Since the gens change due to the environmental and individual factors, the role of these factors is now more important for the human health. In countries that the facilities such as clean air, ...healthy water and food, sport and recreational sites, social security and disease prevention programs readily available for all, the society is healthy and happy. Thus, the overall morbidities and mortalities have been declined. But unfortunately, in some countries like Iran that has not paid attention to these factors, the overall morbidities and mortalities have been increased.
Sézary syndrome is a leukemic form of cutaneous T-cell lymphoma with an aggressive clinical course. The genetic etiology of the disease is poorly understood, with chromosomal abnormalities and ...mutations in some genes being involved in the disease. The goal of our study was to understand the genetic basis of the disease by looking for driver gene mutations and fusion genes in 15 erythrodermic patients with circulating Sézary cells, 14 of them fulfilling the diagnostic criteria of Sézary syndrome. We have discovered genes that could be involved in the pathogenesis of Sézary syndrome. Some of the genes that are affected by somatic point mutations include ITPR1, ITPR2, DSC1, RIPK2, IL6, and RAG2, with some of them mutated in more than one patient. We observed several somatic copy number variations shared between patients, including deletions and duplications of large segments of chromosome 17. Genes with potential function in the T-cell receptor signaling pathway and tumorigenesis were disrupted in Sézary syndrome patients, for example, CBLB, RASA2, BCL7C, RAMP3, TBRG4, and DAD1. Furthermore, we discovered several fusion events of interest involving RASA2, NFKB2, BCR, FASN, ZEB1, TYK2, and SGMS1. Our work has implications for the development of potential therapeutic approaches for this aggressive disease.
This project was funded by “Retos de la Sociedad 2013: Europa Redes y Gestores” Programme from the Spanish Ministry of Economy and Competitiveness no. SAF2013-49108-R (to XE) and RD12/0036/0044 Red Temática de Investigación Cooperativa en Cancer, Fondo Europeo de Desarrollo Regional (to BE, FG, and RP), the Generalitat de Catalunya AGAUR 2014 SGR-1138 (to XE) and 2014 SGR-585 (to BE, A Puiggros, and FG), the European Commission 7th Framework Program (FP7/2007-2013) under grant agreement 282510 (A BLUEPRINT of haematopoietic Epigenomes to XE) and 262055 (European Sequencing and Genotyping Infrastructure to XE), Instituto de Salud Carlos III FEDER (PT13/0010/0005), and the “Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya.” We would also like to thank “Xarxa de Limfomes Cutanis de Catalunaya.” A Prasad is a Marie Curie Postdoctoral fellow supported by the European Commission 7th framework program (FP7/2007-2013) under grant agreement no. 625356. We acknowledge the support of the Spanish Ministry of Economy and Competitiveness, Centro de Excelencia Severo Ochoa 2013-2017, SEV-2012-0208.
A powerful underdog story, Soaring delivers practical leadership advice, business lessons, and tips for success mined from the real-life strategies of Lee E. Rhyant's forty years as a corporate ...leader. Born into poverty in the postwar South, Rhyant was the fourth of eight children raised by a family of African American sharecroppers struggling to survive the last decades of segregation. Soaring combines compelling storytelling with practical lessons to demonstrate the transformative power of perseverance.In the trajectory of his life, Rhyant has achieved many goals considered beyond his reach. Here he shares compelling stories of growing up in the segregated South, working at an early age, graduating from the HBCU Bethune-Cookman University and Indiana University, and ultimately excelling at leadership roles at General Motors, Rolls Royce Aeronautics, and Lockheed Martin Marietta. Rhyant's life reveals a great deal about the economic, business, and racial climate in the South in the last quarter of the twentieth century and has much to teach students, business leaders, and interested readers about resiliency and determination.
Chronic stress (CS) is critically involved in the Alzheimer's disease (AD) pathogenesis resulting in cognitive disturbance. Also, amyloid precursor protein (APP) related gens, pro-inflammatory ...cytokines, and stress increases AD-related pathogenesis through increasing APP, all are important players in the development of AD. Herein, we explore the possible neuroprotective and anti-amnestic effect of quercetin (QUER) on cognitive deficits induced by scopolamine (SCOP) in stressed rats. Stress induction was performed by exposed of rats to 2-h chronic restraint stress for 10 days. Then rats were supplemented with QUER (25 mg/kg/day oral gavage, for 1 month). Ratswere submitted to intraperitoneal (i.p.) injection of SCOP (1 mg/kg) during the final 9 days of QUER supplementation to induce dementia like condition. Following the interventions, behavioral tests elevated plus maze (EPM) and novel object recognition memory (NORM) was examined to analysis the cognitive functions. Meanwhile, prefrontal cortex (PFC) and hippocampus of brain were used for gene expression and biochemical studies. Also, the plasma corticosterone (CORT) level was measured. We established that administration of QUER ameliorated the SCOP-related memory impairment. Also, QUER decreased stress related anxiety like behaviors in the EPM. QUER also altered the interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in both PFC and hippocampus of SCOP treated rats in stress and non-stress conditions. We found that QUER increased APP and amyloid precursor-like protein 2 (APLP2) mRNA expression in both non-stress and stressed rats. Also, our findings imply that QUER suppress the effect of SCOP on cognitive functions. Moreover, decreased APP mRNA expression in the hippocampus were observed following pretreatment of rats with QUER in both stress and non-stress groups. Given that decreased amyloid beta (Aβ) expression in the hippocampus of stressed rats, it can be proposed that elevations in APP mRNA expression by QUER activates non-amyloidogenic pathways leading to reduction in Aβ levels. However, our findings indicate that QUER can be a therapeutic candidate, which exerts an anti-amnesic property against SCOP-induced memory decline. On the other hand, prior QUER administration in stress condition could be a promising approach against AD prevention.
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•Administration of QUER ameliorates the SCOP-related memory impairment.•QUER decreased anxiety through the proinflammatory cytokines in both PFC and hippocampus in stress conditions.•APP mRNA expression in the hippocampus decrease following pretreatment with QUER in stress condition.•Elevations in APP mRNA expression by QUER activates non-amyloidogenic pathways leading to reduction in Aβ levels.
High-throughput RNA sequencing is an increasingly accessible method for studying gene structure and activity on a genome-wide scale. A critical step in RNA-seq data analysis is the alignment of ...partial transcript reads to a reference genome sequence. To assess the performance of current mapping software, we invited developers of RNA-seq aligners to process four large human and mouse RNA-seq data sets. In total, we compared 26 mapping protocols based on 11 programs and pipelines and found major performance differences between methods on numerous benchmarks, including alignment yield, basewise accuracy, mismatch and gap placement, exon junction discovery and suitability of alignments for transcript reconstruction. We observed concordant results on real and simulated RNA-seq data, confirming the relevance of the metrics employed. Future developments in RNA-seq alignment methods would benefit from improved placement of multimapped reads, balanced utilization of existing gene annotation and a reduced false discovery rate for splice junctions.
Modified levels of pro- (caspase3, Bax) and anti-apoptotic (Bcl-2) regulatory proteins have been detected in certain brain areas of schizophrenic patients indicating a possible dysregulation of ...apoptosis. In the present study, effects of antipsychotics, haloperidol (HAL) and olanzapine (OLA), on the gene expression of caspase3 (
),
and
were studied
in mouse hippocampal mHippoE-2 cell line and
in the hippocampus of MK-801 animal schizophrenia model with the aim to provide evidence that antipsychotics may affect the activity of apoptosis-related markers.
mHippoE-2 cells were incubated with MK-801 (20 µM), HAL (10 µM), and OLA (10 µM) alone or combined, MK-801+HAL/OLA, for 24, 48, and 72 h. Male Sprague Dawley rats were injected with saline or MK-801 (0.5 mg/kg) for 6 days and since the 7th day, they were treated with vehicle (VEH), HAL (1 mg/kg) or OLA (2 mg/kg) for the next 7 days. The
,
and
gene expression in mHippoE-2 cells and rat hippocampus was measured by RT-PCR.
In mHippoE-2 cells,
gene expression was increased by MK-801 and OLA treatments alone for 48 h, HAL treatment alone for 24 and 72 h, and co-treatment with MK-801+OLA for 24 and 72 h compared to controls. HAL and OLA suppressed the stimulatory effect of MK-801 on
mRNA levels in cells after 48 h of incubation.
mRNA levels in mHippoE-2 cells were decreased after HAL treatment for 24 and 48 h, and also after co-treatment with MK-801+HAL for 72 h.
, MK-801 decreased mRNA levels of both pro-apoptotic markers,
and
, in hippocampus of VEH-treated rats and
mRNA levels in hippocampus of HAL-treated animals. OLA reversed the inhibitory effect of MK-801 on
expression in the VEH-treated animals. Neither MK-801 nor antipsychotics induced changes in the gene expression of anti-apoptotic marker
in mHippoE-2 cells as well as hippocampus of rats.
The results of the present study demonstrate that antipsychotics, HAL and OLA, may affect mRNA levels of pro-apoptotic markers in hippocampal cells
, but not
. The obtained data do not clearly support the assumed potentiating role of MK-801 in inducing apoptosis in specific brain areas and a possible protective role of antipsychotics against induction of apoptosis. The obtained data may contribute to a deeper insight into the neurodevelopmental changes connected with schizophrenia.
Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, which is the most common cancer in acquired immune deficiency syndrome patients. KSHV contains a variety of ...immunoregulatory proteins. There have been many studies on the modulation of antiviral response by these immunoregulatory proteins of KSHV. However, the antiviral effects of extracellular vesicles (EVs) during
KSHV infection have not been investigated to our best knowledge. In this study, we showed that KSHV-infected cells induce interferon-stimulated genes (ISGs) response but not type I interferon in uninfected bystander cells using EVs. mRNA microarray analysis showed that ISGs and IRF-activating genes were prominently activated in EVs from KSHV-infected cells (KSHV EVs)-treated human endothelial cells, which were validated by RT-qPCR and western blot analysis. We also found that this response was not associated with cell death or apoptosis by virus infection. Mechanistically, the cGAS-STING pathway was linked with these KSHV EVs-mediated ISGs expressions, and mitochondrial DNA on the surface of KSHV EVs was one of the causative factors. Besides, KSHV EVs-treated cells showed lower infectivity for KSHV and viral replication activity than mock EVs-treated cells. Our results indicate that EVs from KSHV-infected cells could be an initiating factor for the innate immune response against viral infection, which may be critical to understanding the microenvironment of virus-infected cells.
Our genome contains tens of thousands of long noncoding RNAs (lncRNAs), many of which are likely to have genetic regulatory functions. It has been proposed that lncRNA are organized into combinations ...of discrete functional domains, but the nature of these and their identification remain elusive. One class of sequence elements that is enriched in lncRNA is represented by transposable elements (TEs), repetitive mobile genetic sequences that have contributed widely to genome evolution through a process termed exaptation. Here, we link these two concepts by proposing that exonic TEs act as RNA domains that are essential for lncRNA function. We term such elements Repeat Insertion Domains of LncRNAs (RIDLs). A growing number of RIDLs have been experimentally defined, where TE-derived fragments of lncRNA act as RNA-, DNA-, and protein-binding domains. We propose that these reflect a more general phenomenon of exaptation during lncRNA evolution, where inserted TE sequences are repurposed as recognition sites for both protein and nucleic acids. We discuss a series of genomic screens that may be used in the future to systematically discover RIDLs. The RIDL hypothesis has the potential to explain how functional evolution can keep pace with the rapid gene evolution observed in lncRNA. More practically, TE maps may in the future be used to predict lncRNA function.
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