26 research outputs found
Modular Utilization of Distal cis-Regulatory Elements Controls Ifng Gene Expression in T Cells Activated by Distinct Stimuli
Distal cis-regulatory elements play essential roles in the T lineage-specific expression of cytokine genes. We have mapped interactions of three transacting factors – NF-κB, STAT4 and T-bet – with cis elements in the Ifng locus. We find that RelA is critical for optimal Ifng expression and is differentially recruited to multiple elements contingent upon T cell receptor (TCR) or interleukin-12 (IL-12) plus IL-18 signaling. RelA recruitment to at least four elements is dependent on T-bet-dependent remodeling of the Ifng locus and co-recruitment of STAT4. STAT4 and NF-κB therefore cooperate at multiple cis elements to enable NF-κB–dependent enhancement of Ifng expression. RelA recruitment to distal elements was similar in Th1 and Tc1 effector cells, although T-bet was dispensable in CD8 effectors. These results support a model of Ifng regulation in which distal cis-regulatory elements differentially recruit key transcription factors in a modular fashion to initiate gene transcription induced by distinct activation signals
Compact Incoherent Multidimensional Imaging Systems Using Static Diffractive Coded Apertures
Incoherent holographic imaging technologies, in general, involve multiple optical components for beam splitting—combining and shaping—and in most cases, require an active optical device such as a spatial light modulator (SLM) for generating multiple phase-shifted holograms in time. The above requirements made the realization of holography-based products expensive, heavy, large, and slow. To successfully transfer the holography capabilities discussed in research articles to products, it is necessary to find methods to simplify holography architectures. In this book chapter, two important incoherent holography techniques, namely interference-based Fresnel incoherent correlation holography (FINCH) and interferenceless coded aperture correlation holography (I-COACH), have been successfully simplified in space and time using advanced manufacturing methods and nonlinear reconstruction, respectively. Both techniques have been realized in compact optical architectures using a single static diffractive optical element manufactured using lithography technologies. Randomly multiplexed diffractive lenses were manufactured using electron beam lithography for FINCH. A quasi-random lens and a mask containing a quasi-random array of pinholes were manufactured using electron beam lithography and photolithography, respectively, for I-COACH. In both cases, the compactification has been achieved without sacrificing the performances. The design, fabrication, and experiments of FINCH and I-COACH with static diffractive optical elements are presented in details
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial
Background:
Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.
Methods:
We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515.
Findings:
Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group.
Interpretation:
In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes.
Funding:
GlaxoSmithKline
Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex
VK: “Lähdesmäki, H.”; SyMMyS, CSB; TRITONASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring–Opitz syndrome. Here we demonstrate that ASXL1 truncations confer enhanced activity on the ASXL1–BAP1 complex. Stable expression of truncated, hyperactive ASXL1–BAP1 complexes in a haematopoietic precursor cell line results in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters are marked by both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes require the catalytic activity of BAP1, indicating that they are downstream consequences of H2AK119Ub erasure. In bone marrow precursors, expression of truncated ASXL1–BAP1 complex cooperates with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. Our data raise the possibility that ASXL1 truncation mutations confer gain-of-function on the ASXL–BAP1 complex.Peer reviewe
Sublethal Effects of Arsenic on Oxygen Consumption, Hematological and Gill Histopathological Indices in Chanos chanos
Background: The current study was performed aiming to evaluate possible changes in the effect on oxygen consumption, hematology and gill histopathological parameters in fish (Chanos chanos) upon exposure to sublethal concentration of the metalloid arsenic. Methods: Bioassay tests were conducted for determining the LC50 values of arsenic for 96 h. Oxygen consumption in control and arsenic-exposed fish was estimated using Winkler’s method. Red blood corpuscular (RBC) count was examined with a Neubauer counting chamber under a phase contrast microscope. Hemoglobin (Hb) was estimated following the acid hematin method. Histopathological studies were carried by processing and staining the gill tissues with hematoxylin and eosin in accordance with standard histological techniques. They were then subjected to examination under a scanning electron microscope. Results: Chanos chanos exposed to 1/10th of LC50 (24.61%) for a period of 30 days exhibited a maximum decline in the rate of respiration, followed by a decline in RBC and Hb above 45.59% and 51.60%, respectively. Significant toxic lesions encompassing fused gill lamellae, detached gill epithelium, hyperplasia and hypertrophy of respiratory epithelium became heavy handed on the 30th day. Conclusion: Information synthesized from our study serves to be useful in monitoring and managing (As) contamination in the aquatic environment
Roadmap on digital holography-based quantitative phase imaging
Quantitative Phase Imaging (QPI) provides unique means for the imaging of biological or technical microstructures, merging beneficial features identified with microscopy, interferometry, holography, and numerical computations. This roadmap article reviews several digital holography-based QPI approaches developed by prominent research groups. It also briefly discusses the present and future perspectives of 2D and 3D QPI research based on digital holographic microscopy, holographic tomography, and their applications.ImPhys/Imaging PhysicsImPhys/Computational ImagingIndustrial Design Engineerin
Deletion of a Conserved <i>cis</i>-Element in the <i>Ifng</i> Locus Highlights the Role of Acute Histone Acetylation in Modulating Inducible Gene Transcription
<div><p>Differentiation-dependent regulation of the <i>Ifng</i> cytokine gene locus in T helper (Th) cells has emerged as an excellent model for functional study of distal elements that control lineage-specific gene expression. We previously identified a <i>cis</i>-regulatory element located 22 kb upstream of the <i>Ifng</i> gene (<u>C</u>onserved <u>N</u>on-coding <u>S</u>equence -22, or CNS-22) that is a site for recruitment of the transcription factors T-bet, Runx3, NF-κB and STAT4, which act to regulate transcription of the <i>Ifng</i> gene in Th1 cells. Here, we report the generation of mice with a conditional deletion of CNS-22 that has enabled us to define the epigenetic and functional consequences of its absence. Deletion of CNS-22 led to a defect in induction of <i>Ifng</i> by the cytokines IL-12 and IL-18, with a more modest effect on induction via T-cell receptor activation. To better understand how CNS-22 and other <i>Ifng</i> CNSs regulated <i>Ifng</i> transcription in response to these distinct stimuli, we examined activation-dependent changes in epigenetic modifications across the extended <i>Ifng</i> locus in CNS-22-deficient T cells. We demonstrate that in response to both cytokine and TCR driven activation signals, CNS-22 and other <i>Ifng</i> CNSs recruit increased activity of histone acetyl transferases (HATs) that transiently enhance levels of histones H3 and H4 acetylation across the extended <i>Ifng</i> locus. We also demonstrate that activation-responsive increases in histone acetylation levels are directly linked to the ability of <i>Ifng</i> CNSs to acutely enhance Pol II recruitment to the <i>Ifng</i> promoter. Finally, we show that impairment in IL-12+IL-18 dependent induction of <i>Ifng</i> stems from the importance of CNS-22 in coordinating locus-wide levels of histone acetylation in response to these cytokines. These findings identify a role for acute histone acetylation in the enhancer function of distal conserved <i>cis</i>-elements that regulate of <i>Ifng</i> gene expression.</p></div