Divergent Roles for RalA and RalB in Malignant Growth of Human Pancreatic Carcinoma Cells

SummaryBackgroundThe Ral guanine nucleotide-exchange factors (RalGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RalGEFs are activators of the highly related RalA and RalB small GTPases, although only the former has been found to promote Ras-mediated growth transformation of human cells. In the present study, we determined whether RalA and RalB also had divergent roles in promoting the aberrant growth of pancreatic cancers, which are characterized by the highest occurrence of Ras mutations.ResultsWe now show that inhibition of RalA but not RalB expression universally reduced the transformed and tumorigenic growth in a panel of ten genetically diverse human pancreatic cancer cell lines. Despite the apparent unimportant role of RalB in tumorigenic growth, it was nevertheless critical for invasion in seven of nine pancreatic cancer cell lines and for metastasis as assessed by tail-vein injection of three different tumorigenic cell lines tested. Moreover, both RalA and RalB were more commonly activated in pancreatic tumor tissue than other Ras effector pathways.ConclusionsRalA function is critical to tumor initiation, whereas RalB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of Ral proteins during the dynamic progression of Ras-driven pancreatic cancers

Almost commuting self-adjoint matrices --- the real and self-dual cases

We show that a pair of almost commuting self-adjoint, symmetric matrices is close to a pair of commuting self-adjoint, symmetric matrices (in a uniform way). Moreover we prove that the same holds with self-dual in place of symmetric. The notion of self-dual Hermitian matrices is important in physics when studying fermionic systems that have time reversal symmetry. Since a symmetric, self-adjoint matrix is real, we get a real version of Huaxin Lin's famous theorem on almost commuting matrices. Similarly the self-dual case gives a version for matrices over the quaternions. We prove analogous results for element of real C^*-algebras of "low rank." In particular, these stronger results apply to paths of almost commuting Hermitian matrices that are real or self-dual. Along the way we develop a theory of semiprojectivity for real C^*-algebras.Comment: Expanded references. 33 page

Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response.

Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 (NLR, nucleotide oligomerization domain-like receptor) inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we used an established nanotechnology capable of generating/releasing NO over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, although human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, tumor necrosis factor-α (TNF-α), IL-8, and IL-6 from human monocytes, and IL-8 and IL-6 from human keratinocytes, respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α nor IL-6 secretion, nor inhibition by NO-np was found to be dependent on this pathway. The observed mechanism by which NO-np impacts IL-1β secretion was through inhibition of caspase-1 and IL-1β gene expression. Together, these data suggest that NO-np can effectively prevent P. acnes-induced inflammation by both clearing the organism and inhibiting microbial stimulation of the innate immune response

Circulating HPV DNA as a Biomarker for Pre-Invasive and Early Invasive Cervical Cancer: A Feasibility Study

BACKGROUND: High-risk HPV infection is responsible for >99% of cervix cancers (CC). In persistent infections that lead to cancer, the tumour breaches the basement membrane, releasing HPV-DNA into the bloodstream (cHPV-DNA). A next-generation sequencing assay (NGS) for detection of plasma HPV circulating DNA (cHPV-DNA) has demonstrated high sensitivity and specificity in patients with locally advanced cervix cancers. We hypothesised that cHPV-DNA is detectable in early invasive cervical cancers but not in pre-invasive lesions (CIN). METHODS: Blood samples were collected from patients with CIN (n = 52) and FIGO stage 1A-1B CC (n = 12) prior to treatment and at follow-up. DNA extraction from plasma, followed by NGS, was used for the detection of cHPV-DNA. RESULTS: None of the patients with pre-invasive lesions were positive for CHPV-DNA. In invasive tumours, plasma from one patient (10%) reached the threshold of positivity for cHPV-DNA in plasma. CONCLUSION: Low detection of cHPV-DNA in early CC may be explained by small tumour size, poorer access to lymphatics and circulation, and therefore little shedding of cHPV-DNA in plasma at detectable levels. The detection rate of cHPV-DNA in patients with early invasive cervix cancer using even the most sensitive of currently available technologies lacks adequate sensitivity for clinical utility

Robust Machine Learning Applied to Astronomical Datasets III: Probabilistic Photometric Redshifts for Galaxies and Quasars in the SDSS and GALEX

We apply machine learning in the form of a nearest neighbor instance-based algorithm (NN) to generate full photometric redshift probability density functions (PDFs) for objects in the Fifth Data Release of the Sloan Digital Sky Survey (SDSS DR5). We use a conceptually simple but novel application of NN to generate the PDFs - perturbing the object colors by their measurement error - and using the resulting instances of nearest neighbor distributions to generate numerous individual redshifts. When the redshifts are compared to existing SDSS spectroscopic data, we find that the mean value of each PDF has a dispersion between the photometric and spectroscopic redshift consistent with other machine learning techniques, being sigma = 0.0207 +/- 0.0001 for main sample galaxies to r < 17.77 mag, sigma = 0.0243 +/- 0.0002 for luminous red galaxies to r < ~19.2 mag, and sigma = 0.343 +/- 0.005 for quasars to i < 20.3 mag. The PDFs allow the selection of subsets with improved statistics. For quasars, the improvement is dramatic: for those with a single peak in their probability distribution, the dispersion is reduced from 0.343 to sigma = 0.117 +/- 0.010, and the photometric redshift is within 0.3 of the spectroscopic redshift for 99.3 +/- 0.1% of the objects. Thus, for this optical quasar sample, we can virtually eliminate 'catastrophic' photometric redshift estimates. In addition to the SDSS sample, we incorporate ultraviolet photometry from the Third Data Release of the Galaxy Evolution Explorer All-Sky Imaging Survey (GALEX AIS GR3) to create PDFs for objects seen in both surveys. For quasars, the increased coverage of the observed frame UV of the SED results in significant improvement over the full SDSS sample, with sigma = 0.234 +/- 0.010. We demonstrate that this improvement is genuine. [Abridged]Comment: Accepted to ApJ, 10 pages, 12 figures, uses emulateapj.cl

Surveys for ticks on wildlife hosts and in the environment at Asian longhorned tick (\u3ci\u3eHaemaphysalis longicornis\u3c/i\u3e)-positive sites in Virginia and New Jersey, 2018

Haemaphysalis longicornis, the Asian longhorned tick (ALT), is native to eastern Asia, but it has become invasive in several countries, including Australia, New Zealand and recently in the eastern United States (US). To identify wild mammal and avian host species in the US, we conducted active wildlife surveillance in two states with known ALT infestations (Virginia and New Jersey). In addition, we conducted environmental surveys in both states. These surveillance efforts resulted in detection of 51 ALTinfested individuals from seven wildlife species, including raccoon (Procyon lotor), Virginia opossum (Didelphis virginiana), red fox (Vulpes vulpes), woodchuck (Marmota monax), eastern cottontail (Sylvilagus floridanus), striped skunk (Mephitis mephitis) and white-tailed deer (Odocoileus virginianus). We found ALT in the environment in both states and also collected three native tick species (Amblyomma americanum, Dermacentor variablis and Ixodes scapularis) that are vectors of pathogens of public health and veterinary importance. This study provides important specific information on the wildlife host range of ALT in the US

Human cardiac pericytes are susceptible to SARS-CoV-2 infection

COVID-19 is associated with serious cardiovascular complications, with incompletely understood mechanism(s). Pericytes have key functions in supporting endothelial cells and maintaining vascular integrity. We demonstrate that human cardiac pericytes are permissive to SARS-CoV-2 infection in organotypic slice and primary cell cultures. Viral entry into pericytes is mediated by endosomal proteases, and infection leads to up-regulation of inflammatory markers, vasoactive mediators, and nuclear factor kappa-B-dependent cell death. Furthermore, we present evidence of cardiac pericyte infection in COVID-19 myocarditis patients. These data demonstrate that human cardiac pericytes are susceptible to SARS-CoV-2 infection and suggest a role for pericyte infection in COVID-19