Informed baseline subtraction of proteomic mass spectrometry data aided by a novel sliding window algorithm

Proteomic matrix-assisted laser desorption/ionisation (MALDI) linear time-of-flight (TOF) mass spectrometry (MS) may be used to produce protein profiles from biological samples with the aim of discovering biomarkers for disease. However, the raw protein profiles suffer from several sources of bias or systematic variation which need to be removed via pre-processing before meaningful downstream analysis of the data can be undertaken. Baseline subtraction, an early pre-processing step that removes the non-peptide signal from the spectra, is complicated by the following: (i) each spectrum has, on average, wider peaks for peptides with higher mass-to-charge ratios (m/z), and (ii) the time-consuming and error-prone trial-and-error process for optimising the baseline subtraction input arguments. With reference to the aforementioned complications, we present an automated pipeline that includes (i) a novel `continuous' line segment algorithm that efficiently operates over data with a transformed m/z-axis to remove the relationship between peptide mass and peak width, and (ii) an input-free algorithm to estimate peak widths on the transformed m/z scale. The automated baseline subtraction method was deployed on six publicly available proteomic MS datasets using six different m/z-axis transformations. Optimality of the automated baseline subtraction pipeline was assessed quantitatively using the mean absolute scaled error (MASE) when compared to a gold-standard baseline subtracted signal. Near-optimal baseline subtraction was achieved using the automated pipeline. The advantages of the proposed pipeline include informed and data specific input arguments for baseline subtraction methods, the avoidance of time-intensive and subjective piecewise baseline subtraction, and the ability to automate baseline subtraction completely. Moreover, individual steps can be adopted as stand-alone routines.Comment: 50 pages, 19 figure

Prevention of stone migration with the Accordion during endoscopic ureteral lithotripsy.

BACKGROUND AND PURPOSE: Endoscopic lithotripsy is often prolonged secondary to the retrograde migration of calculous fragments. Various balloons, baskets, and other devices have been used to prevent this migration. Our purpose is to analyze the effect of the Accordion(®) on stone migration and overall efficiency during lithotripsy. PATIENTS AND METHODS: We prospectively evaluated 21 patients with a total of 23 distal ureteral stones. Patients underwent lithotripsy using an endoscopic impact lithotriptor. The Accordion was randomly used in 11 of these 21 patients. Data were collected regarding stone migration, stone size, stone ablation, ureteral clearing, and lengths of time for various stages of each procedure. RESULTS: Patients who were treated with the Accordion device experienced significantly less retrograde migration during fragmentation (P=0.0064). When stone volume was taken into account (but not on a per stone basis), ablation and ureteral clearing were also expedited, and fewer lithotripter hits and basket sweeps were needed. CONCLUSION: The Accordion device is effective in preventing the migration of stone fragments during endoscopic ureteral lithotripsy. Our data suggest that this device may also increase efficiency of the fragmentation and clearance of ureteral calculi

Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor

Background and Purpose Flecainide is a use-dependent blocker of cardiac Na+ channels. Mechanistic analysis of this block showed that the cationic form of flecainide enters the cytosolic vestibule of the open Na+ channel. Flecainide is also effective in the treatment of catecholaminergic polymorphic ventricular tachycardia but, in this condition, its mechanism of action is contentious. We investigated how flecainide derivatives influence Ca2+-release from the sarcoplasmic reticulum through the ryanodine receptor channel (RyR2) and whether this correlates with their effectiveness as blockers of Na+ and/or RyR2 channels. Experimental Approach We compared the ability of fully charged (QX-FL) and neutral (NU-FL) derivatives of flecainide to block individual recombinant human RyR2 channels incorporated into planar phospholipid bilayers, and their effects on the properties of Ca2+ sparks in intact adult rat cardiac myocytes. Key Results Both QX-FL and NU-FL were partial blockers of the non-physiological cytosolic to luminal flux of cations through RyR2 channels but were significantly less effective than flecainide. None of the compounds influenced the physiologically relevant luminal to cytosol cation flux through RyR2 channels. Intracellular flecainide or QX-FL, but not NU-FL, reduced Ca2+ spark frequency. Conclusions and Implications Given its inability to block physiologically relevant cation flux through RyR2 channels, and its lack of efficacy in blocking the cytosolic-to-luminal current, the effect of QX-FL on Ca2+ sparks is likely, by analogy with flecainide, to result from Na+ channel block. Our data reveal important differences in the interaction of flecainide with sites in the cytosolic vestibules of Na+ and RyR2 channels

Modeling and mapping isotopic patterns in the Northwest Atlantic derived from loggerhead sea turtles

Stable isotope analysis can be used to infer geospatial linkages of highly migratory species. Identifying foraging grounds of marine organisms from their isotopic signatures is becoming de rigueur as it has been with terrestrial organisms. Sea turtles are being increasingly studied using a combination of satellite telemetry and stable isotope analysis; these studies along with those from other charismatic, highly vagile, and widely distributed species (e.g., tuna, billfish, sharks, dolphins, whales) have the potential to yield large datasets to develop methodologies to decipher migratory pathways in the marine realm. We collected tissue samples (epidermis and red blood cells) for carbon (delta C-13) and nitrogen (delta N-15) stable isotope analysis from 214 individual loggerheads (Caretta caretta) in the Northwest Atlantic Ocean (NWA). We used discriminant function analysis (DFA) to examine how well delta C-13 and delta N-15 classify loggerhead foraging areas. The DFA model was derived from isotopic signatures of 58 loggerheads equipped with satellite tags to identify foraging locations. We assessed model accuracy with the remaining 156 untracked loggerheads that were captured at their foraging locations. The DFA model correctly identified the foraging ground of 93.0% of individuals with a probability greater than 66.7%. The results of the external validation (1) confirm that assignment models based on tracked loggerheads in the NWA are robust and (2) provide the first independent evidence supporting the use of these models for migratory marine organisms. Additionally, we used these data to generate loggerhead-specific delta C-13 and delta N-15 isoscapes, the first for a predator in the Atlantic Ocean. We found a latitudinal trend of delta C-13 values with higher values in the southern region (20-25 degrees N) and a more complex pattern with delta N-15, with intermediate latitudes (30-35 degrees N) near large coastal estuaries having higher delta N-15-enrichment. These results indicate that this method with further refinement may provide a viable, more spatially-explicit option for identifying loggerhead foraging grounds

Through a Glass, Darkly:The CIA and Oral History

This article broaches the thorny issue of how we may study the history of the CIA by utilizing oral history interviews. This article argues that while oral history interviews impose particular demands upon the researcher, they are particularly pronounced in relation to studying the history of intelligence services. This article, nevertheless, also argues that while intelligence history and oral history each harbour their own epistemological perils and biases, pitfalls which may in fact be pronounced when they are conjoined, the relationship between them may nevertheless be a productive one. Indeed, each field may enrich the other provided we have thought carefully about the linkages between them: this article's point of departure. The first part of this article outlines some of the problems encountered in studying the CIA by relating them to the author's own work. This involved researching the CIA's role in US foreign policy towards Afghanistan since a landmark year in the history of the late Cold War, 1979 (i.e. the year the Soviet Union invaded that country). The second part of this article then considers some of the issues historians must confront when applying oral history to the study of the CIA. To bring this within the sphere of cognition of the reader the author recounts some of his own experiences interviewing CIA officers in and around Washington DC. The third part then looks at some of the contributions oral history in particular can make towards a better understanding of the history of intelligence services and the CIA

Cosmic Evolution Early Release Science (CEERS) survey: The colour evolution of galaxies in the distant Universe

The wavelength-coverage and sensitivity of JWST now enables us to probe the rest-frame UV - optical spectral energy distributions (SEDs) of galaxies at high-redshift ($z>4$). From these SEDs it is, in principle, through SED fitting possible to infer key physical properties, including stellar masses, star formation rates, and dust attenuation. These in turn can be compared with the predictions of galaxy formation simulations allowing us to validate and refine the incorporated physics. However, the inference of physical properties, particularly from photometry alone, can lead to large uncertainties and potential biases. Instead, it is now possible, and common, for simulations to be \emph{forward-modelled} to yield synthetic observations that can be compared directly to real observations. In this work, we measure the JWST broadband fluxes and colours of a robust sample of $5<z<10$ galaxies using the Cosmic Evolution Early Release Science (CEERS) Survey. We then analyse predictions from a variety of models using the same methodology and compare the NIRCam/F277W magnitude distribution and NIRCam colours with observations. We find that the predicted and observed magnitude distributions are similar, at least at $58$ the distributions differ somewhat, though our observed sample size is small and thus susceptible to statistical fluctuations. Likewise, the predicted and observed colour evolution show broad agreement, at least at $5<z<8$. There is however some disagreement between the observed and modelled strength of the strong line contribution. In particular all the models fails to reproduce the F410M-F444W colour at $z>8$, though, again, the sample size is small here.Comment: 11 pages, 10 figures, submitted to MNRA

CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

INTRODUCTION: CD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix. OBJECTIVE: To determine the role of CD248 in the development of liver fibrosis in the rodent and human setting. DESIGN: CD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248(−/−) and wild-type controls with carbon tetrachloride (CCl(4)) treatment. RESULTS: Expression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248(−/−) mice compared with wild-type mice after CCl(4) treatment. Isolated HSC from wild-type and CD248(−/−) mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248(−/−) HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248(−/−) HSC was confirmed by significantly reduced c-fos expression in CD248(−/−) HSC compared with wild-type HSC. CONCLUSIONS: Our data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury

CEERS Epoch 1 NIRCam Imaging: Reduction Methods and Simulations Enabling Early JWST Science Results

We present the data release and data reduction process for the Epoch 1 NIRCam observations for the Cosmic Evolution Early Release Science Survey (CEERS). These data consist of NIRCam imaging in six broadband filters (F115W, F150W, F200W, F277W, F356W and F444W) and one medium band filter (F410M) over four pointings, obtained in parallel with primary CEERS MIRI observations (Yang et al. in prep). We reduced the NIRCam imaging with the JWST Calibration Pipeline, with custom modifications and reduction steps designed to address additional features and challenges with the data. Here we provide a detailed description of each step in our reduction and a discussion of future expected improvements. Our reduction process includes corrections for known pre-launch issues such as 1/f noise, as well as in-flight issues including snowballs, wisps, and astrometric alignment. Many of our custom reduction processes were first developed with pre-launch simulated NIRCam imaging over the full 10 CEERS NIRCam pointings. We present a description of the creation and reduction of this simulated dataset in the Appendix. We provide mosaics of the real images in a public release, as well as our reduction scripts with detailed explanations to allow users to reproduce our final data products. These represent one of the first official public datasets released from the Directors Discretionary Early Release Science (DD-ERS) program.Comment: 27 pages, 14 figures, submitted to ApJ. Accompanying CEERS public Data Release 0.5 available at ceers.github.io/releases.htm

Expanding the repertoire of low‐molecular‐weight pentafluorosulfanyl‐substituted scaffolds

The pentafluorosulfanyl (-SF5) functional group is of increasing interest as a bioisostere in medicinal chemistry. A library of SF5-containing compounds, including amide, isoxazole, and oxindole derivatives, was synthesised using a range of solution-based and solventless methods, including microwave and ball-mill techniques. The library was tested against targets including human dihydroorotate dehydrogenase (HDHODH). A subsequent focused approach led to synthesis of analogues of the clinically used disease modifying anti-rheumatic drugs (DMARDs), Teriflunomide and Leflunomide, considered for potential COVID-19 use, where SF5 bioisostere deployment led to improved inhibition of HDHODH compared with the parent drugs. The results demonstrate the utility of the SF5 group in medicinal chemistry