Primary Cilium-Autophagy-Nrf2 (PAN) Axis Activation Commits Human Embryonic Stem Cells to a Neuroectoderm Fate.

Under defined differentiation conditions, human embryonic stem cells (hESCs) can be directed toward a mesendoderm (ME) or neuroectoderm (NE) fate, the first decision during hESC differentiation. Coupled with lineage-specific G1 lengthening, a divergent ciliation pattern emerged within the first 24 hr of induced lineage specification, and these changes heralded a neuroectoderm decision before any neural precursor markers were expressed. By day 2, increased ciliation in NE precursors induced autophagy that resulted in the inactivation of Nrf2 and thereby relieved transcriptional activation of OCT4 and NANOG. Nrf2 binds directly to upstream regions of these pluripotency genes to promote their expression and repress NE derivation. Nrf2 suppression was sufficient to rescue poorly neurogenic iPSC lines. Only after these events had been initiated did neural precursor markers get expressed at day 4. Thus, we have identified a primary cilium-autophagy-Nrf2 (PAN) control axis coupled to cell-cycle progression that directs hESCs toward NE.

Salicylic acid functionalized zein for improving plant stress resistance and as a nanopesticide carrier with enhanced anti-photolysis ability.

BACKGROUND: There is a serious global problem of salinization of arable land, causing large reduction in world food production. Use of plant hormones is an effective way to reduce damage caused to crops and salt stress. RESULTS: In this study, PEI-EDA was modified with AM-zein and grafted with plant hormone SA (AM-zein-SA) and used as a nano-pesticide carrier to load emamectin benzoate (EB). The use of AM-zein-SA as a nano-pesticide carrier could reduce the damage caused by salt stress to crops. The structure of AM-zein-SA was characterized by FTIR, UV, fluorescence, Raman, and 1H NMR spectroscopic techniques. AM-zein-SA could effectively improve the resistance of EB to ultraviolet radiations, resistance of cucumber to salt stress, and the absorption of EB by plants. The experimental results showed that AM-zein-SA could effectively improve the anti-UV property of EB by 0.88 fold. When treated with 120 mmol NaCl, the germination rate of cucumber seeds under salt stress increased by 0.93 fold in presence of 6.25 mg/L carrier concentration. The POD and SOD activities increased by 0.50 and 1.21 fold, whereas the content of MDA decreased by 0.23 fold. In conclusion, AM-zein-SA nano-pesticide carrier could be used to improve the salt resistance of crops and the adhesion of pesticides to leaves. CONCLUSION: AM-zein-SA, without undergoing any changes in its insecticidal activity, could simultaneously improve the salt stress resistance and salt stress germination rate of cucumber, reduce growth inhibition due to stress under high-concentration salt, and had a good effect on crops. In addition, EB@AM-zein-SA obviously improved the upward transmission rate of EB, as compared with EB. In this study, SA was grafted onto zein-based nano-pesticide carrier, which provided a green strategy to control plant diseases, insects, and pests while reducing salt stress on crops in saline-alkali soil.

Comparison of thermal stability of Mo/Si multilayers with different crystallinities of Mo layers.

To investigate the thermal stability of Mo/Si multilayers with different initial crystallinities of Mo layers, two kinds of Mo/Si multilayers were deposited by DC magnetron sputtering and annealed at 300°C and 400°C. The period thickness compactions of multilayers with crystalized and quasi-amorphous Mo layers were 0.15 nm and 0.30 nm at 300°C, respectively, and the stronger the crystallinity, the lower the extreme ultraviolet reflectivity loss. At 400°C, the period thickness compactions of multilayers with crystalized and quasi-amorphous Mo layers were 1.25 nm and 1.04 nm, respectively. It was shown that multilayers with a crystalized Mo layer had better thermal stability at 300°C but were less stable at 400°C than multilayers with a quasi-amorphous Mo layer. These changes in stability at 300°C and 400°C were due to the significant transition of the crystalline structure. The transition of the crystal structure leads to increased surface roughness, more interdiffusion, and compound formation.

[CiteSpace knowledge map of research hotspots and frontiers of Polygalae Radix].

In this study, the Web of Science and China National Knowledge Infrastructure(CNKI) were searched comprehensively for the literature about the research on Polygalae Radix. After manual screening, 1 207 Chinese articles and 263 English articles were included in this study. Excel was used to draw the line chart of the annual number of relevant publications. CiteSpace 6.1.R3 was used for the visual analysis of author cooperation, publishing institutions, keyword co-occurrence, keyword clustering, and bursts in the research on Polygalae Radix. The results showed that the number of articles published in Chinese and English increased linearly, which indicated the rising research popularity of Polygalae Radix. WANG J and LIU X were the authors publishing the most articles in Chinese and English, respectively. Shanxi University of Chinese Medicine and Chinese Academy of Medical Sciences were the research institutions with the largest number of Chinese and English publications in this field, respectively. The institutions publishing the relevant articles in English formed a system with the Chinese Academy of Medical Sciences as the core. According to the keywords, the research hotspots of Polygalae Radix included variety selection and breeding, quality standard, extraction and identification of active chemical components, prescription compatibility, processing, clinical medication rules, and pharmacological mechanism. The research frontiers were the molecular mechanisms of Polygalae Radix and its active components in exerting the protective effect on brain nerve, regulating receptor pathways, alleviating anxiety and Alzheimer's disease, as well as data mining and clinical medication summary. This study has reference significance for the topic selection and frontier identification of the future research on Polygalae Radix.

Preparation of mesoporous silica-based nanocomposites with synergistically antibacterial performance from nano-metal (oxide) and polydopamine.

In this work, a novel antibacterial nanocomposite system was developed using mesoporous silica (MSN) as an effective nanocarrier, and the resultant nanocomposites demonstrated remarkable antibacterial performance due to the synergistic effect among nano zinc oxides, silver nanoparticles, and polydopamine (PDA). The successful synthesis of MSN/ZnO@PDA/Ag nanocomposites was confirmed. The physicochemical properties and the morphologies of these nanocomposites were investigated. It was found that the particle size increased along with the evolution of these nanocomposites. Besides, nano zinc oxides were formed in the nanochannels of mesoporous silica with a particle size about 2 nm, and that of silver nanoparticle was less than 50 nm. In addition, the results revealed that the presence of mesoporous silica could effectively prevent the formation of large-size silver nanoparticles and facilitate their well dispersion. Due to the synergistic effect among nano zinc oxides, silver nanoparticles, and polydopamine, these nanocomposites exhibited remarkable antibacterial performance even at a low concentration of 313 ppm, and the antibacterial mechanism was also elucidated. Therefore, this work provides a facile and controllable approach to preparing synergistically antibacterial nanocomposites, and the remarkable antibacterial performance make them suitable for practical applications.

Cr/C multilayer growth on a heavy metal layer for upgrading of high efficiency tender x-ray gratings.

To increase efficiency of single layer gratings used in the tender x-ray range, a high reflectance multilayer can be directly grown on single layer gratings. Multilayer growth quality was studied by depositing the Cr/C multilayer on a Pt single layer using flat substrates. Their structure quality and adhesion were characterized by atomic force microscopy (AFM), grazing incidence x-ray reflectivity (GIXRR), x-ray scattering (XRS), x-ray diffraction (XRD), and layer adhesion measurement. AFM results showed that the surface roughness was 0.218 nm for the multilayer without the Pt layer and 0.272 nm for the multilayer with the Pt layer. As GIXRR results showed, the average interface widths were 0.39 nm for the multilayer without the Pt layer and 0.42 nm for the multilayer with the Pt layer. XRS results indicated that the existence of a Pt layer enlarged slightly the roughness of the multilayer. Simulation results exhibited that these slight changes caused by the Pt layer had an insignificant effect on reflectivity. As XRD results displayed, the crystallization of the Pt layer had negligible effects on the crystallization of Cr in films. The layer adhesion measurement revealed that the critical loads to peel off the layer from the substrate were 84.64 mN for the multilayer without the Pt layer and 33.99 mN for the multilayer with the Pt layer. After 6 months, the latter layer structure is undamaged, demonstrating that the coating is not easily peeled off. This study proves the feasibility to upgrade a low efficiency single Pt layer grating to a highly efficient multilayer grating.

Functionalization of mesoporous silica as an effective composite carrier for essential oils with improved sustained release behavior and long-term antibacterial performance.

In this work, a novel composite carrier system for loading essential oils was developed by using tetraethyl orthosilicate (TEOS) and (3-aminopropyl) triethoxysilane (APTES) as silica precursors and cetyl trimethyl ammonium bromide (CTAB) as a template, and the resultant aminated mesoporous silica was further chemically modified by polyacrylic acid (PAA). The obtained composite carriers exhibited a high loading capability toward tea tree oil (TTO), and they also significantly improved the release behavior of TTO due to the steric hindrance of silica mesopore and the polymer restriction. Besides, it was found that the release behavior followed the First-Order kinetic model, revealing that the release of TTO was driven by the concentration gradient. In addition, these composite carriers with essential oil-loaded demonstrated remarkable antibacterial performance againstE. coliandS. aureus, and they could retain antibacterial performance even after 50 d. Moreover, the antibacterial mechanism was also elucidated with the assistance of nucleic acid and conductivity measurements. Therefore, this work provides a facile and environmentally friendly approach to preparing effective composite carriers for improving the sustained release of essential oils, and the long-term antibacterial performance of these essential oil-loaded composite carriers makes them tremendously potential for practical applications.

Rosin modified aminated mesoporous silica adsorbed tea tree oil sustained-release system for improve synergistic antibacterial and long-term antibacterial effects.

Tea tree oil, a natural antibacterial compound, cannot be used effectively because of its volatile nature. In this work, a biocompatible carrier was prepared and loaded with tea tree essential oil. The carrier was prepared via the electrostatic or chemical action of aminated mesoporous silica and sodium rosin for achieving a low volatilization rate of tea tree essential oil. A synergistic antibacterial effect was observed between sodium rosin and tea tree essential oil. This method utilized the positive charge of the amino group and the condensation reaction with the carboxyl group to achieve physical and chemical interactions with sodium rosin. Fourier Transform Infrared, Brunauer-Emmet-Teller, Zeta potential, SEM, TEM, and TG were performed to characterize the structure and properties of the samples. Compared to the electrostatic effect, the chemically modified system exhibited a longer sustained release, and the sustained release curve followed the Korsmeyer-Peppas release model. Also, the antibacterial properties of the chemically modified system exhibited better minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) respectively, the MIC and MBC forE. coliwere 0.3 mg ml-1and 0.6 mg ml-1respectively, forS. aureuswere 0.15 mg ml-1and 0.3 mg ml-1respectively. More strikingly, the sample also demonstrated long-term antibacterial performance. Therefore, this work provides a new way for the delivery of volatile antibacterial drugs to achieve sustained-release and long-lasting antibacterial effects.

Circ_101064 regulates the proliferation, invasion and migration of glioma cells through miR-154-5p/ PIWIL1 axis.

This study aimed to investigate the effects of Circ_101064 on glioma cell proliferation, invasion, migration and explore the underlying mechanisms. The expression levels of Circ_101064 in glioma/para-carcinoma tissues and glioma cells were analyzed using RT-qPCR. Moreover, U251 and U87 cells were transfected with si-Circ_101064 or miR-154-5p mimics. Cell proliferation rate was determined by CCK-8 assay; the invasion and migration activities were examined using Transwell assay; the expression levels of PIWIL1 were evaluated by RT-qPCR and western blotting. The expression level of Circ_101064 was significantly upregulated in glioma tissues compared with control, and was closely associated with tumor grading and diameter. Furthermore, increased Circ_101064 expression was detected in human glioma cell lines. In addition, knockdown of Circ_101064 remarkably suppressed cell proliferation, invasion and migration in glioma cells in vitro. Moreover, microRNA-154-5p (miR-154-5p) could be a target of Circ_101064. Additionally, PIWIL1 is a putative downstream molecule of miR-154-5p, and its expression was downregulated by knockdown of Circ_101064. The effects on cell growth and metastasis caused by si-Circ_101064 were notably enhanced by miR-154-5p mimics. However, the influences of miR-154-5p-suppressed proliferation, migration and invasion of glioma cells could be abolished by overexpressed PIWIL1. In summary, our findings provided novel insight into the regulatory functions of Circ_101064 during tumor development in glioma. More importantly, Circ_101064/miR-154-5p/PIWIL1 axis could be a promising therapeutic target for the treatment of this disease.

A microRNA-mRNA expression network during oral siphon regeneration in Ciona.

Here we present a parallel study of mRNA and microRNA expression during oral siphon (OS) regeneration in Ciona robusta, and the derived network of their interactions. In the process of identifying 248 mRNAs and 15 microRNAs as differentially expressed, we also identified 57 novel microRNAs, several of which are among the most highly differentially expressed. Analysis of functional categories identified enriched transcripts related to stress responses and apoptosis at the wound healing stage, signaling pathways including Wnt and TGFß during early regrowth, and negative regulation of extracellular proteases in late stage regeneration. Consistent with the expression results, we found that inhibition of TGFß signaling blocked OS regeneration. A correlation network was subsequently inferred for all predicted microRNA-mRNA target pairs expressed during regeneration. Network-based clustering associated transcripts into 22 non-overlapping groups, the functional analysis of which showed enrichment of stress response, signaling pathway and extracellular protease categories that could be related to specific microRNAs. Predicted targets of the miR-9 cluster suggest a role in regulating differentiation and the proliferative state of neural progenitors through regulation of the cytoskeleton and cell cycle.

Genome-wide survey of the bHLH super gene family in Brassica napus.

BACKGROUND: The basic helix-loop-helix (bHLH) gene family is one of the largest transcription factor families in plants and is functionally characterized in diverse species. However, less is known about its functions in the economically important allopolyploid oil crop, Brassica napus. RESULTS: We identified 602 potential bHLHs in the B. napus genome (BnabHLHs) and categorized them into 35 subfamilies, including seven newly separated subfamilies, based on phylogeny, protein structure, and exon-intron organization analysis. The intron insertion patterns of this gene family were analyzed and a total of eight types were identified in the bHLH regions of BnabHLHs. Chromosome distribution and synteny analyses revealed that hybridization between Brassica rapa and Brassica oleracea was the main expansion mechanism for BnabHLHs. Expression analyses showed that BnabHLHs were widely in different plant tissues and formed seven main patterns, suggesting they may participate in various aspects of B. napus development. Furthermore, when roots were treated with five different hormones (IAA, auxin; GA3, gibberellin; 6-BA, cytokinin; ABA, abscisic acid and ACC, ethylene), the expression profiles of BnabHLHs changed significantly, with many showing increased expression. The induction of five candidate BnabHLHs was confirmed following the five hormone treatments via qRT-PCR. Up to 246 BnabHLHs from nine subfamilies were predicted to have potential roles relating to root development through the joint analysis of their expression profiles and homolog function. CONCLUSION: The 602 BnabHLHs identified from B. napus were classified into 35 subfamilies, and those members from the same subfamily generally had similar sequence motifs. Overall, we found that BnabHLHs may be widely involved in root development in B. napus. Moreover, this study provides important insights into the potential functions of the BnabHLHs super gene family and thus will be useful in future gene function research.

RNA stores tau reversibly in complex coacervates.

Nonmembrane-bound organelles that behave like liquid droplets are widespread among eukaryotic cells. Their dysregulation appears to be a critical step in several neurodegenerative conditions. Here, we report that tau protein, the primary constituent of Alzheimer neurofibrillary tangles, can form liquid droplets and therefore has the necessary biophysical properties to undergo liquid-liquid phase separation (LLPS) in cells. Consonant with the factors that induce LLPS, tau is an intrinsically disordered protein that complexes with RNA to form droplets. Uniquely, the pool of RNAs to which tau binds in living cells are tRNAs. This phase state of tau is held in an approximately 1:1 charge balance across the protein and the nucleic acid constituents, and can thus be maximal at different RNA:tau mass ratios, depending on the biopolymer constituents involved. This feature is characteristic of complex coacervation. We furthermore show that the LLPS process is directly and sensitively tuned by salt concentration and temperature, implying it is modulated by both electrostatic interactions between the involved protein and nucleic acid constituents, as well as net changes in entropy. Despite the high protein concentration within the complex coacervate phase, tau is locally freely tumbling and capable of diffusing through the droplet interior. In fact, tau in the condensed phase state does not reveal any immediate changes in local protein packing, local conformations and local protein dynamics from that of tau in the dilute solution state. In contrast, the population of aggregation-prone tau as induced by the complexation with heparin is accompanied by large changes in local tau conformations and irreversible aggregation. However, prolonged residency within the droplet state eventually results in the emergence of detectable ß-sheet structures according to thioflavin-T assay. These findings suggest that the droplet state can incubate tau and predispose the protein toward the formation of insoluble fibrils.

Ischemic damage may play an important role in spinal cord injury during dancing.

STUDY DESIGN: Retrospective analysis. SETTING: China Rehabilitation Research Center, Beijing, China. OBJECTIVE: To explore possible mechanisms underlying spinal cord injury (SCI) in children caused by hyperextension of the spine while dancing. METHODS: The clinical records of 88 children with SCI (mean age, 5.97 years; age range, 4-10 years) admitted to our hospital from January 1989 to October 2019 were retrospectively reviewed. Computed tomography and magnetic resonance imaging were performed on the day of injury. The time from injury to development of paralysis, as well as post-injury activities were surveyed, while abnormal patterns on images, the range of the involved vertebrae, and the extents of edema and atrophy were assessed. RESULTS: Among the 88 patients, 6 (6.8%) were unable to move immediately after SCI, while paralysis occurred in 42, 23, and 17 patients at <30, 30-60, and >60 min after SCI, respectively. The neurological level of injury of 84 patients was between T4 and T12. On sagittal T2-weighted images (T2WIs), the longitudinal range of spinal cord edema was more than one vertebral body in 65 patients, while spinal cord atrophy below T8 was found in 40 patients. On axial T2WIs, although three patients had none, long T2 signals were found in the central gray matter of seven patients. Meanwhile, necrosis of the central area combined with the peripheral white matter was observed in 57 patients, while three patients had total involvement on a cross section. CONCLUSION: Ischemia-related damage, rather than direct trauma to the spinal cord, may play an important role in SCI due to spinal hyperextension during dancing.

Genome-Wide Survey and Expression Analysis of the KT/HAK/KUP Family in Brassica napus and Its Potential Roles in the Response to K+ Deficiency.

The KT/HAK/KUP (HAK) family is the largest potassium (K+) transporter family in plants, which plays key roles in K+ uptake and homeostasis, stress resistance, and root and embryo development. However, the HAK family has not yet been characterized in Brassica napus. In this study, 40 putative B. napus HAK genes (BnaHAKs) are identified and divided into four groups (Groups I-III and V) on the basis of phylogenetic analysis. Gene structure analysis revealed 10 conserved intron insertion sites across different groups. Collinearity analysis demonstrated that both allopolyploidization and small-scale duplication events contributed to the large expansion of BnaHAKs. Transcription factor (TF)-binding network construction, cis-element analysis, and microRNA prediction revealed that the expression of BnaHAKs is regulated by multiple factors. Analysis of RNA-sequencing data further revealed extensive expression profiles of the BnaHAKs in groups II, III, and V, with limited expression in group I. Compared with group I, most of the BnaHAKs in groups II, III, and V were more upregulated by hormone induction based on RNA-sequencing data. Reverse transcription-quantitative polymerase reaction analysis revealed that the expression of eight BnaHAKs of groups I and V was markedly upregulated under K+-deficiency treatment. Collectively, our results provide valuable information and key candidate genes for further functional studies of BnaHAKs.

Global Survey and Expressions of the Phosphate Transporter Gene Families in Brassica napus and Their Roles in Phosphorus Response.

Phosphate (Pi) transporters play critical roles in Pi acquisition and homeostasis. However, currently little is known about these genes in oil crops. In this study, we aimed to characterize the five Pi transporter gene families (PHT1-5) in allotetraploid Brassica napus. We identified and characterized 81 putative PHT genes in B. napus (BnaPHTs), including 45 genes in PHT1 family (BnaPHT1s), four BnaPHT2s, 10 BnaPHT3s, 13 BnaPHT4s and nine BnaPHT5s. Phylogenetic analyses showed that the largest PHT1 family could be divided into two groups (Group I and II), while PHT4 may be classified into five, Groups I-V. Gene structure analysis revealed that the exon-intron pattern was conservative within the same family or group. The sequence characteristics of these five families were quite different, which may contribute to their functional divergence. Transcription factor (TF) binding network analyses identified many potential TF binding sites in the promoter regions of candidates, implying their possible regulating patterns. Collinearity analysis demonstrated that most BnaPHTs were derived from an allopolyploidization event (~40.7%) between Brassica rapa and Brassica oleracea ancestors, and small-scale segmental duplication events (~39.5%) in the descendant. RNA-Seq analyses proved that many BnaPHTs were preferentially expressed in leaf and flower tissues. The expression profiles of most colinearity-pairs in B. napus are highly correlated, implying functional redundancy, while a few pairs may have undergone neo-functionalization or sub-functionalization during evolution. The expression levels of many BnaPHTs tend to be up-regulated by different hormones inductions, especially for IAA, ABA and 6-BA treatments. qRT-PCR assay demonstrated that six BnaPHT1s (BnaPHT1.11, BnaPHT1.14, BnaPHT1.20, BnaPHT1.35, BnaPHT1.41, BnaPHT1.44) were significantly up-regulated under low- and/or rich- Pi conditions in B. napus roots. This work analyzes the evolution and expression of the PHT family in Brassica napus, which will help further research on their role in Pi transport.

Soft X-ray varied-line-spacing gratings fabricated by near-field holography using an electron beam lithography-written phase mask.

A fabrication method comprising near-field holography (NFH) with an electron beam lithography (EBL)-written phase mask was developed to fabricate soft X-ray varied-line-spacing gratings (VLSGs). An EBL-written phase mask with an area of 52 mm × 30 mm and a central line density greater than 3000 lines mm-1 was used. The introduction of the EBL-written phase mask substantially simplified the NFH optics for pattern transfer. The characterization of the groove density distribution and diffraction efficiency of the fabricated VLSGs indicates that the EBL-NFH method is feasible and promising for achieving high-accuracy groove density distributions with corresponding image properties. Vertical stray light is suppressed in the soft X-ray spectral range.

Stability of Cr/C multilayer during synchrotron radiation exposure and thermal annealing.

The stability of Cr/C multilayer during irradiation or thermal annealing was investigated using grazing incidence X-ray reflectivity measurement, X-ray photoelectron spectroscopy, X-ray diffraction analysis, small-angle X-ray scattering analysis, and soft X-ray reflectivity measurement. One sample was irradiated with a white beam of synchrotron radiation and five other samples were annealed at various temperatures. The 18-h irradiation treatment caused local surface contaminants but did not affect the buried stacks. The annealing treatment resulted in increased reflectivity at approximately 1.2 keV, and the multilayer remained stable for temperature up to 700 °C. Thus, the Cr/C multilayers exhibited excellent stability during irradiation and thermal treatments and can be used for the mirrors and multilayer gratings of third-generation synchrotron radiation systems.

Validation of a novel cone tool for pinprick sensation examination in patients with spinal cord injury.

STUDY DESIGN: Psychometrics study. OBJECTIVE: The objective of this study was to introduce a novel tool for pinprick sensation examination and validate its usefulness in patients with spinal cord injury (SCI). SETTING: China Rehabilitation Research Center, Capital Medical University School of Rehabilitation Medicine, China. METHODS: A set of cone tools with different tapers (22.5°, 45°, 67.5°, 90°, 112.5°, 135°, 157.5°, and 180°) was made. The cone tool was validated first in 91 able-bodied individuals and then in 30 patients with SCI. The reliability and validity of the cone tool were analyzed by comparing the results of a pinprick sensation examination with the results of the International Standards for the Neurological Classification of SCI (ISNCSCI), the cone tool, and the thermal analyzer. RESULTS: The intraclass correlation coefficient (ICC) of the cone tool in able-bodied individuals was between 0.48 and 0.94 while that of the cone tool and the ISNCSCI tool ranged between 0.43 and 0.78. Pinprick sensation in patients with SCI can be graded into five levels using four tapers (22.5°, 45°, 67.5°, and 90°): normal, slight impairment, moderate impairment, severe impairment, and complete loss of sensation. CONCLUSION: This easy-to-use cone tool can produce a reliable semi-quantitative pinprick test result and is useful for pinprick sensation examination in patients with SCI.

Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways.

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.

Gut microbiota dysbiosis in male patients with chronic traumatic complete spinal cord injury.

BACKGROUND: Neurogenic bowel dysfunction (NBD) is a major physical and psychological problem in patients with spinal cord injury (SCI), and gut dysbiosis is commonly occurs in SCI. Here, we document neurogenic bowel management of male patients with chronic traumatic complete SCI in our centre and perform comparative analysis of the gut microbiota between our patients and healthy males. METHODS: A total of 43 male patients with chronic traumatic complete SCI (20 with quadriplegia and 23 with paraplegia) and 23 healthy male adults were enrolled. Clinical data and fresh stool specimens were collected from all participants. Face-to-face interviews were conducted to survey the neurogenic bowel management of 43 patients with SCI. Gut microbiomes were analysed by sequencing of the V3-V4 region of the 16S rRNA gene. RESULTS: NBD was common in adult male patients with chronic traumatic complete SCI. Patients with quadriplegia exhibited a longer time to defecate than did those with paraplegia and had higher NBD scores and heavier neurogenic bowel symptoms. The diversity of the gut microbiota in the SCI group was reduced, and the structural composition was different from that of the healthy adult male group. The abundance of Veillonellaceae and Prevotellaceae increased, while Bacteroidaceae and Bacteroides decreased in the SCI group. The abundance of Bacteroidaceae and Bacteroides in the quadriplegia group and Acidaminococcaceae, Blautia, Porphyromonadaceae, and Lachnoclostridium in the paraplegia group were significantly higher than those in the healthy male group. Serum biomarkers (GLU, HDL, CR, and CRP), NBD defecation time and COURSE had significant correlations with microbial community structure. Microbial community structure was significantly associated with serum biomarkers (GLU, HDL, CR, and CRP), NBD defecation time, and COURSE. CONCLUSIONS: This study presents a comprehensive landscape of the gut microbiota in adult male patients with chronic traumatic complete SCI and documents their neurogenic bowel management. Gut microbiota dysbiosis in SCI patients was correlated with serum biomarkers and NBD symptoms.