cAMP/CREB-regulated LINC00473 marks LKB1-inactivated lung cancer and mediates tumor growth

The LKB1 tumor suppressor gene is frequently mutated and inactivated in non–small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB1-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1-inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP–responsive element–binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC

AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder:COORDINATE-MDD consortium design and rationale

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project

An open science resource for establishing reliability and reproducibility in functional connectomics

Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included

cDNA Cloning of the Chicken DDB1 Gene Encoding the p127 Subunit of Damaged DNA-binding Protein

DDB (damaged DNA-binding protein) is a heterodimer, comprised of p48 (DDB2) and p127 (DDB1) subunits, which has a high affinity for a variety of DNA lesions including UV-photoproducts. The mutations in DDB2 gene have been found in a subset of xeroderma pigmentosum complementation group E patients. However, no natural mutation has been identified so far in the cDNA of human DDB1 and the precise roles of DDB1 are still unknown. We have cloned the DDB1 cDNA from the chicken B lymphocyte line DT40 and revealed an open reading frame of 3420 bp encoding a polypeptide of 1140 amino acids, which is identical in size to the orthologs of human, monkey, mouse, rat and Drosophila melanogaster in databases. The amino acid sequence deduced from the chicken DDB1 cDNA shows a high homology to the mammalian DDB1 orthologs (96-97% identity). Northern blot analysis using 5 portion of the chicken DDB1 cDNA as a probe detected a single transcript of ~ 4.3 kb in chicken DT40 cells as well as in human HeLa cells and mouse embryonic fibroblasts. Furthermore, the chicken DDB1 (tagged with enhanced GFP) transiently expressed in human cells mainly localized in the cytoplasm, and coexpression of human DDB2 dramatically changed the localization from the cytoplasm to nucleus. These results suggest that DDB1 is evolutionarily conserved in the primary structure and function, and may play a fundamental role in higher eukaryotes

Chemical looping CO2 capture and in-situ conversion as a promising platform for green and low-carbon industry transition: Review and perspective

Industrial flue gas and solid waste with the characteristics of large emissions and complicated distributions are two issues for industry, due to that sequential CO2 capture and utilization for flue gas shows high energy-cost penalties and solid waste faces with low reutilization ratio. As a powerful process intensification strategy, chemical looping CO2 capture and in-situ conversion (CL-ICCC) provides an effective solution to handle those two issues. However, current researches on CL-ICCC aim to develop process configurations, design bifunctional materials, and reveal reaction mechanisms, which ignore how to apply CL-ICCC for realizing flue gas purification and solid waste reutilization simultaneously in industry. Herein, after reviewing the current status of CL-ICCC for flue gas upgrade, industrial solid waste reutilization and industrial system integration, a perspective is proposed to highlight CL-ICCC as a promising platform for green and low-carbon industry transition. In the proposed system, industrial flue gas enters the capture reactor and reacts with industrial solid waste derived bifunctional materials to separate CO2 from other impurities. In the conversion reactor, reduction agents are introduced to spill CO2 over bifunctional materials and convert it into value-added chemicals. This review and perspective provide a new pathway to establish a low-carbon and self-digestion industrial system

Supplemental Material, DS_10.1369_0022155418778546 – Islet Microvasculature Alterations With Loss of Beta-cells in Patients With Type 1 Diabetes

<p>Supplemental Material, DS_10.1369_0022155418778546 for Islet Microvasculature Alterations With Loss of Beta-cells in Patients With Type 1 Diabetes by Joseph S. Canzano, Lith H. Nasif, Elizabeth A. Butterworth, Dongtao A. Fu, Mark A. Atkinson, and Martha Campbell-Thompson in Journal of Histochemistry & Cytochemistry</p

Mutations in the maize zeta-carotene desaturase gene lead to viviparous kernel

<div><p>Preharvest sprouting reduces the maize quality and causes a significant yield loss in maize production. <i>vp-wl2</i> is a <i>Mutator</i> (<i>Mu</i>)-induced viviparous mutant in maize, causing white or pale yellow kernels, dramatically reduced carotenoid and ABA content, and a high level of zeta-carotene accumulation. Here, we reported the cloning of the <i>vp-wl2</i> gene using a modified digestion-ligation-amplification method (DLA). The results showed that an insertion of <i>Mu9</i> in the first intron of the zeta-carotene desaturase (<i>ZDS</i>) gene results in the <i>vp-wl2</i> mutation. Previous studies have suggested that <i>ZDS</i> is likely the structural gene of the <i>viviparous9</i> (<i>vp9</i>) locus. Therefore, we performed an allelic test using <i>vp-wl2</i> and three <i>vp9</i> mutants. The results showed that <i>vp-wl2</i> is a novel allele of the <i>vp9</i> locus. In addition, the sequences of <i>ZDS</i> gene were identified in these three <i>vp9</i> alleles. The <i>vp-wl2</i> mutant gene was subsequently introgressed into four maize inbred lines, and a viviparous phenotype was observed with yield losses from 7.69% to 13.33%.</p></div

Lung microhaemorrhage drives oxidative/inflammatory damage in α1-antitrypsin deficiency

Background Animal models using intratracheal instillation show that elastase, unopposed by α1-antitrypsin (AAT), causes alveolar damage and haemorrhage associated with emphysematous changes. The aim of the present study was to characterise any relationship between alveolar haemorrhage and human AAT deficiency (AATD) using bronchoalveolar lavage (BAL) and lung explant samples from AATD subjects. Methods BAL samples (17 patients, 15 controls) were evaluated for free haem (iron protoporphyrin IX) and total iron concentrations. Alveolar macrophage activation patterns were assessed using RNA sequencing and validated in vitro using haem-stimulated, monocyte-derived macrophages. Lung explants (seven patients, four controls) were assessed for iron sequestration protein expression patterns using Prussian blue stain and ferritin immunohistochemistry, as well as ferritin iron imaging and elemental analysis by transmission electron microscopy. Tissue oxidative damage was assessed using 8-hydroxy-2′-deoxyguanosine immunohistochemistry. Results BAL collected from AATD patients showed significantly elevated free haem and total iron concentrations. Alveolar and interstitial macrophages in AATD explants showed elevated iron and ferritin accumulation in large lysosomes packed by iron oxide cores with degraded ferritin protein cages. BAL macrophage RNA sequencing showed innate pro-inflammatory activation, replicated in vitro by haemin exposure, which also triggered reactive oxygen species generation. AATD explants showed massive oxidative DNA damage in both lung epithelial cells and macrophages. Conclusions BAL and tissue markers of alveolar haemorrhage, together with molecular and cellular evidence of macrophage innate pro-inflammatory activation and oxidative damage, are consistent with free haem stimulation. Overall, this initial study provides evidence for a pathogenetic role of elastase-induced alveolar haemorrhage in AATD emphysema