SETBP1 variants occur as somatic mutations in several hematological malignancies such as atypical chronic myeloid leukemia and as de novo germline mutations in the Schinzel-Giedion syndrome. Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex. Deletion of two AT-hooks abrogates the binding of SETBP1 to gDNA and impairs target gene upregulation. Genes controlled by SETBP1 such as MECOM are significantly upregulated in leukemias containing SETBP1 mutations. Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis. In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration. In summary, this work unveils a SETBP1 function that directly affects gene transcription and clarifies the mechanism operating in myeloid malignancies and in the Schinzel-Giedion syndrome caused by SETBP1 mutations.

Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels.

The decomposition of large stocks of soil organic carbon in thawing permafrost might depend on more than climate change-induced temperature increases: indirect effects of thawing via altered bacterial community structure (BCS) or rooting patterns are largely unexplored. We used a 10-year in situ permafrost thaw experiment and aerobic incubations to investigate alterations in BCS and potential respiration at different depths, and the extent to which they are related with each other and with root density. Active layer and permafrost BCS strongly differed, and the BCS in formerly frozen soils (below the natural thawfront) converged under induced deep thaw to strongly resemble the active layer BCS, possibly as a result of colonization by overlying microorganisms. Overall, respiration rates decreased with depth and soils showed lower potential respiration when subjected to deeper thaw, which we attributed to gradual labile carbon pool depletion. Despite deeper rooting under induced deep thaw, root density measurements did not improve soil chemistry-based models of potential respiration. However, BCS explained an additional unique portion of variation in respiration, particularly when accounting for differences in organic matter content. Our results suggest that by measuring bacterial community composition, we can improve both our understanding and the modeling of the permafrost carbon feedback.

Human immunodeficiency virus type 1 (HIV-1) Tat, an important regulator of viral transcription, interacts with diverse cellular proteins and promotes or inhibits cell proliferation. Here, we show that ribosomal protein S3 (RPS3) plays an important role in mitosis through an interaction with α-tubulin and that Tat binds to and inhibits the localization of RPS3 in the mitotic spindle during mitosis. RPS3 colocalized with α-tubulin around chromosomes in the mitotic spindle. Depletion of RPS3 promoted α-tubulin assembly, while overexpression of RPS3 impaired α-tubulin assembly. Depletion of RPS3 resulted in aberrant mitotic spindle formation, segregation failure, and defective abscission. Moreover, ectopic expression of RPS3 rescued the cell proliferation defect in RPS3-knockdown cells. HIV-1 Tat interacted with RPS3 through its basic domain and increased the level of RPS3 in the nucleus. Expression of Tat caused defects in mitotic spindle formation and chromosome assembly in mitosis. Moreover, the localization of RPS3 in the mitotic spindle was disrupted when HIV-1 Tat was expressed in HeLa and Jurkat cells. These results suggest that Tat inhibits cell proliferation via an interaction with RPS3 and thereby disrupts mitotic spindle formation during HIV-1 infection. These results might provide insight into the mechanism underlying lymphocyte pathogenesis during HIV-1 infection.

To describe a crowdsourced disease surveillance project (EpiCore) and evaluate its usefulness in obtaining information regarding potential disease outbreaks.

One of the most interesting effects of probiotics is their ability to modulate the immune system through the induction of cytokines and to enhance the host immune response.

Cleft lip and/or palate is the most common congenital craniofacial anomaly. Prenatal diagnosis of the craniofacial anomalies is possible with the advent of newer imaging modalities. The identification of the defect at an early stage in the pregnancy helps the parents to be well informed and counseled regarding the treatment possibilities and outcomes of cleft lip and palate (CLP) treatment.

In plants, several transposable elements are conserved across species. We found a homolog of ONSEN, which is a heat-activated retrotransposon originally isolated from Arabidopsis thaliana, in Vigna. The ONSEN-like elements (VaONS) were detected in all the analyzed Japanese accessions of Vigna angularis (adzuki bean) by Southern blot analysis. However, VaONS sequences were observed to be polymorphic in the different accessions. Interestingly, extrachromosomal DNA (ecDNA) was detected in some accessions of adzuki bean, indicating the conserved heat-activation of VaONS. Furthermore, we successfully induced retrotransposition of VaONS in adzuki plant regenerated through callus. Findings of our study should provide a new tool for molecular breeding of adzuki bean.

Single seed weight (SSW), or seed size, is a seed yield components (SYC) in soybean, and it is suggested that the genetic factors regulating SSW are involved in the control of other SYCs. The quantitative trait loci (QTLs) for SSW and their effects on the other SYCs were investigated using a recombinant inbred line population derived from typical small- and large-seeded cultivars that were cultivated in two different environments. QTL analysis detected four environmentally stable QTLs for SSW, two of which coincided with the defined loci, qSw17-1 and Ln. The effects of the other loci, qSw12-1 and qSw13-1, were confirmed by analyzing residual heterozygous line progenies derived from the recombinant population. These four QTL regions were also involved in the control of an additional SYC, namely the large-seeded allele at each locus that reduced either the number of pods per plant or the number of ovules per pod. These results suggest the presence of at least two different regulatory mechanisms for SSW. Isolation of genes responsible for these QTLs provides an important tool in the understanding and utilization of SSW diversity for soybean breeding.

Apomixis, or asexual seed formation, is of great value for plant breeding and seed production, and is desirable in modern agriculture, but natural apomixis occurs in cassava at very low frequency. In present study, apomixis was induced by the treatments of female flower buds with 1%, 1.5% and 2% (v/v) dimethyl sulfoxide (DMSO) and the results showed that 1.5% DMSO treatment was most effective for the induction of apomictic seed formation in cassava cultivar SC5 with the highest percentages of fruit set and true apomictic seeds. The germinated seedlings resembled their parents and displayed no morphological characteristics of cassava polyploid. Flow cytometry and chromosome counting showed that these plants were uniform diploids. Analysis of 34 DMSO-induced cassava progenies by the expressed sequence tag-simple sequence repeat (EST-SSR) and sequence-related amplified polymorphism (SRAP) markers showed that three true apomictic seeds were obtained from the group of SC5 treated with 1.5% DMSO.

Pepper (Capsicum) is one of the most important vegetable and spice crops. Aphid-transmitted cucumber mosaic virus (CMV) causes significant damage to pepper crops across the world. The genetic basis of CMV resistance in pepper is complex, and the mechanisms underlying resistance remain largely unknown. Here, we employed a SLAF-seq approach to generate a high-density genetic map of pepper. The map spanned 1,785.46 cM, containing 12,727 markers on 12 chromosomes, with a mean marker distance of 0.16 cM between adjacent markers. We used this map and the interval mapping (IM) and multiple QTL mapping (MQM) procedures to detect genetic regions associated with quantitative trait for CMV resistance. Three QTLs, qcmv11.1, qcmv11.2 and qcmv12.1, conferred resistance to CMV and showed trait variation of 10.2%, 19.2% and 7.3% respectively. Our results will help to develop markers linked to CMV-resistant QTLs to improve pepper resistance to CMV.

Propofol inhibits long-term potentiation (LTP) in the hippocampal CA1 region and impedes episodic memory formation. However, the molecular mechanisms involved in the effect of propofol are still poorly understood. It had been reported that propofol inhibited cAMP response element binding protein signaling, which was proposed to contribute to memory retention impairment in rats. Here, we first demonstrated that propofol perfusion could inhibit forskolin induced LTP in the rat hippocampal CA1 slices. Propofol also reduced the level of cAMP, which could be reversed by non-selective PDE inhibitor IBMX. We further discovered that propofol could increase both PDE4 activity and PDE4AX protein expressions in the hippocampal CA1 region. Furthermore, pretreatment of rolipram, a PDE4 inhibitor, rescued propofol induced inhibition of CA1 LTP and the impairment of hippocampus-dependent memory formation in rats. Thus, our results suggest that reduced levels of cAMP by increasing PDE4 activity and PDE4AX protein expressions in the hippocampal CA1 region plays an important role in the propofol-induced amnesia.

Peripheral nerve injuries are generally associated with incomplete restoration of motor function. The slow rate of nerve regeneration after injury may account for this. Although many benefits of resveratrol have been shown in the nervous system, it is not clear whether resveratrol could promote fast nerve regeneration and motor repair after peripheral nerve injury. This study showed that the motor deficits caused by sciatic nerve crush injury were alleviated by daily systematic resveratrol treatment within 10 days. Resveratrol increased the number of axons in the distal part of the injured nerve, indicating enhanced nerve regeneration. In the affected ventral spinal cord, resveratrol enhanced the expression of several vascular endothelial growth factor family proteins (VEGFs) and increased the phosphorylation of p300 through Akt signaling, indicating activation of p300 acetyltransferase. Inactivation of p300 acetyltransferase reversed the resveratrol-induced expression of VEGFs and motor repair in rats that had undergone sciatic nerve crush injury. The above results indicated that daily systematic resveratrol treatment promoted nerve regeneration and led to rapid motor repair. Resveratrol activated p300 acetyltransferase-mediated VEGF signaling in the affected ventral spinal cord, which may have thus contributed to the acceleration of nerve regeneration and motor repair.

Compared to sites in protein-coding sequences many more targets undergoing adenosine to inosine (A-to-I) RNA editing were discovered in non-coding regions of human cerebral transcripts, particularly in genetic transposable elements called retrotransposons. We review here the interaction mechanisms of RNA editing and retrotransposons and their impact on normal function and human neurological diseases. Exemplarily, A-to-I editing of retrotransposons embedded in protein-coding mRNAs can contribute to protein abundance and function via circular RNA formation, alternative splicing, and exonization or silencing of retrotransposons. Interactions leading to disease are not very well understood. We describe human diseases with involvement of the central nervous system including inborn errors of metabolism, neurodevelopmental disorders, neuroinflammatory and neurodegenerative and paroxysmal diseases, in which retrotransposons (Alu and/or L1 elements) appear to be causally involved in genetic rearrangements. Sole binding of single-stranded retrotransposon transcripts by RNA editing enzymes rather than enzymatic deamination may have a homeostatic effect on retrotransposon turnover. We also review evidence in support of the emerging pathophysiological function of A-to-I editing of retrotransposons in inflammation and its implication for different neurological diseases including amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's and Parkinson's disease, and epilepsy.

Many genes controlling neuronal development also regulate adult neurogenesis. We investigated in vivo the effect of Sonic hedgehog (Shh) signaling activation on patterning and neurogenesis of the hippocampus and behavior of Patched1 (Ptch1) heterozygous mice (Ptch1+/- ). We demonstrated for the first time, that Ptch1+/- mice exhibit morphological, cellular and molecular alterations in the dentate gyrus (DG), including elongation and reduced width of the DG as well as deregulations at multiple steps during lineage progression from neural stem cells to neurons. By using stage-specific cellular markers, we detected reduction of quiescent stem cells, newborn neurons and astrocytes and accumulation of proliferating intermediate progenitors, indicative of defects in the dynamic transition among neural stages. Phenotypic alterations in Ptch1+/- mice were accompanied by expression changes in Notch pathway downstream components and TLX nuclear receptor, as well as perturbations in inflammatory and synaptic networks and mouse behavior, pointing to complex biological interactions and highlighting cooperation between Shh and Notch signaling in the regulation of neurogenesis.

The spatial organization of synaptic inputs on the dendritic tree of cortical neurons is considered to play an important role in the dendritic integration of synaptic activity. Active electrical properties of dendrites and mechanisms of dendritic integration have been studied for a long time. New technological developments are now enabling the characterization of the spatial organization of synaptic inputs on dendrites. However, quantitative methods for the analysis of such data are lacking. In order to place cluster parameters into the framework of dendritic integration and synaptic summation, these parameters need to be assessed rigorously in a quantitative manner. Here I present an approach for the analysis of synaptic input clusters on the dendritic tree that is based on combinatorial analysis of the likelihoods to observe specific input arrangements. This approach is superior to the commonly applied analysis of nearest neighbor distances between synaptic inputs comparing their distribution to simulations with random reshuffling or bootstrapping. First, the new approach yields exact likelihood values rather than approximate numbers obtained from simulations. Second and more importantly, the new approach identifies individual clusters and thereby allows to quantify and characterize individual cluster properties.

The development of 3D visualization and reconstruction methods to analyse microscopic structures at different levels of resolutions is of great importance to define brain microorganization and connectivity. MultiMap is a new tool that allows the visualization, 3D segmentation and quantification of fluorescent structures selectively in the neuropil from large stacks of confocal microscopy images. The major contribution of this tool is the posibility to easily navigate and create regions of interest of any shape and size within a large brain area that will be automatically 3D segmented and quantified to determine the density of puncta in the neuropil. As a proof of concept, we focused on the analysis of glutamatergic and GABAergic presynaptic axon terminals in the mouse hippocampal region to demonstrate its use as a tool to provide putative excitatory and inhibitory synaptic maps. The segmentation and quantification method has been validated over expert labeled images of the mouse hippocampus and over two benchmark datasets, obtaining comparable results to the expert detections.

Leukoaraiosis (LA) is neuroimaging abnormalities of the cerebral white matter in elderly people. However, the molecular mechanisms underlying the cerebral white matter lesions remain unclear. Here, we reported an epigenetic basis and potential pathogenesis for this complex illness. 317 differentially methylated genes were identified to distinguish the mechanism of occurrence and progression of LA. Gene-Ontology pathway analysis highlighted that those genes with epigenetic changes are mostly involved in four major signaling pathways including inflammation and immune response-associated processes (antigen processing and presentation, T cell costimulation and interferon-γ-mediated signaling pathway), synapse assembly, synaptic transmission and cell adhesion. Moreover, immune response seems to be specific to LA occurrence and subsequent disruption of nervous system functions could drive the progression of LA. The significant change of inflammation-associated ZC3H12D in promoter methylation and mRNA expression was implicated in the occurrence of LA, suggesting its potential functions in the molecular mechanism of LA. Our results suggested that inflammation-associated signaling pathways were involved in the pathogenesis of LA and ZC3H12D may contribute to such inflammatory process underlying LA, and further echoed it as a neuroinflammatory disorder in central nervous system (CNS).

Permanent bilateral common carotid occlusion (2VO) is well-established to investigate the chronic cerebral hypoperfusion (CCH)-induced cognitive deficits. Besides, previous studies suggested that disturbance of Neuregulin1 (NRG1)/ErbB4 signaling is associated with cognitive impairments, as well as neuronal apoptosis and neuroinflammation in CNS. However, the expression pattern of hippocampal NRG1/ErbB4 has not been systematically investigated during CCH. Here, we aim to investigate the temporal changes of hippocampal NRG1/ErbB4 during CCH and their possible relationship with neuronal apoptosis and glial activation. Morris water maze (MWM) and Radial arm water maze (RAWM) tests were used to analyze cognitive impairment in 2VO rats at 28 days post-surgery, and Enzyme-Linked Immunosorbent Assay (ELISA), western blotting and immunostaining were performed at different time points (24 h, 7 days, 14 days, 28 days) to detect the expression pattern of NRG1/ErbB4 and the distribution of ErbB4. Neuronal nuclei (NeuN), NeuN/TUNEL, Iba1 and GFAP immunostaining and caspase activity in hippocampal CA1 subarea were assessed during CCH as well. We found that the expression of NRG1 and phosphorylated ErbB4 (pErbB4)/ErbB4 changed in a time-dependent manner (up-regulated in the acute phase and then decreased in the chronic phase of CCH). Besides, ErbB4-expressed neurons and selective types of GABAergic cells decreased after CCH, but the distribution pattern of ErbB4 remained unchanged. In addition, the expression of hippocampal NRG1/ErbB4 positively correlated with the level of neuronal apoptosis (both NeuN/TUNEL immunostaining and caspase-3 activity), but not with glial activation according to Pearson's correlation. These findings indicated that hippocampal NRG1/ErbB4 may be involved in the pathogenesis of CCH, especially neuronal apoptosis during CCH.

Alzheimer's disease (AD) is a neurodegenerative disorder contributing to rapid decline in cognitive function and ultimately dementia. Most cases of AD occur in elderly and later years. There is a growing need for understanding the relationship between aging and AD to identify shared and unique hallmarks associated with the disease in a region and cell-type specific manner. Although genomic studies on AD have been performed extensively, the molecular mechanism of disease progression is still not clear. The major objective of our study is to obtain a higher-order network-level understanding of aging and AD, and their relationship using the hippocampal gene expression profiles of young (20-50 years), aging (70-99 years), and AD (70-99 years). The hippocampus is vulnerable to damage at early stages of AD and altered neurogenesis in the hippocampus is linked to the onset of AD. We combined the weighted gene co-expression network and weighted protein-protein interaction network-level approaches to study the transition from young to aging to AD. The network analysis revealed the organization of co-expression network into functional modules that are cell-type specific in aging and AD. We found that modules associated with astrocytes, endothelial cells and microglial cells are upregulated and significantly correlate with both aging and AD. The modules associated with neurons, mitochondria and endoplasmic reticulum are downregulated and significantly correlate with AD than aging. The oligodendrocytes module does not show significant correlation with neither aging nor disease. Further, we identified aging- and AD-specific interactions/subnetworks by integrating the gene expression with a human protein-protein interaction network. We found dysregulation of genes encoding protein kinases (FYN, SYK, SRC, PKC, MAPK1, ephrin receptors) and transcription factors (FOS, STAT3, CEBPB, MYC, NFKβ, and EGR1) in AD. Further, we found genes that encode proteins with neuroprotective function (14-3-3 proteins, PIN1, ATXN1, BDNF, VEGFA) to be part of the downregulated AD subnetwork. Our study highlights that simultaneously analyzing aging and AD will help to understand the pre-clinical and clinical phase of AD and aid in developing the treatment strategies.