Identification of Pou5f1, Sox2, and Nanog downstream target genes with statistical confidence by applying a novel algorithm to time course microarray and genome-wide chromatin immunoprecipitation data

<p>Abstract</p> <p>Background</p> <p>Target genes of a transcription factor (TF) <it>Pou5f1 </it>(<it>Oct3/4 </it>or <it>Oct4</it>), which is essential for pluripotency maintenance and self-renewal of embryonic stem (ES) cells, have previously been identified based on their response to <it>Pou5f1 </it>manipulation and occurrence of Chromatin-immunoprecipitation (ChIP)-binding sites in promoters. However, many responding genes with binding sites may not be direct targets because response may be mediated by other genes and ChIP-binding site may not be functional in terms of transcription regulation.</p> <p>Results</p> <p>To reduce the number of false positives, we propose to separate responding genes into groups according to direction, magnitude, and time of response, and to apply the false discovery rate (FDR) criterion to each group individually. Using this novel algorithm with stringent statistical criteria (FDR < 0.2) to a compendium of published and new microarray data (3, 6, 12, and 24 hr after <it>Pou5f1 </it>suppression) and published ChIP data, we identified 420 tentative target genes (TTGs) for <it>Pou5f1</it>. The majority of TTGs (372) were down-regulated after <it>Pou5f1 </it>suppression, indicating that the <it>Pou5f1 </it>functions as an activator of gene expression when it binds to promoters. Interestingly, many activated genes are potent suppressors of transcription, which include polycomb genes, zinc finger TFs, chromatin remodeling factors, and suppressors of signaling. Similar analysis showed that <it>Sox2 </it>and <it>Nanog </it>also function mostly as transcription activators in cooperation with <it>Pou5f1</it>.</p> <p>Conclusion</p> <p>We have identified the most reliable sets of direct target genes for key pluripotency genes – <it>Pou5f1</it>, <it>Sox2</it>, and <it>Nanog</it>, and found that they predominantly function as activators of downstream gene expression. Thus, most genes related to cell differentiation are suppressed indirectly.</p

EGFR Gene Overexpression Retained in an Invasive Xenograft Model by Solid Orthotopic Transplantation of Human Glioblastoma Multiforme Into Nude Mice

Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM

The phylogenetically-related pattern recognition receptors EFR and XA21 recruit similar immune signaling components in monocots and dicots

During plant immunity, surface-localized pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs). The transfer of PRRs between plant species is a promising strategy for engineering broad-spectrum disease resistance. Thus, there is a great interest in understanding the mechanisms of PRR-mediated resistance across different plant species. Two well-characterized plant PRRs are the leucine-rich repeat receptor kinases (LRR-RKs) EFR and XA21 from Arabidopsis thaliana (Arabidopsis) and rice, respectively. Interestingly, despite being evolutionary distant, EFR and XA21 are phylogenetically closely related and are both members of the sub-family XII of LRR-RKs that contains numerous potential PRRs. Here, we compared the ability of these related PRRs to engage immune signaling across the monocots-dicots taxonomic divide. Using chimera between Arabidopsis EFR and rice XA21, we show that the kinase domain of the rice XA21 is functional in triggering elf18-induced signaling and quantitative immunity to the bacteria Pseudomonas syringae pv. tomato (Pto) DC3000 and Agrobacterium tumefaciens in Arabidopsis. Furthermore, the EFR:XA21 chimera associates dynamically in a ligand-dependent manner with known components of the EFR complex. Conversely, EFR associates with Arabidopsis orthologues of rice XA21-interacting proteins, which appear to be involved in EFR-mediated signaling and immunity in Arabidopsis. Our work indicates the overall functional conservation of immune components acting downstream of distinct LRR-RK-type PRRs between monocots and dicots

Burnout and work-related stressors in gastroenterology: a protocol for a multinational observational study in the ASEAN region.

BACKGROUND: Clinician burnout is an important occupational hazard that may be exacerbated by the novel COVID-19 pandemic. Within Southeast Asia, burnout in gastroenterology is understudied. The primary objective of this study is to estimate the prevalence of burnout symptoms within gastroenterology, in member states of the Associations of Southeast Asian Nations (ASEAN), during and after the COVID-19 pandemic. The secondary objective is to identify work-related stressors that contribute to burnout in ASEAN gastroenterologists. METHODS AND ANALYSIS: This is an observational study that will use anonymised online surveys to estimate the prevalence of burnout symptoms at two time points: during the COVID-19 pandemic in 2020 and in 2022 (assumed to be after the pandemic). Gastroenterologists from Singapore, Malaysia, Thailand, Indonesia, Philippines and Brunei will be invited to participate in the online survey through their national gastroenterology and endoscopy societies. Burnout will be assessed using the Maslach Burnout Inventory-Human Services Survey tool. Supplementary questions will collect demographic and qualitative data. Associations between demographic characteristics and burnout will be tested by multiple regression. RESULTS: The prevalence of burnout symptoms in gastroenterology during the COVID-19 pandemic, and the baseline prevalence after COVID-19, will be established in the above-mentioned countries. Work-related stressors commonly associated with burnout will be identified, allowing the introduction of preventative measures to reduce burnout in the future. ETHICS AND DISSEMINATION: Ethical approval was granted by the Singhealth Centralised Institutional Review Board (2020/2709). Results will be submitted for publication

The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1.

BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury

On tree amplitudes with gluons coupled to gravitons

In this paper, we study the tree amplitudes with gluons coupled to gravitons. We first study the relations among the mixed amplitudes. With BCFW on-shell recursion relation, we will show the color-order reversed relation, $U(1)$-decoupling relation and KK relation hold for tree amplitudes with gluons coupled to gravitons. We then study the disk relation which expresses mixed amplitudes by pure gluon amplitudes. More specifically we will prove the disk relation for mixed amplitudes with gluons coupled to one graviton. Using the disk relation and the properties of pure gluon amplitudes, the color-order reversed relation, $U(1)$-decoupling relation and KK relation for mixed amplitudes can also be proved. Finally, we give some brief discussions on BCJ-like relation for mixed amplitudes.Comment: 33pages,no figur

Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations

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