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Very long and noisy sequence data arise from biological sciences to social science including high throughput data in genomics and stock prices in econometrics. Often such data are collected in order to identify and understand shifts in trends, for example, from a bull market to a bear market in finance or from a normal number of chromosome copies to an excessive number of chromosome copies in genetics. Thus, identifying multiple change points in a long, possibly very long, sequence is an important problem. In this article, we review both classical and new multiple change-point detection strategies. Considering the long history and the extensive literature on the change-point detection, we provide an in-depth discussion on a normal mean change-point model from aspects of regression analysis, hypothesis testing, consistency and inference. In particular, we present a strategy to gather and aggregate local information for change-point detection that has become the cornerstone of several emerging methods because of its attractiveness in both computational and theoretical properties.

SummaryRomosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options.IntroductionIn patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course.MethodsIn this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score ≤ − 2.0 and ≥ − 3.5) received romosozumab or placebo (month 0–24) followed by placebo or denosumab (month 24–36); participants then received a year of romosozumab (month 36–48).ResultsOf 167 participants who entered the month 36–48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (n = 19) increased BMD by amounts similar to their initial treatment (month 0–12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (n = 16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses.ConclusionsAfter 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.

Memory conformity may develop when people are confronted with distinct memories reported by others in social situations and knowingly/unknowingly adhere to these exogenous memories. Earlier research on memory conformity suggests that (1) subjects were more likely to conform to confederate with high confidence; (2) subjects with low confidence on their memory accuracy were more likely to conform, and; (3) this subjective confidence could be adjusted by social manipulations. Nonetheless, it remains unclear how the confidence levels of ours and others may interact and produce a combined effect on our degree of conformity. More importantly, is memory conformity, defined by a complete adoption of the opposite side, the result of a gradual accumulation of subtler changes at the confidence level, i.e., a buildup of confidence conformity? Here, we followed participant’s confidence transformation quantitatively over three confederate sessions in a memory test. After studying a set of human motion videos, participants had to answer simultaneously whether a target or lure video had appeared before by indicating their side (i.e., Yes/No) and their associated confidence rating. Participants were allowed to adjust their responses as they were being shown randomly-generated confederates’ answers and confidence values. Results show that participants indeed demonstrated confidence conformity. Interestingly, they tended to become committed to their side early on and gain confidence gradually over subsequent sessions. This polarizing behaviour may be explained by two kinds of preferences: (1) Participant’s confidence enhancement towards same-sided confederates was greater in magnitude compared to the decrement towards an opposite-sided confederate; and (2) Participants had the most effective confidence boost when the same-sided confederates shared similar, but not considerably different, confidence level to theirs. In other words, humans exhibit side- and similarity-biases during confidence conformity.

High-strength steel fasteners characterized by tensile strengths above 1100 MPa are often used in critical applications where a failure can have catastrophic consequences. Preventing hydrogen embrittlement (HE) failure is a fundamental concern implicating the entire fastener supply chain. Research is typically conducted under idealized conditions that cannot be translated into know-how prescribed in fastener industry standards and practices. Additionally, inconsistencies and even contradictions in fastener industry standards have led to much confusion and many preventable or misdiagnosed fastener failures. HE susceptibility is a function of the material condition, which is comprehensively described by the metallurgical and mechanical properties. Material strength has a first-order effect on HE susceptibility, which increases significantly above 1200 MPa and is characterized by a ductile--brittle transition. For a given concentration of hydrogen and at equal strength, the critical strength above which the ductile-brittle transition begins can vary due to second-order effects of chemistry, tempering temperature and sub-microstructure. Additionally, non-homogeneity of the metallurgical structure resulting from poorly controlled heat treatment, impurities and non-metallic inclusions can increase HE susceptibility of steel in ways that are measurable but unpredictable. Below 1200 MPa, non-conforming quality is often the root cause of real-life failures. This article is part of the themed issue ‘The challenges of hydrogen and metals’.

The molecular circadian clocks in the mammalian retina are locally synchronized by environmental light cycles independent of the suprachiasmatic nuclei (SCN) in the brain. Unexpectedly, this entrainment does not require rods, cones, or melanopsin (OPN4), possibly suggesting the involvement of another retinal photopigment. Here, we show that the ex vivo mouse retinal rhythm is most sensitive to short-wavelength light but that this photoentrainment requires neither the short-wavelength–sensitive cone pigment [S-pigment or cone opsin (OPN1SW)] nor encephalopsin (OPN3). However, retinas lacking neuropsin (OPN5) fail to photoentrain, even though other visual functions appear largely normal. Initial evidence suggests that OPN5 is expressed in select retinal ganglion cells. Remarkably, the mouse corneal circadian rhythm is also photoentrainable ex vivo, and this photoentrainment likewise requires OPN5. Our findings reveal a light-sensing function for mammalian OPN5, until now an orphan opsin.

DNA Copy number variation (CNV) has recently gained considerable interest as a source of genetic variation that likely influences phenotypic differences. Many statistical and computational methods have been proposed and applied to detect CNVs based on data that generated by genome analysis platforms. However, most algorithms are computationally intensive with complexity at least O(n²), where n is the number of probes in the experiments. Moreover, the theoretical properties of those existing methods are not well understood. A faster and better characterized algorithm is desirable for the ultra high throughput data. In this study, we propose the Screening and Ranking algorithm (SaRa) which can detect CNVs fast and accurately with complexity down to O(n). In addition, we characterize theoretical properties and present numerical analysis for our algorithm.

G protein-coupled receptor (GPCR) signaling is crucial for many physiological processes. A signature of such pathways is high amplification, a concept originating from retinal rod phototransduction, whereby one photoactivated rhodopsin molecule (Rho*) was long reported to activate several hundred transducins (GT*s), each then activating a cGMP-phosphodiesterase catalytic subunit (GT*·PDE*). This high gain at the Rho*-to-GT* step has been challenged more recently, but estimates remain dispersed and rely on some nonintact rod measurements. With two independent approaches, one with an extremely inefficient mutant rhodopsin and the other with WT bleached rhodopsin, which has exceedingly weak constitutive activity in darkness, we obtained an estimate for the electrical effect from a single GT*·PDE* molecular complex in intact mouse rods. Comparing the single-GT*·PDE* effect to the WT single-photon response, both in Gcaps −/− background, gives an effective gain of only ∼12–14 GT*·PDE*s produced per Rho*. Our findings have finally dispelled the entrenched concept of very high gain at the receptor-to-G protein/effector step in GPCR systems.

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes. It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.

To explore the relationship between weather phenomena and pollution levels and daily hospital admissions (as an approximation to morbidity patterns) in Hong Kong Special Administrative Region (SAR), China, in 1998-2009. Generalized additive models and lag models were constructed with data from official sources on hospital admissions and on mean daily temperature, mean daily wind speed, mean relative humidity, daily total global solar radiation, total daily rainfall and daily pollution levels. During the hot season, admissions increased by 4.5% for every increase of 1 °C above 29 °C; during the cold season, admissions increased by 1.4% for every decrease of 1 °C within the 8.2-26.9 °C range. In subgroup analyses, admissions for respiratory and infectious diseases increased during extreme heat and cold, but cardiovascular disease admissions increased only during cold temperatures. For every increase of 1 °C above 29 °C, admissions for unintentional injuries increased by 1.9%. During the cold season, for every decrease of 1 °C within the 8.2-26.9 °C range, admissions for cardiovascular diseases and intentional injuries rose by 2.1% and 2.4%, respectively. Admission patterns were not sensitive to sex. Admissions for respiratory diseases rose during hot and cold temperatures among children but only during cold temperatures among the elderly. In people aged 75 years or older, admissions for infectious diseases rose during both temperature extremes. In Hong Kong SAR, hospitalizations rise during extreme temperatures. Public health interventions should be developed to protect children, the elderly and other vulnerable groups from excessive heat and cold.

ObjectiveSporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.DesignWe established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.ResultsWe observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.ConclusionsThese organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.