lower inter-network connectivity and participation coefficient) of the visual network but more intra-network integration (i.e. higher intra-network connectivity and local efficiency) and cross-network interaction (i.e. higher inter-network connectivity and participation coefficient) of the salience network. Across all participants, mental rotation performance was negatively correlated with cross-network interaction (i.e. participation coefficient) of the visual network, was positively correlated with cross-network interaction (i.e. inter-network connectivity) of the salience network, and was positively correlated with intra-network integration (i.e. local efficiency) of the somato-motor network. Interestingly, the cross-network integration indexes of both the visual and salience networks significantly mediated sex difference in mental rotation performance. The present findings suggest that large-scale brain network connectivity may constitute an essential neural basis for sex difference in mental rotation, and highlight the importance of considering sex as a research variable in investigating the complex network underpinnings of spatial cognition.

Early Gray Matter Structural Covariance Predicts Longitudinal Gain in Arithmetic Ability in Children.

Previous neuroimaging studies on arithmetic development have mainly focused on functional activation or functional connectivity between brain regions. It remains largely unknown how brain structures support arithmetic development. The present study investigated whether early gray matter structural covariance contributes to later gain in arithmetic ability in children. We used a public longitudinal sample comprising 63 typically developing children. The participants received structural magnetic resonance imaging scanning when they were 11 years old and were tested with a multiplication task at 11 years old (time 1) and 13 years old (time 2), respectively. Mean gray matter volumes were extracted from eight brain regions of interest to anchor salience network (SN), frontal-parietal network (FPN), motor network (MN), and default mode network (DMN) at time 1. We found that longitudinal gain in arithmetic ability was associated with stronger structural covariance of the SN seed with frontal and parietal regions and stronger structural covariance of the FPN seed with insula, but weaker structural covariance of the FPN seed with motor and temporal regions, weaker structural covariance of the MN seed with frontal and motor regions, and weaker structural covariance of the DMN seed with temporal region. However, we did not detect correlation between longitudinal gain in arithmetic ability and behavioral measure or regional gray matter volume at time 1. Our study provides novel evidence for a specific contribution of gray matter structural covariance to longitudinal gain in arithmetic ability in childhood.

Temporal recall in the shadow of emotion: separate emotional contexts during encoding enhance the temporal source memory retrieval.

Episodic memory, with its emphasis on temporal-spatial contexts, has been a longstanding focus in memory research. While previous studies have investigated the role of emotion in temporal source memory using emotionally charged stimuli, such as emotional words or images, the influence of a separated emotional context remains less explored. This study sought to understand the impact of separate emotional contexts on temporal source memory. Participants were shown Chinese characters alongside separate emotional contexts (i.e. a neutral or negative picture) and then engaged in either a retrieval practice or a control condition. Finally, they were tested for recognition, temporal source memory, and emotional source memory for all the learned characters. Results revealed that a negative emotional context, unlike a neutral setting, enhanced the accuracy of temporal memory for adjacent neutral characters. However, this negative context reduced the accuracy of recalling the associated emotion. Importantly, the boost in temporal memory due to the emotional context remained even when participants were unsure or mistaken about the associated emotion. This study demonstrates the complex interplay between emotion and temporal memory, underscoring the enhancement effect of separated emotional contexts on temporal recall, irrespective of explicit emotional memory retrieval.

Cross-cultural adaptation and clinical application of the Perth Empathy Scale.

OBJECTIVE: Alterations of empathy have been observed in patients with various mental disorders. The Perth Empathy Scale (PES) was recently developed to measure a multidimensional construct of empathy across positive and negative emotions. However, its psychometric properties and clinical applications have not been examined in the Chinese context. METHODS: The Chinese version of the PES was developed and administered to a large Chinese sample (n = 1090). Factor structure, internal consistency, test-retest reliability, and convergent, discriminant, as well as concurrent validity were examined. Moreover, 50 patients with major depressive disorder (MDD) and 50 healthy controls were recruited to explore the clinical utility of the PES. RESULTS: Confirmatory factor analyses supported a theoretically congruent three-factor structure of empathy, namely Cognitive Empathy, Negative Affective Empathy and Positive Affective Empathy. The PES showed good to excellent internal consistency reliability, good convergent and discriminant validity, acceptable concurrent validity, and moderate to high test-retest reliability. Patients with MDD had significantly lower PES scores compared to healthy controls. Linear discriminant function comprised of the three factors correctly differentiated 71% of participants, which further verified the clinical utility of the PES. CONCLUSIONS: Our findings indicated that the Chinese version of the PES is a reliable and valid instrument to measure cognitive and affective empathy across negative and positive emotions, and could therefore be used in both research and clinical practice.

Construction of a Chinese traditional instrumental music dataset: A validated set of naturalistic affective music excerpts.

Music is omnipresent among human cultures and moves us both physically and emotionally. The perception of emotions in music is influenced by both psychophysical and cultural factors. Chinese traditional instrumental music differs significantly from Western music in cultural origin and music elements. However, previous studies on music emotion perception are based almost exclusively on Western music. Therefore, the construction of a dataset of Chinese traditional instrumental music is important for exploring the perception of music emotions in the context of Chinese culture. The present dataset included 273 10-second naturalistic music excerpts. We provided rating data for each excerpt on ten variables: familiarity, dimensional emotions (valence and arousal), and discrete emotions (anger, gentleness, happiness, peacefulness, sadness, solemnness, and transcendence). The excerpts were rated by a total of 168 participants on a seven-point Likert scale for the ten variables. Three labels for the excerpts were obtained: familiarity, discrete emotion, and cluster. Our dataset demonstrates good reliability, and we believe it could contribute to cross-cultural studies on emotional responses to music.

DSCAM Deficiency Leads to Premature Spine Maturation and Autism-like Behaviors.

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1ß (NRXN1ß) interaction. DSCAM extracellular domain was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors, such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine maturation and excessive glutamatergic transmission, and its deficiency could lead to autism-like behaviors. Our study provides new insight into the potential pathophysiological mechanisms of ASDs.SIGNIFICANCE STATEMENTDSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1ß interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism.

Microglia are involved in regulating histamine-dependent and non-dependent itch transmissions with distinguished signal pathways.

Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.

Negative emotion amplifies retrieval practice effect for both task-relevant and task-irrelevant information.

Selective retrieval of task-relevant information often facilitates memory retention of that information. However, it is still unclear if selective retrieval of task-relevant information can alter memory for task-irrelevant information, and the role of emotional arousal in it. In two experiments, we used emotional and neutral faces as stimuli, and participants were asked to memorise the name (who is this person?) and location (where does he/she come from?) associated with each face in initial study. Then, half of the studied faces were presented as cues, and participants were asked to retrieve the corresponding names (Experiment 1) or locations (Experiment 2). Finally, all the faces were presented and participants were asked to retrieve both the corresponding names and locations. The results of the final test showed that retrieval practice not only enhanced memory of task-relevant information but also enhanced memory of task-irrelevant information. More importantly, negative emotion amplified the retrieval practice effect overall, with a larger retrieval-induced benefit for the negative than neutral condition. These findings demonstrated an emotional arousal amplification effect on retrieval-induced enhancement effects, suggesting that the advantage of the retrieved memory representations can be amplified by emotional arousal even without explicit goals in a task setting.

The longitudinal development of large-scale functional brain networks for arithmetic ability from childhood to adolescence.

Arithmetic ability is an important high-level cognitive function that requires interaction among multiple brain regions. Previous studies on arithmetic development have focused on task-induced activation in isolated brain regions or functional connectivity among particular seed regions. However, it remains largely unknown whether and how functional connectivity among large-scale brain modules contributes to arithmetic development. In the present study, we used a longitudinal sample of task-based functional magnetic resonance imaging (fMRI) data comprising 63 typically developing children, with two testing points being about 2 years apart. With graph theory, we examined the longitudinal development of large-scale brain modules for a multiplication task in younger (mean age 9.88 at time 1) and older children (mean age 12.34 at time 1), respectively. The results showed that the default-mode (DMN) and frontal-parietal networks (FPN) became increasingly segregated over time. Specifically, intra-connectivity within the DMN and FPN increased significantly with age, and inter-connectivity between the DMN and visual network decreased significantly with age. Such developmental changes were mainly observed in the younger children but not in the older children. Moreover, the change in network segregation of the DMN was positively correlated with longitudinal gain in arithmetic performance in the younger children, and individual difference in network segregation of the FPN was positively correlated with arithmetic performance at Time 2 in the older children. Taken together, the present results highlight the development of the functional architecture in large-scale brain networks from childhood to adolescence, which may provide insights into potential neural mechanisms underlying arithmetic development.

Genetic recovery of ErbB4 in adulthood partially restores brain functions in null mice.

Neurotrophic factor NRG1 and its receptor ErbB4 play a role in GABAergic circuit assembly during development. ErbB4 null mice possess fewer interneurons, have decreased GABA release, and show impaired behavior in various paradigms. In addition, NRG1 and ErbB4 have also been implicated in regulating GABAergic transmission and plasticity in matured brains. However, current ErbB4 mutant strains are unable to determine whether phenotypes in adult mutant mice result from abnormal neural development. This important question, a glaring gap in understanding NRG1-ErbB4 function, was addressed by using two strains of mice with temporal control of ErbB4 deletion and expression, respectively. We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology. On the other hand, some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate a critical role of NRG1-ErbB4 signaling in GABAergic transmission and behavior in adulthood and suggest that restoring NRG1-ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders.

Controlling of glutamate release by neuregulin3 via inhibiting the assembly of the SNARE complex.

Neuregulin3 (NRG3) is a growth factor of the neuregulin (NRG) family and a risk gene of various severe mental illnesses including schizophrenia, bipolar disorders, and major depression. However, the physiological function of NRG3 remains poorly understood. Here we show that loss of Nrg3 in GFAP-Nrg3f/f mice increased glutamatergic transmission, but had no effect on GABAergic transmission. These phenotypes were observed in Nex-Nrg3f/f mice, where Nrg3 was specifically knocked out in pyramidal neurons, indicating that Nrg3 regulates glutamatergic transmission by a cell-autonomous mechanism. Consequently, in the absence of Nrg3 in pyramidal neurons, mutant mice displayed various behavioral deficits related to mental illnesses. We show that the Nrg3 mutation decreased paired-pulse facilitation, increased decay of NMDAR currents when treated with MK801, and increased minimal stimulation-elicited response, providing evidence that the Nrg3 mutation increases glutamate release probability. Notably, Nrg3 is a presynaptic protein that regulates the SNARE-complex assembly. Finally, increased Nrg3 levels, as observed in patients with severe mental illnesses, suppressed glutamatergic transmission. Together, these observations indicate that, unlike the prototype Nrg1, the effect of which is mediated by activating ErbB4 in interneurons, Nrg3 is critical in controlling glutamatergic transmission by regulating the SNARE complex at the presynaptic terminals, identifying a function of Nrg3 and revealing a pathophysiological mechanism for hypofunction of the glutamatergic pathway in Nrg3-related severe mental illnesses.

Alleviation of Anxiety/Depressive-Like Behaviors and Improvement of Cognitive Functions by Lactobacillus plantarum WLPL04 in Chronically Stressed Mice.

BACKGROUND: Intestinal microorganisms play an important role in regulating the neurodevelopment and the brain functions of the host through the gut-brain axis. Lactobacillus, one of the most representative intestinal probiotics, produces important effects on human physiological functions. Our previous studies reveal that the Lactobacillus plantarum WLPL04 has a series of beneficial actions, such as antiadhesion of pathogens, protection from the harmful effect of sodium dodecyl sulfate, and anti-inflammatory stress on Caco2 cells. However, its effects on brain functions remain unknown. The present study aims to evaluate the potential effect of L. plantarum WLPL04 on anxiety/depressive-like behaviors in chronically restrained mice. METHODS: Newly weaned mice were exposed to chronic restraint stress for four weeks and raised daily with or without L. plantarum WLPL04 water supplement. Animals were behaviorally assessed for anxiety/depression and cognitive functions. The 16S rRNA sequencing was performed to analyze the intestinal microbiota structure. The levels of the medial prefrontal cortical (mPFC) brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) and serum 5-hydroxytryptamine (5-HT) were examined using Western blot and enzyme-linked immunosorbent assay. RESULTS: The chronic stress-induced anxiety/depressive-like behaviors and cognitive deficits were significantly alleviated by the L. plantarum WLPL04 treatment. The 16S rRNA sequencing analysis showed that the chronic stress reduced the diversity and the richness of intestinal microbiota, which were rescued by the L. plantarum WLPL04 treatment. The levels of BDNF and TrkB in the mPFC and the concentration of 5-HT in the serum remained unchanged in chronically restrained mice treated with the L. plantarum WLPL04. CONCLUSIONS: The L. plantarum WLPL04 can rescue anxiety/depressive-like behaviors and cognitive dysfunctions, reverse the abnormal change in intestinal microbiota, and alleviate the reduced levels of 5-HT, BDNF, and TrkB induced by chronic stress in mice, providing an experimental basis for the therapeutic application of L. plantarum on anxiety/depression.

[Automatic three-dimensional segmentation of liver and tumors regions based on conditional generative adversarial networks].

The three-dimensional (3D) liver and tumor segmentation of liver computed tomography (CT) has very important clinical value for assisting doctors in diagnosis and prognosis. This paper proposes a tumor 3D conditional generation confrontation segmentation network (T3scGAN) based on conditional generation confrontation network (cGAN), and at the same time, a coarse-to-fine 3D automatic segmentation framework is used to accurately segment liver and tumor area. This paper uses 130 cases in the 2017 Liver and Tumor Segmentation Challenge (LiTS) public data set to train, verify and test the T3scGAN model. Finally, the average Dice coefficients of the validation set and test set segmented in the 3D liver regions were 0.963 and 0.961, respectively, while the average Dice coefficients of the validation set and test set segmented in the 3D tumor regions were 0.819 and 0.796, respectively. Experimental results show that the proposed T3scGAN model can effectively segment the 3D liver and its tumor regions, so it can better assist doctors in the accurate diagnosis and treatment of liver cancer.

miR-454 suppresses the proliferation and invasion of ovarian cancer by targeting E2F6.

BACKGROUND: The aberrant expression of microRNA-454 (miR-454) has been confirmed to be involved in the development of cancers. However, the functional role of miR-454 in the progression of ovarian cancer remains unclear. METHODS: The expression of miR-454 in ovarian cancer cells and serum of ovarian cancer patients was detected by RT-PCR. CCK8, colony formation, transwell, and flow cytometry assays were conducted to assess the effects of miR-454 on ovarian cancer cell proliferation, migration, invasion, and apoptosis, respectively. Dual-luciferase reporter assay was used to confirm the targeting relationship between miR-454 and E2F6. The expression pattern of E2F6 in ovarian cancer tissues was detected using immunohistochemistry (IHC) assay. The relative expression of related proteins was examined using western blot analysis. RESULTS: miR-454 was markedly down-regulated by hypoxia in ovarian cancer cells. Compared with normal samples, the expression of miR-454 was up-regulated in the serum of ovarian cancer patients, and correlated with the clinicopathological stages of ovarian cancer. Next, we found that miR-454 overexpression inhibited the proliferation, migration and invasion of OVCAR3 and SKOV3 cells, as well as promoted apoptosis. In addition, the Akt/mTOR and Wnt/ß-catenin signaling pathway were inhibited by miR-454 in ovarian cancer cells. Mechanically, bioinformatic analysis and dual-luciferase reporter assay confirmed that E2F6 was a direct target of miR-454 and negatively regulated by miR-454 in ovarian cancer cells. Moreover, IHC analysis showed that E2F6 was highly expressed in ovarian cancer tissues. Finally, we found that the increasing cell proliferation and migration triggered by E2F6 overexpression were abolished by miR-454 overexpression. CONCLUSION: Taken together, these results highlight the role of miR-454 as a tumor suppressor in ovarian cancer cells by targeting E2F6, indicating that miR-454 may be a potential diagnostic biomarker and therapeutic target for ovarian cancer.

Transmembrane protein 108 is required for glutamatergic transmission in dentate gyrus.

Neurotransmission in dentate gyrus (DG) is critical for spatial coding, learning memory, and emotion processing. Although DG dysfunction is implicated in psychiatric disorders, including schizophrenia, underlying pathological mechanisms remain unclear. Here we report that transmembrane protein 108 (Tmem108), a novel schizophrenia susceptibility gene, is highly enriched in DG granule neurons and its expression increased at the postnatal period critical for DG development. Tmem108 is specifically expressed in the nervous system and enriched in the postsynaptic density fraction. Tmem108-deficient neurons form fewer and smaller spines, suggesting that Tmem108 is required for spine formation and maturation. In agreement, excitatory postsynaptic currents of DG granule neurons were decreased in Tmem108 mutant mice, indicating a hypofunction of glutamatergic activity. Further cell biological studies indicate that Tmem108 is necessary for surface expression of AMPA receptors. Tmem108-deficient mice display compromised sensorimotor gating and cognitive function. Together, these observations indicate that Tmem108 plays a critical role in regulating spine development and excitatory transmission in DG granule neurons. When Tmem108 is mutated, mice displayed excitatory/inhibitory imbalance and behavioral deficits relevant to schizophrenia, revealing potential pathophysiological mechanisms of schizophrenia.

A High Reliability 3D Scanning Measurement of the Complex Shape Rail Surface of the Electromagnetic Launcher.

After an electromagnetic railgun launch, a series of damage phenomena may cause the inner bore surface to become complex, such as gouging and deposition. Furthermore, the rail surface will be uneven and blackened by oxidation. To understand these forms of rail degradation, many previous studies have mentioned several surface scanning methods, but none of these can be used in the complex inner bore. Therefore, we present a 3D scanning system based on binocular stereovision technology combined with the active illumination, which can be used to obtain the rail surface topography under a complex inner bore environment. The laser dot projection is applied as the active illumination. In contrast with other active illumination, laser dot projection has high reconstruction reliability. By combining laser dot projection with binocular stereovision, the object can be completely reconstructed. In addition, an image acquisition method which can improve image signal-to-noise ratio is proposed. The proof-of-principle experiment of the system is done under dim light conditions. Through the experiment, the 3D depth map of the rail surface is obtained and the gouge crater is scanned out. Meanwhile, system evaluation and measurement uncertainty analysis have also been carried out.

Is Continuous Heart Rate Monitoring of Livestock a Dream or Is It Realistic? A Review.

For all homoeothermic living organisms, heart rate (HR) is a core variable to control the metabolic energy production in the body, which is crucial to realize essential bodily functions. Consequently, HR monitoring is becoming increasingly important in research of farm animals, not only for production efficiency, but also for animal welfare. Real-time HR monitoring for humans has become feasible though there are still shortcomings for continuously accurate measuring. This paper is an effort to estimate whether it is realistic to get a continuous HR sensor for livestock that can be used for long term monitoring. The review provides the reported techniques to monitor HR of living organisms by emphasizing their principles, advantages, and drawbacks. Various properties and capabilities of these techniques are compared to check the potential to transfer the mostly adequate sensor technology of humans to livestock in term of application. Based upon this review, we conclude that the photoplethysmographic (PPG) technique seems feasible for implementation in livestock. Therefore, we present the contributions to overcome challenges to evolve to better solutions. Our study indicates that it is realistic today to develop a PPG sensor able to be integrated into an ear tag for mid-sized and larger farm animals for continuously and accurately monitoring their HRs.

[Advances in studies on structure and pharmacological activities of natural tirucallane-type triterpenoids].

The tirucallane-type triterpenoids, composed of six isoprene units, belong to a group of tetracyclic triterpenoids. Although the naturally-derived tirucallane-type triterpenoids were found in a small amount, the kind of compounds showed various structures, which consist of apo-type, linear said-chain-type and cyclolike said-chain-type and broad bioactivities, such as cytotoxicity, anti-inflammation, antioxidation and anti-plasmin, etc. This paper summarized origins, structures and bioactivities of tirucallane-type triterpenoids in recent ten years. The future research and exploration of tirucallane-type triterpenoids were discussed and prospected.

Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in both chd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.