High-Throughput, Whole-Genome Sequencing

Since the completion of the Human Genome Project, research focusing on the consequence of known human genetic code has advanced by leaps and bounds. The development of personalized medicine, a field focused on enumerating the effects of individual genetic variations, termed SNPs, has become a reality for those researching the molecular basis of disease. With clinical correlates between genotype and prognosis becoming ever more common, the utility of personal genetic screening has become impossible to ignore. In this report, we present PennBio: a whole-genome sequencing company utilizing a novel single-molecule, real time sequencing-by-synthesis technology. Using unique zero-mode waveguides, which have revolutionized single-molecule detection, individual enzymes polymerizing novel phospholinked fluorescence labeled nucleotides can be observed as they sequence genomic template DNA. Modern optical techniques record these fragmented sequences, which are then analyzed by highly efficient alignment algorithms. A personal genomic code will ultimately allow consumers to be aware of their genetic predispositions as the medical community continues to discover them

A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression.

Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression

Integrins Form an Expanding Diffusional Barrier that Coordinates Phagocytosis

Phagocytosis is initiated by lateral clustering of receptors, which in turn activates Src-family kinases (SFKs). Activation of SFKs requires depletion of tyrosine phosphatases from the area of particle engagement. We investigated how the major phosphatase CD45 is excluded from contact sites, using single-molecule tracking. The mobility of CD45 increased markedly upon engagement of Fcγ receptors. While individual CD45 molecules moved randomly, they were displaced from the advancing phagocytic cup by an expanding diffusional barrier. By micropatterning IgG, the ligand of Fcγ receptors, we found that the barrier extended well beyond the perimeter of the receptor-ligand engagement zone. Second messengers generated by Fcγ receptors activated integrins, which formed an actin-tethered diffusion barrier that excluded CD45. The expanding integrin wave facilitates the “zippering” of Fcγ receptors onto the target and integrates the information from sparse receptor-ligand complexes, coordinating the progression and ultimate closure of the phagocytic cup

Brain size and brain/intracranial volume ratio in major mental illness

<p>Abstract</p> <p>Background</p> <p>This paper summarizes the findings of a long term study addressing the question of how several brain volume measure are related to three major mental illnesses in a Colorado subject group. It reports results obtained from a large N, collected and analyzed by the same laboratory over a multiyear period, with visually guided MRI segmentation being the primary initial analytic tool.</p> <p>Methods</p> <p>Intracerebral volume (ICV), total brain volume (TBV), ventricular volume (VV), ventricular/brain ratio (VBR), and TBV/ICV ratios were calculated from a total of 224 subject MRIs collected over a period of 13 years. Subject groups included controls (C, N = 89), and patients with schizophrenia (SZ, N = 58), bipolar disorder (BD, N = 51), and schizoaffective disorder (SAD, N = 26).</p> <p>Results</p> <p>ICV, TBV, and VV measures compared favorably with values obtained by other research groups, but in this study did not differ significantly between groups. TBV/ICV ratios were significantly decreased, and VBR increased, in the SZ and BD groups compared to the C group. The SAD group did not differ from C on any measure.</p> <p>Conclusions</p> <p>In this study TBV/ICV and VBR ratios separated SZ and BD patients from controls. Of interest however, SAD patients did not differ from controls on these measures. The findings suggest that the gross measure of TBV may not reliably differ in the major mental illnesses to a degree useful in diagnosis, likely due to the intrinsic variability of the measures in question; the differences in VBR appear more robust across studies. Differences in some of these findings compared to earlier reports from several laboratories finding significant differences between groups in VV and TBV may relate to phenomenological drift, differences in analytic techniques, and possibly the "file drawer problem".</p

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The NASA Airborne Tropical TRopopause EXperiment (ATTREX): High-Altitude Aircraft Measurements in the Tropical Western Pacific

The February through March 2014 deployment of the NASA Airborne Tropical TRopopause EXperiment (ATTREX) provided unique in situ measurements in the western Pacific Tropical Tropopause Layer (TTL). Six flights were conducted from Guam with the long-range, high-altitude, unmanned Global Hawk aircraft. The ATTREX Global Hawk payload provided measurements of water vapor, meteorological conditions, cloud properties, tracer and chemical radical concentrations, and radiative fluxes. The campaign was partially coincident with the CONTRAST and CAST airborne campaigns based in Guam using lower-altitude aircraft (see companion articles in this issue). The ATTREX dataset is being used for investigations of TTL cloud, transport, dynamical, and chemical processes as well as for evaluation and improvement of global-model representations of TTL processes. The ATTREX data is openly available at https:espoarchive.nasa.gov

Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Measurement of jet fragmentation in Pb+Pb and pp collisions at √s NN =5.02 TeV with the ATLAS detector

This paper presents a measurement of jet fragmentation functions in 0.49 nb −1 of Pb+Pb collisions and 25 pb −1 of pp collisions at √ sNN =5.02 TeV collected in 2015 with the ATLAS detector at the LHC. These measurements provide insight into the jet quenching process in the quark-gluon plasma created in the aftermath of ultra-relativistic collisions between two nuclei. The modifications to the jet fragmentation functions are quantified by dividing the measurements in Pb+Pb collisions by baseline measurements in pp collisions. This ratio is studied as a function of the transverse momentum of the jet, the jet rapidity, and the centrality of the collision. In both collision systems, the jet fragmentation functions are measured for jets with transverse momentum between 126 GeV and 398 GeV and with an absolute value of jet rapidity less than 2.1. An enhancement of particles carrying a small fraction of the jet momentum is observed, which increases with centrality and with increasing jet transverse momentum. Yields of particles carrying a very large fraction of the jet momentum are also observed to be enhanced. Between these two enhancements of the fragmentation functions a suppression of particles carrying an intermediate fraction of the jet momentum is observed in Pb+Pb collisions. A small dependence of the modifications on jet rapidity is observed