Detecting variable responses in time-series using repeated measures ANOVA: Application to physiologic challenges.

We present an approach to analyzing physiologic timetrends recorded during a stimulus by comparing means at each time point using repeated measures analysis of variance (RMANOVA). The approach allows temporal patterns to be examined without an a priori model of expected timing or pattern of response. The approach was originally applied to signals recorded from functional magnetic resonance imaging (fMRI) volumes-of-interest (VOI) during a physiologic challenge, but we have used the same technique to analyze continuous recordings of other physiological signals such as heart rate, breathing rate, and pulse oximetry. For fMRI, the method serves as a complement to whole-brain voxel-based analyses, and is useful for detecting complex responses within pre-determined brain regions, or as a post-hoc analysis of regions of interest identified by whole-brain assessments. We illustrate an implementation of the technique in the statistical software packages R and SAS. VOI timetrends are extracted from conventionally preprocessed fMRI images. A timetrend of average signal intensity across the VOI during the scanning period is calculated for each subject. The values are scaled relative to baseline periods, and time points are binned. In SAS, the procedure PROC MIXED implements the RMANOVA in a single step. In R, we present one option for implementing RMANOVA with the mixed model function "lme". Model diagnostics, and predicted means and differences are best performed with additional libraries and commands in R; we present one example. The ensuing results allow determination of significant overall effects, and time-point specific within- and between-group responses relative to baseline. We illustrate the technique using fMRI data from two groups of subjects who underwent a respiratory challenge. RMANOVA allows insight into the timing of responses and response differences between groups, and so is suited to physiologic testing paradigms eliciting complex response patterns

Stem cell patterning and fate in human epidermis

AbstractWithin human epidermis there are two types of proliferating keratinocyte: stem cells, which have high proliferative potential, and transit-amplifying cells, which are destined to undergo terminal differentiation after a few rounds of division. We show that, in vivo, stem cells express higher levels of the α2β1, and α3β1 integrins than transit-amplifying cells and that this can be used both to determine the location of stem cells within the epidermis and to isolate them directly from the tissue. The distribution of stem cells and transit-amplifying cells is not random: patches of integrin-bright and integrin-dull cells have a specific location with respect to the epidermal-dermal junction that varies between body sites and that correlates with the distribution of S phase cells. Stem cell patterning can be recreated in culture, in the absence of dermis, and appears to be subject to autoregulation

Orbitally modulated photoexcited Si I emission in the eclipsing composite-spectrum binary [zeta] Aurigae

Publisher's Version/PDFWe examine the little-known phenomenon of orbitally modulated Si I emission at [lambda] 3905.523 [angstrom] and [lambda] 4102.936 [angstrom] in composite-spectrum binaries, with specific reference to [zeta] Aurigae (K4 Ib + B5 V). The emission is detected in the isolated spectrum of the B-type dwarf secondary, and while [lambda] 4102 [angstrom] is heavily blended with H[delta], [lambda] 3905 [angstrom] falls in the B-star’s featureless continuum. The narrowness of the emission (v [subscript turb] [similar or equal to] 6 km s[superscript-1]) demonstrates that it originates in the upper photosphere or deep chromosphere of the K star primary. We propose that photoexcitation by the hot star’s UV continuum, followed by recombination and cascades, leads to resonant scattering and subsequent pumping of lower opacity transitions in the singlet and triplet systems of Si I. This process channels the UV continuum into select narrow emission lines. We have also identified weaker photoexcited emission of Fe II at [lambda] 3938.289 [angstrom]. The strengths, positions, and widths of the [lambda] 3905 [angstrom] emission line vary with orbital phase owing to changes in the dilution of the irradiating flux and in the geometrical aspect of the irradiated hemisphere. Utilizing the inherent spatial resolution provided by the illuminated patch, and assuming that the K star is spherical with isotropic emission, yields vsin i [similar to] 5.7 km s[superscript-1]. Evidence of tidal distortion was deduced from the timing of the rapidly rising phase of the emission just after periastron. Increasing the diagnostic potential requires radiative transfer modelling of the formation and centre-to-limb variation of the emission

Haptoglobin Phenotype, Preeclampsia Risk and the Efficacy of Vitamin C and E Supplementation to Prevent Preeclampsia in a Racially Diverse Population

Haptoglobin's (Hp) antioxidant and pro-angiogenic properties differ between the 1-1, 2-1, and 2-2 phenotypes. Hp phenotype affects cardiovascular disease risk and treatment response to antioxidant vitamins in some non-pregnant populations. We previously demonstrated that preeclampsia risk was doubled in white Hp 2-1 women, compared to Hp 1-1 women. Our objectives were to determine whether we could reproduce this finding in a larger cohort, and to determine whether Hp phenotype influences lack of efficacy of antioxidant vitamins in preventing preeclampsia and serious complications of pregnancy-associated hypertension (PAH). This is a secondary analysis of a randomized controlled trial in which 10,154 low-risk women received daily vitamin C and E, or placebo, from 9-16 weeks gestation until delivery. Hp phenotype was determined in the study prediction cohort (n = 2,393) and a case-control cohort (703 cases, 1,406 controls). The primary outcome was severe PAH, or mild or severe PAH with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclampsia, fetal growth restriction, medically indicated preterm birth or perinatal death. Preeclampsia was a secondary outcome. Odds ratios were estimated by logistic regression. Sampling weights were used to reduce bias from an overrepresentation of women with preeclampsia or the primary outcome. There was no relationship between Hp phenotype and the primary outcome or preeclampsia in Hispanic, white/other or black women. Vitamin supplementation did not reduce the risk of the primary outcome or preeclampsia in women of any phenotype. Supplementation increased preeclampsia risk (odds ratio 3.30; 95% confidence interval 1.61-6.82, p<0.01) in Hispanic Hp 2-2 women. Hp phenotype does not influence preeclampsia risk, or identify a subset of women who may benefit from vitamin C and E supplementation to prevent preeclampsia

Comparison of Tissue Injury from Focused Ultrasonic Propulsion of Kidney Stones Versus Extracorporeal Shock Wave Lithotripsy

Purpose Focused ultrasonic propulsion is a new non-invasive technique designed to move kidney stones and stone fragments out of the urinary collecting system. However, the extent of tissue injury associated with this technique is not known. As such, we quantitated the amount of tissue injury produced by focused ultrasonic propulsion under simulated clinical treatment conditions, and under conditions of higher power or continuous duty cycles, and compared those results to SWL injury. Materials and Methods A human calcium oxalate monohydrate stone and/or nickel beads were implanted (with ureteroscopy) into 3 kidneys of live pigs (45–55 kg) and repositioned using focused ultrasonic propulsion. Additional pig kidneys were exposed to SWL level pulse intensities or continuous ultrasound exposure of 10 minutes duration (ultrasound probe either transcutaneous or on the kidney). These kidneys were compared to 6 kidneys treated with an unmodified Dornier HM3 Lithotripter (2400 shocks, 120 SWs/min and 24 kV). Histological analysis was performed to assess the volume of hemorrhagic tissue injury created by each technique (% functional renal volume, FRV). Results SWL produced a lesion of 1.56±0.45% FRV. Ultrasonic propulsion produced no detectable lesion with the simulated clinical treatment. A lesion of 0.46±0.37% FRV or 1.15±0.49% FRV could be produced if excessive treatment parameters were used while the ultrasound probe was placed on the kidney. Conclusions Focused ultrasonic propulsion produced no detectable morphological injury to the renal parenchyma when using clinical treatment parameters and produced injury comparable in size to SWL when using excessive treatment parameters

Male reproductive aging arises via multifaceted mating-dependent sperm and seminal proteome declines, but is postponable in Drosophila

I.S. and S.W. were supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Fellowship to S.W. (BB/K014544/1) and S.W. additionally by a Dresden Senior Fellowship. B.M.K., P.D.C., and R.F. were supported by the Kennedy Trust and John Fell Funds. R.D. was supported by Marie Curie Actions (Grant 655392). B.R.H. was funded by the EP Abraham Cephalosporin-Oxford Graduate Scholarship with additional support from the BBSRC Doctoral Training Programme. M.F.W. was supported by a NIH Grant R01HD038921. Work in the J.S. Laboratory was supported by NIH Grant R15HD080511.Declining ejaculate performance with male age is taxonomically widespread and has broad fitness consequences. Ejaculate success requires fully functional germline (sperm) and soma (seminal fluid) components. However, some aging theories predict that resources should be preferentially diverted to the germline at the expense of the soma, suggesting differential impacts of aging on sperm and seminal fluid and trade-offs between them or, more broadly, be-tween reproduction and lifespan. While harmful effects of male age on sperm are well known, we do not know how much seminal fluid deteriorates in comparison. Moreover, given the predicted trade-offs, it remains unclear whether systemic lifespan-extending inter-ventions could ameliorate the declining performance of the ejacu-late as a whole. Here, we address these problems using Drosophila melanogaster. We demonstrate that seminal fluid deterioration con-tributes to male reproductive decline via mating-dependent mech-anisms that include posttranslational modifications to seminal proteins and altered seminal proteome composition and transfer. Additionally, we find that sperm production declines chronologically with age, invariant to mating activity such that older multiply mated males become infertile principally via reduced sperm transfer and viability. Our data, therefore, support the idea that both germline and soma components of the ejaculate contribute to male reproduc-tive aging but reveal a mismatch in their aging patterns. Our data do not generally support the idea that the germline is prioritized over soma, at least, within the ejaculate. Moreover, we find that lifespan-extending systemic down-regulation of insulin signaling re-sults in improved late-life ejaculate performance, indicating simul-taneous amelioration of both somatic and reproductive aging.Publisher PDFPeer reviewe

A synopsis of the Ordovician System in its birthplace - Britain and Ireland

Rock successions in Britain and Ireland, and more especially those in North Wales, were instrumental in the founding and naming of the Ordovician System, and the Anglo-Welsh series established both initially and subsequently were used widely as a standard for Ordovician chronostratigraphy. Although now largely superseded in the global scheme of series and stages, they retain their local and regional importance. The Ordovician System in Britain and Ireland documents the history of a segment of the Earth's crust that incorporated opposing peri-Gondwanan and peri-Laurentian/Laurentian margins of the Iapetus Ocean during its closure, and is accordingly complex. The complexity arises from the volcanic and tectonic processes that accompanied oceanic closure coupled with the effects of eustatic sea-level changes, including the far-field effects of the Late Ordovician glaciation. For the past three decades, Ordovician successions in Britain and Ireland have been discussed in terms of terranes. Here we review Ordovician successions in each terrane, incorporating the results of recent research and correlating those successions via biostratigraphical schemes and radiometric dates to the global Ordovician series and stages

Conducting robust ecological analyses with climate data

Although the number of studies discerning the impact of climate change on ecological systems continues to increase, there has been relatively little sharing of the lessons learnt when accumulating this evidence. At a recent workshop entitled ‘Using climate data in ecological research’ held at the UK Met Office, ecologists and climate scientists came together to discuss the robust analysis of climate data in ecology. The discussions identified three common pitfalls encountered by ecologists: 1) selection of inappropriate spatial resolutions for analysis; 2) improper use of publically available data or code; and 3) insufficient representation of the uncertainties behind the adopted approach. Here, we discuss how these pitfalls can be avoided, before suggesting ways that both ecology and climate science can move forward. Our main recommendation is that ecologists and climate scientists collaborate more closely, on grant proposals and scientific publications, and informally through online media and workshops. More sharing of data and code (e.g. via online repositories), lessons and guidance would help to reconcile differing approaches to the robust handling of data. We call on ecologists to think critically about which aspects of the climate are relevant to their study system, and to acknowledge and actively explore uncertainty in all types of climate data. And we call on climate scientists to make simple estimates of uncertainty available to the wider research community. Through steps such as these, we will improve our ability to robustly attribute observed ecological changes to climate or other factors, while providing the sort of influential, comprehensive analyses that efforts to mitigate and adapt to climate change so urgently require

Haptoglobin phenotype and abnormal uterine artery Doppler in a racially diverse cohort

The anti-oxidant and proangiogenic protein haptoglobin (Hp) is believed to be important for implantation and pregnancy, although its specific role is not known. The three phenotypes (1-1, 2-1 and 2-2) differ in structure and function. Hp 2-2 is associated with increased vascular stiffness in other populations. We examined whether Hp phenotype is associated with abnormal uterine artery Doppler (UAD) in pregnancy

Health seeking behaviour, health system experience and tuberculosis case finding in Gambians with cough

BACKGROUND: Studies in Africa investigating health-seeking behaviour by interviewing tuberculosis patients have revealed patient knowledge issues and significant delays to diagnosis. We aimed to study health-seeking behaviour and experience of those with cough in The Gambia and to identify whether they had tuberculosis. METHODS: During a round of a population under 3-monthly demographic surveillance, we identified people >10 years old who had been coughing ≥ 3 weeks. A questionnaire was administered concerning demographic data, cough, knowledge, health seeking, and experience at health facilities. Case finding utilised sputum smear and chest X-ray. RESULTS: 122/29,871 coughing individuals were identified. Of 115 interviewed, 93 (81%) had sought treatment; 76 (81.7%) from the health system. Those that visited an alternative health provider first were significantly older than those who visited the health system first (p = 0.03). The median time to seek treatment was 2 weeks (range 0 – 106). 54 (58.1%) made their choice of provider because they believed it was right. Of those who left the health system to an alternative provider (n = 13): 7 believed it was the best place, 3 cited cost and 2 failure to improve. 3 cases were identified by sputum analysis, 11 more by X-ray; all had visited the health system first. Total 'excess' cough time was 1079 person weeks. CONCLUSION: The majority of people with cough in this population seek appropriate help early. Improved case detection might be achieved through the use of chest X-ray in addition to sputum smear