To directly test the requirement for hedgehog signaling in the telencephalon from early neurogenesis, we examined conditional null alleles of both the Sonic hedgehog and Smoothened genes. While the removal of Shh signaling in these animals resulted in only minor patterning abnormalities, the number of neural progenitors in both the postnatal subventricular zone and hippocampus was dramatically reduced. In the subventricular zone, this was partially attributable to a marked increase in programmed cell death. Consistent with Hedgehog signaling being required for the maintenance of stem cell niches in the adult brain, progenitors from the subventricular zone of floxed Smo animals formed significantly fewer neurospheres. The loss of hedgehog signaling also resulted in abnormalities in the dentate gyrus and olfactory bulb. Furthermore, stimulation of the hedgehog pathway in the mature brain resulted in elevated proliferation in telencephalic progenitors. These results suggest that hedgehog signaling is required to maintain progenitor cells in the postnatal telencephalon.

Cotton fiber is an economically important seed trichome and the world's leading natural fiber used in the manufacture of textiles. As a step toward elucidating the genomic organization and distribution of gene networks responsible for cotton fiber development, we investigated the distribution of fiber genes in the cotton genome. Results revealed the presence of gene-rich islands for fiber genes with a biased distribution in the tetraploid cotton (Gossypium hirsutum L.) genome that was also linked to discrete fiber developmental stages based on expression profiles. There were 3 fiber gene-rich islands associated with fiber initiation on chromosome 5, 3 islands for the early to middle elongation stage on chromosome 10, 3 islands for the middle to late elongation stage on chromosome 14, and 1 island on chromosome 15 for secondary cell wall deposition, for a total of 10 fiber gene-rich islands. Clustering of functionally related gene clusters in the cotton genome displaying similar transcriptional regulation indicates an organizational hierarchy with significant implications for the genetic enhancement of particular fiber quality traits. The relationship between gene-island distribution and functional expression profiling suggests for the first time the existence of functional coupling gene clusters in the cotton genome.

Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome the deficiencies of conventional chemotherapy drugs and improve the efficacy. Many studies have revealed that the combination of histone deacetylase inhibitors (HDACi) and alkylating agents have synergistic effects. We reported a novel hybrid NL-101, in which the side chain of bendamustine was replaced with the hydroxamic acid of HDACi vorinostat (SAHA). NL-101 exhibited efficient anti-proliferative activity on myeloid leukemia cells especially Kasumi-1 and NB4 cells, accompanied by S phase arrest and caspase-3 dependent apoptosis. Importantly, it presented both the properties of HDAC inhibition and DNA damaging, as assessed by the acetylation of histone H3 and DNA double-strand breaks marker γ-H2AX. NL-101 also down-regulated the expression of anti-apoptotic protein Bcl-xL which was involved in the mitochondrial death pathway. Meanwhile, NL-101 induced apoptosis and DNA damage in primary cells from acute myeloid leukemia (AML) patients. NL-101 treatment could significantly prolong the survival time of t(8;21) leukemia mice with enhanced efficacy than bendamustine. These data demonstrate that NL-101 could be a potent and selective agent for leukemia treatment.

Mutations in the Bone Morphogenetic Protein (BMP) pathway are associated with a range of defects in skeletal formation. Genetic analysis of BMP signaling requirements is complicated by the presence of three partially redundant BMPs that are required for multiple stages of limb development. We generated an inducible allele of a BMP inhibitor, Gremlin, which reduces BMP signaling. We show that BMPs act in a dose and time dependent manner in which early reduction of BMPs result in digit loss, while inhibiting overall BMP signaling between E10.5 and E11.5 allows polydactylous digit formation. During this period, inhibiting BMPs extends the duration of FGF signaling. Sox9 is initially expressed in normal digit ray domains but at reduced levels that correlate with the reduction in BMP signaling. The persistence of elevated FGF signaling likely promotes cell proliferation and survival, inhibiting the activation of Sox9 and secondarily, inhibiting the differentiation of Sox9-expressing chondrocytes. Our results provide new insights into the timing and clarify the mechanisms underlying BMP signaling during digit morphogenesis.

The mammalian kidney has an intrinsic ability to repair after significant injury. However, this process is inefficient: patients are at high risk for the loss of kidney function in later life. No therapy exists to treat established acute kidney injury (AKI) per se: strategies to promote endogenous repair processes and retard associated fibrosis are a high priority. Whole-organ gene expression profiling has been used to identify repair responses initiated with AKI, and factors that may promote the transition from AKI to chronic kidney disease. Transcriptional profiling has shown molecular markers and potential regulatory pathways of renal repair. Activation of a few key developmental pathways has been reported during repair. Whether these are comparable networks with similar target genes with those in earlier nephrogenesis remains unclear. Altered microRNA profiles, persistent tubular injury responses, and distinct late inflammatory responses highlight continuing kidney pathology. Additional insights into injury and repair processes will be gained by study of the repair transcriptome and cell-specific translatome using high-resolution technologies such as RNA sequencing and translational profiling tailored to specific cellular compartments within the kidney. An enhanced understanding holds promise for both the identification of novel therapeutic targets and biomarker-based evaluation of the damage-repair process.

The Second Heart Field (SHF) has been implicated in several forms of congenital heart disease (CHD), including atrioventricular septal defects (AVSDs). Identifying the SHF gene regulatory networks required for atrioventricular septation is therefore an essential goal for understanding the molecular basis of AVSDs. We defined a SHF Hedgehog-dependent gene regulatory network using whole genome transcriptional profiling and GLI-chromatin interaction studies. The Forkhead box transcription factors Foxf1a and Foxf2 were identified as SHF Hedgehog targets. Compound haploinsufficiency for Foxf1a and Foxf2 caused atrioventricular septal defects, demonstrating the biological relevance of this regulatory network. We identified a Foxf1a cis-regulatory element that bound the Hedgehog transcriptional regulators GLI1 and GLI3 and the T-box transcription factor TBX5 in vivo. GLI1 and TBX5 synergistically activated transcription from this cis-regulatory element in vitro. This enhancer drove reproducible expression in vivo in the posterior SHF, the only region where Gli1 and Tbx5 expression overlaps. Our findings implicate Foxf genes in atrioventricular septation, describe the molecular underpinnings of the genetic interaction between Hedgehog signaling and Tbx5, and establish a molecular model for the selection of the SHF gene regulatory network for cardiac septation.

Clinical evidence shows that visceral fat accumulation decreases whereas sc fat increases in patients treated with thiazolidinediones (TZDs), a type of peroxisome proliferator-activated receptor (PPAR)γ agonist. To clarify the molecular mechanism of the differential effects of PPARγ agonists on sc and visceral adipose, we investigated expression profiling of PPARγ-regulated micro-RNAs (miRNAs) using miRNA microarray. The level of 182 miRNAs changed in human sc adipose treated with pioglitazone, whereas only 46 miRNAs changed in visceral adipose. Among these miRNAs, 27 miRNAs changed in both human sc and visceral adipocytes. Specifically, 7 miRNAs changed at the same direction in sc and visceral adipocytes, whereas 20 miRNAs changed at opposite directions in these two fat depots. Bioinformatics analysis showed that these miRNAs and the predicted target genes were involved in TGF-β-, Wnt/β-catenin-, and insulin-signaling pathways and related to metabolic regulation or cell cycle. Among the miRNAs changed at the same direction in sc and visceral adipocytes, miR-378, located in the first intron of PPARγ coactivator 1β (PGC1β), was coordinately expressed with PGC1β during adipogenesis. Moreover, miR-378 and PGC1β were both up-regulated by PPARγ agonist. We also provided evidence that miR-378 promoted adipogenesis in sc fat, but not in visceral fat. These results display miRNAs expression profiling altered in sc and visceral adipogenesis regulated by PPARγ and suggest a potential mechanism underlying the differential effects of TZDs on the 2 fat depot accumulations.

The Genome Database for Rosaceae (GDR) and CottonGen are comprehensive online data repositories that provide access to integrated genomic, genetic and breeding data through search, visualization and analysis tools for Rosaceae crops and Gossypium (cotton). These online databases use Chado, an open-source, generic and ontology-driven database schema for biological data, as the primary data storage platform. Chado is highly normalized and uses ontologies to indicate the 'types' of data. Therefore, Chado is flexible such that it has been used to house genomic, genetic and breeding data for GDR and CottonGen. These data include whole genome sequence and annotation, transcripts, molecular markers, genetic maps, Quantitative Trait Loci, Mendelian Trait Loci, traits, germplasm, pedigrees, large scale phenotypic and genotypic data, ontologies and publications. We provide information about how to store these types of data in Chado using GDR and CottonGen as examples sites that were converted from an older legacy infrastructure. Database URL: GDR (www.rosaceae.org), CottonGen (www.cottongen.org).

Previous work suggests that aging is associated with changes in risk taking but less is known about their underlying neural basis, such as the potential age differences in the neural processing of value and risk. The goal of the present study was to investigate adult age differences in functional neural responses in a naturalistic risk-taking task. Twenty-six young adults and 27 healthy older adults completed the Balloon Analogue Risk Task while undergoing functional magnetic resonance imaging. Young and older adults showed similar overt risk-taking behavior. Group comparison of neural activity in response to risky vs. control stimuli revealed similar patterns of activation in the bilateral striatum, anterior insula (AI) and ventromedial prefrontal cortex (vmPFC). Group comparison of parametrically modulated activity in response to continued pumping similarly revealed comparable results for both age groups in the AI and, potentially, the striatum, yet differences emerged for regional activity in the vmPFC. At whole brain level, insular, striatal and vmPFC activation was predictive of behavioral risk taking for young but not older adults. The current results are interpreted and discussed as preserved neural tracking of risk and reward in the AI and striatum, respectively, but altered value coding in the vmPFC in the two age groups. The latter finding points toward older adults exhibiting differential vmPFC-related integration and value coding. Furthermore, neural activation holds differential predictive validity for behavioral risk taking in young and older adults.

Mitochondrial transcription factor A (TFAM), the first well-characterized transcription factor from vertebrate mitochondria, is closely related to mitochondrial DNA (mtDNA) maintenance and repair. Recent evidence has shown that the ratio of mtDNA to nuclearDNA (nDNA) is increased in both human cells and murine tissues after ionizing radiation (IR). However, the underlying mechanism has not as yet been clearly identified. In the present study, we demonstrated that in human lung adenocarcinoma A549 cells, expression of TFAM was upregulated, together with the increase of the relative mtDNA copy number and cytochrome c oxidase (COX) activity after α-particle irradiation. Furthermore, short hairpin RNA (shRNA)-mediated TFAM knockdown inhibited the enhancement of the relative mtDNA copy number and COX activity caused by α-particles. Taken together, our data suggested that TFAM plays a crucial role in regulating mtDNA amplification and mitochondrial biogenesis under IR conditions.

Deltamethrin (DM) insecticides are currently being promoted worldwide for mosquito control, because of the high efficacy, low mammalian toxicity and less environmental impact. Widespread and improper use of insecticides induced resistance, which has become a major obstacle for the insect-borne disease management. Resistance development is a complex and dynamic process involving many genes. To better understand the possible molecular mechanisms involved in DM resistance, a proteomic approach was employed for screening of differentially expressed proteins in DM-susceptible and -resistant mosquito cells. Twenty-seven differentially expressed proteins were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry (MS). Four members of the ubiquitin-proteasome system were significantly elevated in DM-resistant cells, suggesting that the ubiquitin-proteasome pathway may play an important role in DM resistance. Proteasome subunit beta type 6 (PSMB6) is a member of 20S proteasomal subunit family, which forms the proteolytic core of 26S proteasome. We used pharmaceutical inhibitor and molecular approaches to study the contributions of PSMB6 in DM resistance: the proteasome inhibitor MG-132 and bortezomib were used to suppress the proteasomal activity and siRNA was designed to block the function of PSMB6. The results revealed that both MG-132 and bortezomib increased the susceptibility in DM-resistant cells and resistance larvae. Moreover, PSMB6 knockdown decreased cellular viability under DM treatment. Taken together, our study indicated that PSMB6 is associated with DM resistance in mosquitoes and that proteasome inhibitors such as MG-132 or bortezomib are suitable for use as a DM synergist for vector control.

The Genome Database for Rosaceae (GDR, http:/www.rosaceae.org), the long-standing central repository and data mining resource for Rosaceae research, has been enhanced with new genomic, genetic and breeding data, and improved functionality. Whole genome sequences of apple, peach and strawberry are available to browse or download with a range of annotations, including gene model predictions, aligned transcripts, repetitive elements, polymorphisms, mapped genetic markers, mapped NCBI Rosaceae genes, gene homologs and association of InterPro protein domains, GO terms and Kyoto Encyclopedia of Genes and Genomes pathway terms. Annotated sequences can be queried using search interfaces and visualized using GBrowse. New expressed sequence tag unigene sets are available for major genera, and Pathway data are available through FragariaCyc, AppleCyc and PeachCyc databases. Synteny among the three sequenced genomes can be viewed using GBrowse_Syn. New markers, genetic maps and extensively curated qualitative/Mendelian and quantitative trait loci are available. Phenotype and genotype data from breeding projects and genetic diversity projects are also included. Improved search pages are available for marker, trait locus, genetic diversity and publication data. New search tools for breeders enable selection comparison and assistance with breeding decision making.

CottonGen (http://www.cottongen.org) is a curated and integrated web-based relational database providing access to publicly available genomic, genetic and breeding data for cotton. CottonGen supercedes CottonDB and the Cotton Marker Database, with enhanced tools for easier data sharing, mining, visualization and data retrieval of cotton research data. CottonGen contains annotated whole genome sequences, unigenes from expressed sequence tags (ESTs), markers, trait loci, genetic maps, genes, taxonomy, germplasm, publications and communication resources for the cotton community. Annotated whole genome sequences of Gossypium raimondii are available with aligned genetic markers and transcripts. These whole genome data can be accessed through genome pages, search tools and GBrowse, a popular genome browser. Most of the published cotton genetic maps can be viewed and compared using CMap, a comparative map viewer, and are searchable via map search tools. Search tools also exist for markers, quantitative trait loci (QTLs), germplasm, publications and trait evaluation data. CottonGen also provides online analysis tools such as NCBI BLAST and Batch BLAST.

Although sex difference in the mean level of depressive symptoms has been well established, the sex difference in genetic and environmental influences on adolescent depressive symptoms is unclear. The current study conducted a meta-analysis of twin studies on sex differences in self- and parent-reported adolescent depressive symptoms. For self-reports, genetic factors influenced adolescent depressive symptoms equally for boys and girls, accounting for 46% of variation, but shared environmental factors had stronger impacts on adolescent girls' versus boys' depressive symptoms (13% versus 1% of the variance). For parent-reports, genetic, shared, and nonshared environmental factors influenced adolescent depressive symptoms equally, with separate estimates of 34%, 35%, and 31%. The implications of sex difference in genetic and environmental etiologies of depressive symptoms are discussed.

Cecropins are the most potent induced peptides to resist invading microorganisms. In the present study, two full length cDNA encoding cecropin2 (Px-cec2) and cecropin3 (Px-cec3) were obtained from P. xylostella by integrated analysis of genome and transcriptome data. qRT-PCR analysis revealed the high levels of transcripts of Px-cecs (Px-cec1, Px-cec2 and Px-cec3) in epidermis, fat body and hemocytes after 24, 30 and 36 h induction of Metarhizium anisopliae, respectively. Silencing of Spätzle and Dorsal separately caused the low expression of cecropins in the fat body, epidermis and hemocytes, and made the P.xylostella larvae more susceptible to M. anisopliae. Antimicrobial assays demonstrated that the purified recombinant cecropins, i.e., Px-cec1, Px-cec2 and Px-cec3, exerted a broad spectrum of antimicrobial activity against fungi, as well as Gram-positive and Gram-negative bacteria. Especially, Px-cecs showed higher activity against M. anisopliae than another selected fungi isolates. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that cecropins exerted the vital morphological alterations to the spores of M. anisopliae. Based on our results, cecropins played an imperative role in resisting infection of M. anisopliae, which will provide the foundation of biological control of insect pests by using cecorpins as a target in the future.

An early event in skeletal joint development is the specification of articular chondrocytes at the joint surface. Articular chondrocytes are distinct in producing lower levels of cartilage matrix and not being replaced by bone, yet how they acquire these properties remains poorly understood. Here, we show that two members of the Iroquois transcriptional repressor family, Irx7 and Irx5a, function to block chondrocyte maturation at the developing hyoid joint of zebrafish. These Irx factors suppress the production of cartilage matrix at the joint in part by preventing the activation of a col2a1a enhancer by Sox9a. Further, both zebrafish Irx7 and mouse IRX1 are able to repress cartilage matrix production in a murine chondrogenic cell line. Iroquois proteins may therefore have a conserved role in keeping chondrocytes in an immature state, with the lower levels of cartilage matrix produced by these immature cells contributing to joint flexibility.

Current vector control programs are largely dependent on pyrethroids, which are the most commonly used and only insecticides recommended by the World Health Organization for insecticide-treated nets (ITNs). However, the rapid spread of pyrethroid resistance worldwide compromises the effectiveness of control programs and threatens public health. Since few new insecticide classes for vector control are anticipated, limiting the development of resistance is crucial for prolonging efficacy of pyrethroids. In this study, we exposed a field-collected population of Culex pipiens pallens to different insecticide selection intensities to dynamically monitor the development of resistance. Moreover, we detected kdr mutations and three detoxification enzyme activities in order to explore the evolutionary mechanism of pyrethroid resistance. Our results revealed that the level of pyrethroid resistance was proportional to the insecticide selection pressure. The kdr and metabolic resistance both contributed to pyrethroid resistance in the Cx. pipiens pallens populations, but they had different roles under different selection pressures. We have provided important evidence for better understanding of the development and mechanisms of pyrethroid resistance which may guide future insecticide use and vector management in order to avoid or delay resistance.

Highly pathogenic avian influenza virus (HPAIV) H5N1 is a highly contagious virus that can cause acute respiratory infections and high human fatality ratio due to excessive inflammatory response. Short-term heat shock, as a stressful condition, could induce the expression of heat shock proteins that function as molecular chaperones to protect cells against multiple stresses. However, the protective effect of short-term heat shock in influenza infection is far from being understood. In this study, mice were treated at 39°C for 4 h before being infected with HPAIV H5N1. Interestingly, short-term heat shock significantly increased the levels of HSP70 and pro-inflammatory cytokines IL-6, TNF-α, IFN-β, and IFN-γ in the lung tissues of mice. Following HPAIV H5N1 infection, short-term heat shock alleviated immunopathology and viral replication in lung tissue and repressed the weight loss and increased the survival rate of H5N1-infected mice. Our data reported that short-term heat shock provided beneficial anti-HPAIV H5N1 properties in mice model, which offers an alternative strategy for non-drug prevention for influenza infection.

The influence of atrial fibrillation (AF) on the clinical outcomes of patients with ischemic stroke (IS) has not been completely determined. We aimed to perform a systematic review and meta-analysis to assess the relationship between AF and adverse events in patients with acute IS treated with thrombolysis.PubMed, EMBASE, and the Cochrane Library were searched for relevant studies regarding the association between AF and the outcomes of patients with IS treated with thrombolysis. Random and fixed effect models were used for pooling data.Twelve cohort studies involving 14,801 patients with acute IS were included. Meta-analysis revealed that patients with AF were more likely to die within 90 days after thrombolysis (odds ratio [OR], 2.13; 95% confidence interval [CI]: 1.68-2.70, P < 0.001), whereas this association was not observed in hospitalized patients (OR, 1.50; 95% CI, 0.86-2.60; P = 0.150). AF was associated with a reduced incidence of favorable outcomes (modified Rankin Scale ≤ 2) (OR, 1.95; 95% CI: 1.33-2.85, P = 0.001) and an increased risk of symptomatic intracerebral hemorrhage (OR, 1.28; 95% CI: 1.08-1.52, P = 0.006). No evident publication bias was found by Begg's test or Egger's test.Comorbidity of AF may increase the risk of adverse outcomes for patients with IS undergoing thrombolysis. Further well-designed trials are warranted to confirm this association.

The basic unit of kidney function is the nephron. In the mouse, around 14,000 nephrons form in a 10-day period extending into early neonatal life, while the human fetus forms the adult complement of nephrons in a 32-week period completed prior to birth. This review discusses our current understanding of mammalian nephrogenesis: the contributing cell types and the regulatory processes at play. A conceptual developmental framework has emerged for the mouse kidney. This framework is now guiding studies of human kidney development enabled in part by in vitro systems of pluripotent stem cell-seeded nephrogenesis. A near future goal will be to translate our developmental knowledge-base to the productive engineering of new kidney structures for regenerative medicine.