Erratum to: Genetic alterations of m6A regulators predict poorer survival in acute myeloid leukemia

Abstract Methylation of N6 adenosine (m6A) is known to be important for diverse biological processes including gene expression control, translation of protein, and messenger RNA (mRNA) splicing. However, its role in the development of human cancers is poorly understood. By analyzing datasets from the Cancer Genome Atlas Research Network (TCGA) acute myeloid leukemia (AML) study, we discover that mutations and/or copy number variations of m6A regulatory genes are strongly associated with the presence of TP53 mutations in AML patients. Further, our analyses reveal that alterations in m6A regulatory genes confer a worse survival in AML. Our work indicates that genetic alterations of m6A regulatory genes may cooperate with TP53 and/or its regulator/downstream targets in the pathogenesis and/or maintenance of AML

Three patients with homozygous familial hypercholesterolemia: Genomic sequencing and kindred analysis.

BackgroundHomozygous Familial Hypercholesterolemia (HoFH) is an inherited recessive condition associated with extremely high levels of low-density lipoprotein (LDL) cholesterol in affected individuals. It is usually caused by homozygous or compound heterozygous functional mutations in the LDL receptor (LDLR). A number of mutations causing FH have been reported in literature and such genetic heterogeneity presents great challenges for disease diagnosis.ObjectiveWe aim to determine the likely genetic defects responsible for three cases of pediatric HoFH in two kindreds.MethodsWe applied whole exome sequencing (WES) on the two probands to determine the likely functional variants among candidate FH genes. We additionally applied 10x Genomics (10xG) Linked-Reads whole genome sequencing (WGS) on one of the kindreds to identify potentially deleterious structural variants (SVs) underlying HoFH. A PCR-based screening assay was also established to detect the LDLR structural variant in a cohort of 641 patients with elevated LDL.ResultsIn the Caucasian kindred, the FH homozygosity can be attributed to two compound heterozygous LDLR damaging variants, an exon 12 p.G592E missense mutation and a novel 3kb exon 1 deletion. By analyzing the 10xG phased data, we ascertained that this deletion allele was most likely to have originated from a Russian ancestor. In the Mexican kindred, the strikingly elevated LDL cholesterol level can be attributed to a homozygous frameshift LDLR variant p.E113fs.ConclusionsWhile the application of WES can provide a cost-effective way of identifying the genetic causes of FH, it often lacks sensitivity for detecting structural variants. Our finding of the LDLR exon 1 deletion highlights the broader utility of Linked-Read WGS in detecting SVs in the clinical setting, especially when HoFH patients remain undiagnosed after WES

Ground-state fidelity of Luttinger liquids: A wave functional approach

We use a wave functional approach to calculate the fidelity of ground states in the Luttinger liquid universality class of one-dimensional gapless quantum many-body systems. The ground-state wave functionals are discussed using both the Schrodinger (functional differential equation) formulation and a path integral formulation. The fidelity between Luttinger liquids with Luttinger parameters K and K' is found to decay exponentially with system size, and to obey the symmetry F(K,K')=F(1/K,1/K') as a consequence of a duality in the bosonization description of Luttinger liquids.Comment: 13 pages, IOP single-column format. Sec. 3 expanded with discussion of short-distance cut-off. Some typos corrected. Ref. 44 in v2 is now footnote 2 (moved by copy editor). Published versio

Time Course and Cellular Localization of SARS-CoV Nucleoprotein and RNA in Lungs from Fatal Cases of SARS

BACKGROUND: Cellular localization of severe acute respiratory syndrome coronavirus (SARS-CoV) in the lungs of patients with SARS is important in confirming the etiological association of the virus with disease as well as in understanding the pathogenesis of the disease. To our knowledge, there have been no comprehensive studies investigating viral infection at the cellular level in humans. METHODS AND FINDINGS: We collected the largest series of fatal cases of SARS with autopsy material to date by merging the pathological material from two regions involved in the 2003 worldwide SARS outbreak in Hong Kong, China, and Toronto, Canada. We developed a monoclonal antibody against the SARS-CoV nucleoprotein and used it together with in situ hybridization (ISH) to analyze the autopsy lung tissues of 32 patients with SARS from Hong Kong and Toronto. We compared the results of these assays with the pulmonary pathologies and the clinical course of illness for each patient. SARS-CoV nucleoprotein and RNA were detected by immunohistochemistry and ISH, respectively, primarily in alveolar pneumocytes and, less frequently, in macrophages. Such localization was detected in four of the seven patients who died within two weeks of illness onset, and in none of the 25 patients who died later than two weeks after symptom onset. CONCLUSIONS: The pulmonary alveolar epithelium is the chief target of SARS-CoV, with macrophages infected subsequently. Viral replication appears to be limited to the first two weeks after symptom onset, with little evidence of continued widespread replication after this period. If antiviral therapy is considered for future treatment, it should be focused on this two-week period of acute clinical disease

Emerging Technologies and Approaches for In Situ, Autonomous Observing in the Arctic

Understanding and predicting Arctic change and its impacts on global climate requires broad, sustained observations of the atmosphere-ice-ocean system, yet technological and logistical challenges severely restrict the temporal and spatial scope of observing efforts. Satellite remote sensing provides unprecedented, pan-Arctic measurements of the surface, but complementary in situ observations are required to complete the picture. Over the past few decades, a diverse range of autonomous platforms have been developed to make broad, sustained observations of the ice-free ocean, often with near-real-time data delivery. Though these technologies are well suited to the difficult environmental conditions and remote logistics that complicate Arctic observing, they face a suite of additional challenges, such as limited access to satellite services that make geolocation and communication possible. This paper reviews new platform and sensor developments, adaptations of mature technologies, and approaches for their use, placed within the framework of Arctic Ocean observing needs

Development of a specific affinity-matured exosite inhibitor to MT1-MMP that efficiently inhibits tumor cell invasion in vitro and metastasis in vivo.

This is the final version of the article. It first appeared from Impact Journals via https://doi.org/10.18632/oncotarget.7780The membrane-associated matrix metalloproteinase-14, MT1-MMP, has been implicated in pericellular proteolysis with an important role in cellular invasion of collagenous tissues. It is substantially upregulated in various cancers and rheumatoid arthritis, and has been considered as a potential therapeutic target. Here, we report the identification of antibody fragments to MT1-MMP that potently and specifically inhibit its cell surface functions. Lead antibody clones displayed inhibitory activity towards pro-MMP-2 activation, collagen-film degradation and gelatin-film degradation, and were shown to bind to the MT1-MMP catalytic domain outside the active site cleft, inhibiting binding to triple helical collagen. Affinity maturation using CDR3 randomization created a second generation of antibody fragments with dissociation constants down to 0.11 nM, corresponding to an improved affinity of 332-fold with the ability to interfere with cell-surface MT1-MMP functions, displaying IC50 values down to 5 nM. Importantly, the new inhibitors were able to inhibit collagen invasion by tumor-cells in vitro and in vivo primary tumor growth and metastasis of MDA-MB-231 cells in a mouse orthotopic xenograft model. Herein is the first demonstration that an inhibitory antibody targeting sites outside the catalytic cleft of MT1-MMP can effectively abrogate its in vivo activity during tumorigenesis and metastasis.KAB was supported by a grant from the Danish Cancer Society (R40-A1838). HJD was supported in part by grants from the Danish Cancer Society, The Danish Research Council. HFK and GM were supported by Cancer Research UK and Hutchison Whampoa Ltd. HFK was also supported in part by grants from the University of Macau Start-Up Research Grant (SRG2014-00006-FHS) and Multi-Year Research Grant (MYRG2015-00065-FHS)

Radio Astronomy

Contains reports on isx research projects.National Aeronautics and Space Administration, Langley Research Center (Contract NAS1-10693)National Science Foundation (Grant GP-21348)National Science Foundation (Grant GP-14589)California Institute of Technology Contract 952568Joint Services Electronics Programs (U. S. Army, U. S. Navy, and U. S. Air Force) under Contract DAAB07-71-C-030

Snow Property Controls on Modeled Ku-Band Altimeter Estimates of First-Year Sea Ice Thickness: Case Studies From the Canadian and Norwegian Arctic

Uncertainty in snow properties impacts the accuracy of Arctic sea ice thickness estimates from radar altimetry. On first-year sea ice (FYI), spatiotemporal variations in snow properties can cause the Ku-band main radar scattering horizon to appear above the snow/sea ice interface. This can increase the estimated sea ice freeboard by several centimeters, leading to FYI thickness overestimations. This article examines the expected changes in Ku-band main scattering horizon and its impact on FYI thickness estimates, with variations in snow temperature, salinity, and density derived from ten naturally occurring Arctic FYI Cases encompassing saline/nonsaline, warm/cold, simple/complexly layered snow (4–45 cm) overlying FYI (48–170 cm). Using a semi-empirical modeling approach, snow properties from these Cases are used to derive layer-wise brine volume and dielectric constant estimates, to simulate the Ku-band main scattering horizon and delays in radar propagation speed. Differences between modeled and observed FYI thickness are calculated to assess sources of error. Under both cold and warm conditions, saline snow covers are shown to shift the main scattering horizon above from the snow/sea ice interface, causing thickness retrieval errors. Overestimates in FYI thicknesses of up to 65% are found for warm, saline snow overlaying thin sea ice. Our simulations exhibited a distinct shift in the main scattering horizon when the snow layer densities became greater than 440 kg/m 3 , especially under warmer snow conditions. Our simulations suggest a mean Ku-band propagation delay for snow of 39%, which is higher than 25%, suggested in previous studies

Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit