Change point analysis has applications in a wide variety of fields. The general problem concerns the inference of a change in distribution for a set of time-ordered observations. Sequential detection ...is an online version in which new data are continually arriving and are analyzed adaptively. We are concerned with the related, but distinct, offline version, in which retrospective analysis of an entire sequence is performed. For a set of multivariate observations of arbitrary dimension, we consider nonparametric estimation of both the number of change points and the positions at which they occur. We do not make any assumptions regarding the nature of the change in distribution or any distribution assumptions beyond the existence of the αth absolute moment, for some α ∈ (0, 2). Estimation is based on hierarchical clustering and we propose both divisive and agglomerative algorithms. The divisive method is shown to provide consistent estimates of both the number and the location of change points under standard regularity assumptions. We compare the proposed approach with competing methods in a simulation study. Methods from cluster analysis are applied to assess performance and to allow simple comparisons of location estimates, even when the estimated number differs. We conclude with applications in genetics, finance, and spatio-temporal analysis. Supplementary materials for this article are available online.
Abstract
Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental ...manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.
Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder ...cancer should enable the development of such tests based on urinary DNA.
DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free).
Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity).
This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.
Summary Background Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone ...metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov , number NCT00699751. Findings Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months 95% CI 13·5–18·0 vs 9·8 months 7·3–23·7; hazard ratio HR=0·66, 95% CI 0·52–0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53–0·85) and spinal cord compression (HR=0·52, 95% CI 0·29–0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35–1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28–1·82). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Funding Algeta and Bayer HealthCare Pharmaceuticals.
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•Review of in-line and on-line sensors for industrial mixing processes.•Reviewed techniques are suitable for process control and within Industry 4.0.•Liquid-liquid, gas-liquid, ...solid-liquid, solid-gas-liquid, solids mixing included.•Pharmaceutical, food, polymers, rubber, cement and concrete industries included.•Spectroscopic and tomographic techniques reviewed in addition to many others.
Mixing is a ubiquitous operation in process engineering. It is not only used for combining materials, but also for promoting heat and mass transfer, increasing aeration, suspending solids, and modifying material structure. Measurement techniques have the potential to optimise industrial mixing processes and improve product quality by monitoring critical process parameters. Real-time sensing techniques that do not require manual material sampling are of particular interest owing to their automatic data acquisition capability. This makes them suitable for use in control systems for process automation and eventually as connected sensors in Industry 4.0. This review article focuses on these measurement techniques, defined as in- and on-line, along with their capability for implementation in industrial processes. The applications reviewed include liquid–liquid, gas–liquid, solid–liquid, solid–gas–liquid, in addition to solids blending. A technique selection section discussing the decision-making process when choosing a sensor and a summary table including the advantages, disadvantages, applications and limitations of each technique are provided. The article concludes by discussing the future of monitoring techniques for mixing processes.
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after ...injury
, but efficient reversal of this regrowth failure remains elusive
. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity
, (ii) growth-supportive substrate
and (iii) chemoattraction
-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI
; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor
delivered via spatially and temporally controlled release from biomaterial depots
, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
ABSTRACT
We present multiwavelength observations of supernova (SN) 2017hcc with the Chandra X-ray telescope and the X-ray telescope onboard Swift (Swift-XRT) in X-ray bands, with the Spitzer and the ...TripleSpec spectrometer in near-infrared (IR) and mid-IR bands and with the Karl G. Jansky Very Large Array (VLA) for radio bands. The X-ray observations cover a period of 29 to 1310 d, with the first X-ray detection on day 727 with the Chandra. The SN was subsequently detected in the VLA radio bands from day 1000 onwards. While the radio data are sparse, synchrotron-self absorption is clearly ruled out as the radio absorption mechanism. The near- and the mid-IR observations showed that late time IR emission dominates the spectral energy distribution. The early properties of SN 2017hcc are consistent with shock breakout into a dense mass-loss region, with $\dot{M} \sim 0.1$ M⊙ yr−1 for a decade. At few 100 d, the mass-loss rate declined to ∼0.02 M⊙ yr−1, as determined from the dominant IR luminosity. In addition, radio data also allowed us to calculate a mass-loss rate at around day 1000, which is two orders of magnitude smaller than the mass-loss rate estimates around the bolometric peak. These values indicate that the SN progenitor underwent an enhanced mass-loss event a decade before the explosion. The high ratio of IR to X-ray luminosity is not expected in simple models and is possible evidence for an asymmetric circumstellar region.
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