How Many Clocks, How Many Times? On the Sensory Basis and Computational Challenges of Circadian Systems

A vital task for every organism is not only to decide what to do but also when to do it. For this reason, “circadian clocks” have evolved in virtually all forms of life. Conceptually, circadian clocks can be divided into two functional domains; an autonomous oscillator creates a ∼24 h self-sustained rhythm and sensory machinery interprets external information to alter the phase of the autonomous oscillation. It is through this simple design that variations in external stimuli (for example, daylight) can alter our sense of time. However, the clock’s simplicity ends with its basic concept. In metazoan animals, multiple external and internal stimuli, from light to temperature and even metabolism have been shown to affect clock time. This raises the fundamental question of cue integration: how are the many, and potentially conflicting, sources of information combined to sense a single time of day? Moreover, individual stimuli, are often detected through various sensory pathways. Some sensory cells, such as insect chordotonal neurons, provide the clock with both temperature and mechanical information. Adding confusion to complexity, there seems to be not only one central clock in the animal’s brain but numerous additional clocks in the body’s periphery. It is currently not clear how (or if) these “peripheral clocks” are synchronized to their central counterparts or if both clocks “tick” independently from one another. In this review article, we would like to leave the comfort zones of conceptual simplicity and assume a more holistic perspective of circadian clock function. Focusing on recent results from Drosophila melanogaster we will discuss some of the sensory, and computational, challenges organisms face when keeping track of time

Time to Pregnancy for Women Using a Fertility Awareness Based Mobile Application to Plan a Pregnancy

Background: Time to pregnancy (TTP) is a biomarker of fecundability and has been associated with behavioral and environmental characteristics; however, these associations have not been examined in a large population-based sample of application (app) users. Materials and Methods: This observational study followed 5,376 women with an age range of 18 to 45 years who used an app to identify their fertile window. We included women who started trying to conceive between September 30, 2017 and August 31, 2018. TTP was calculated as the number of menstrual cycles from when the user switched to "Plan" mode up to and including the cycle in which they logged a positive pregnancy test. We examined associations with several characteristics, including age, gravidity, body mass index, cycle length and cycle length variation, frequency of sexual intercourse, and temperature measuring frequency. Discrete time fecundability models were used to estimate fecundability odds ratios. Results: For the complete cohort the 6-cycle and 12-cycle cumulative pregnancy probabilities were found to be 61% (95% confidence interval [CI]: 59-62) and 74% (95% CI: 73-76), respectively. The median TTP was four cycles. The highest fecundability was associated with an age of less than 35 years, with cycle length variation <5 days and logging sexual intercourse on at least 20% of days added (the proportion of days in which intercourse was logged) (11.5% [n = 613] of entire sample). This group achieved a 6- and 12-cycle cumulative pregnancy probability of 88% (95% CI: 85-91) and 95% (95% CI: 94-97), respectively, and a TTP of 2 cycles. Conclusions: Natural Cycles was an effective method of identifying the fertile window and a noninvasive educational option for women planning a pregnancy. Women under age 35 with regular cycles showed a high pregnancy rate

Light Dominates Peripheral Circadian Oscillations in Drosophila melanogaster During Sensory Conflict

In Drosophila, as in other animals, the circadian clock is a singular entity in name and concept only. In reality, clock functions emerge from multiple processes and anatomical substrates. One distinction has conventionally been made between a central clock (in the brain) and peripheral clocks (e.g., in the gut and the eyes). Both types of clock generate robust circadian oscillations, which do not require external input. Furthermore, the phases of these oscillations remain exquisitely sensitive to specific environmental cues, such as the daily changes of light and temperature. When these cues conflict with one another, the central clock displays complex forms of sensory integration; how peripheral clocks respond to conflicting input is unclear. We therefore explored the effects of light and temperature misalignments on peripheral clocks. We show that under conflict, peripheral clocks preferentially synchronize to the light stimulus. This photic dominance requires the presence of the circadian photoreceptor, Cryptochrome

Progesterone from the Cumulus Cells Is the Sperm Chemoattractant Secreted by the Rabbit Oocyte Cumulus Complex

Sperm chemotaxis in mammals have been identified towards several female sources as follicular fluid (FF), oviduct fluid, and conditioned medium from the cumulus oophorus (CU) and the oocyte (O). Though several substances were confirmed as sperm chemoattractant, Progesterone (P) seems to be the best chemoattractant candidate, because: 1) spermatozoa express a cell surface P receptor, 2) capacitated spermatozoa are chemotactically attracted in vitro by gradients of low quantities of P; 3) the CU cells produce and secrete P after ovulation; 4) a gradient of P may be kept stable along the CU; and 5) the most probable site for sperm chemotaxis in vivo could be near and/or inside the CU. The aim of this study was to verify whether P is the sperm chemoattractant secreted by the rabbit oocyte-cumulus complex (OCC) in the rabbit, as a mammalian animal model. By means of videomicroscopy and computer image analysis we observed that only the CU are a stable source of sperm attractants. The CU produce and secrete P since the hormone was localized inside these cells by immunocytochemistry and in the conditioned medium by enzyme immunoassay. In addition, rabbit spermatozoa express a cell surface P receptor detected by western blot and localized over the acrosomal region by immunocytochemistry. To confirm that P is the sperm chemoattractant secreted by the CU, the sperm chemotactic response towards the OCC conditioned medium was inhibited by three different approaches: P from the OCC conditioned medium was removed with an anti-P antibody, the attractant gradient of the OCC conditioned medium was disrupted by a P counter gradient, and the sperm P receptor was blocked with a specific antibody. We concluded that only the CU but not the oocyte secretes P, and the latter chemoattract spermatozoa by means of a cell surface receptor. Our findings may be of interest in assisted reproduction procedures in humans, animals of economic importance and endangered species

Patterns of atrophy in pathologically confirmed dementias: a voxelwise analysis

$\textbf{OBJECTIVE}$: Imaging is recommended to support the clinical diagnoses of dementias, yet imaging research studies rarely have pathological confirmation of disease. This study aims to characterise patterns of brain volume loss in six primary pathologies compared with controls and to each other. $\textbf{METHODS}$: One hundred and eighty-six patients with a clinical diagnosis of dementia and histopathological confirmation of underlying pathology, and 73 healthy controls were included in this study. Voxel-based morphometry, based on ante-mortem T1-weighted MRI, was used to identify cross-sectional group differences in brain volume. $\textbf{RESULTS}$: Early-onset and late-onset Alzheimer's disease exhibited different patterns of grey matter volume loss, with more extensive temporoparietal involvement in the early-onset group, and more focal medial temporal lobe loss in the late-onset group. The Presenilin-1 group had similar parietal involvement to the early-onset group with localised volume loss in the thalamus, medial temporal lobe and temporal neocortex. Lewy body pathology was associated with less extensive volume loss than the other pathologies, although precentral/postcentral gyri volume was reduced in comparison with other pathological groups. Tau and TDP43A pathologies demonstrated similar patterns of frontotemporal volume loss, although less extensive on the right in the 4-repeat-tau group, with greater parietal involvement in the TDP43A group. The TDP43C group demonstrated greater left anterior-temporal involvement. $\textbf{CONCLUSIONS}$: Pathologically distinct dementias exhibit characteristic patterns of regional volume loss compared with controls and other dementias. Voxelwise differences identified in these cohorts highlight imaging signatures that may aid in the differentiation of dementia subtypes during life. The results of this study are available for further examination via NeuroVault (http://neurovault.org/collections/ADHMHOPN/).The Dementia Research Centre is an Alzheimer’s Research UK coordinating centre. The authors acknowledge the support of Alzheimer’s Research UK (grant number ART-NCG2010B-2), the Medical Research Council (grant number MR/J014257/2), the NIHR Queen Square Dementia Biomedical Research Unit, UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the NIHR Newcastle Biomedical Research Unit in Lewy body dementia and the NIHR Cambridge Biomedical Research Unit in Dementia. LH is supported by funding from Alzheimer’s Research UK and a UCL Impact Studentship. NCF and JTOB hold NIHR Senior Investigator Awards. JMS acknowledges the support of the NIHR Queen Square Dementia BRU, the NIHR UCL/H Biomedical Research Centre, Wolfson Foundation, EPSRC (EP/J020990/1), MRC (CSUB19166), ARUK (ARUK-Network 2012–6-ICE; ARUK-PG2014-1946) and European Commission (H2020-PHC-2014-2015-666992)

Advances in Nondietary Management of Children with Atopic Dermatitis

This paper discusses recent advances in therapy of atopic dermatitis (AD), excluding those that include dietary management. Some of these therapies are anecdotal, experimental, or somewhat controversial. It is important to emphasize that physicians should not try what is new without first having given standard therapy a long and reasonable chance to succeed. This is important because AD does not last forever, and in many patients, mild disease heals spontaneously.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72467/1/j.1525-1470.1989.tb00820.x.pd

There Is No Safe Dose of Prions

Understanding the circumstances under which exposure to transmissible spongiform encephalopathies (TSEs) leads to infection is important for managing risks to public health. Based upon ideas in toxicology and radiology, it is plausible that exposure to harmful agents, including TSEs, is completely safe if the dose is low enough. However, the existence of a threshold, below which infection probability is zero has never been demonstrated experimentally. Here we explore this question by combining data and mathematical models that describe scrapie infections in mice following experimental challenge over a broad range of doses. We analyse data from 4338 mice inoculated at doses ranging over ten orders of magnitude. These data are compared to results from a within-host model in which prions accumulate according to a stochastic birth-death process. Crucially, this model assumes no threshold on the dose required for infection. Our data reveal that infection is possible at the very low dose of a 1000 fold dilution of the dose that infects half the challenged animals (ID50). Furthermore, the dose response curve closely matches that predicted by the model. These findings imply that there is no safe dose of prions and that assessments of the risk from low dose exposure are right to assume a linear relationship between dose and probability of infection. We also refine two common perceptions about TSE incubation periods: that their mean values decrease linearly with logarithmic decreases in dose and that they are highly reproducible between hosts. The model and data both show that the linear decrease in incubation period holds only for doses above the ID50. Furthermore, variability in incubation periods is greater than predicted by the model, not smaller. This result poses new questions about the sources of variability in prion incubation periods. It also provides insight into the limitations of the incubation period assay

Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents and young adults (BREATHER): Extended follow-up results of a randomised, open-label, non-inferiority trial

BACKGROUND: Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation. METHODS: BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virological suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL≥50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz. FINDINGS: Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9-216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12-18), median CD4 count 735 cells/μL (IQR 576-968). 16 SCT and 16 CT participants had confirmed VL≥50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50-2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6-10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12; p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71-8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART following viral failure (p = 0.50). CONCLUSIONS: Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring. TRIAL REGISTRATION: EudraCT 2009-012947-40 ISRCTN 97755073 ClinicalTrials.gov NCT01641016

A Hypothesis for the Evolution of Nuclear-Encoded, Plastid-Targeted Glyceraldehyde-3-Phosphate Dehydrogenase Genes in “Chromalveolate” Members

Eukaryotes bearing red alga-derived plastids — photosynthetic alveolates (dinoflagellates plus the apicomplexan Toxoplasma gondii plus the chromerid Chromera velia), photosynthetic stramenopiles, haptophytes, and cryptophytes — possess unique plastid-targeted glyceraldehyde-3-phosphate dehydrogenases (henceforth designated as “GapC1”). Pioneering phylogenetic studies have indicated a single origin of the GapC1 enzymes in eukaryotic evolution, but there are two potential idiosyncrasies in the GapC1 phylogeny: Firstly, the GapC1 tree topology is apparently inconsistent with the organismal relationship among the “GapC1-containing” groups. Secondly, four stramenopile GapC1 homologues are consistently paraphyletic in previously published studies, although these organisms have been widely accepted as monophyletic. For a closer examination of the above issues, in this study GapC1 gene sampling was improved by determining/identifying nine stramenopile and two cryptophyte genes. Phylogenetic analyses of our GapC1 dataset, which is particularly rich in the stramenopile homologues, prompt us to propose a new scenario that assumes multiple, lateral GapC1 gene transfer events to explain the incongruity between the GapC1 phylogeny and the organismal relationships amongst the “GapC1-containing” groups. Under our new scenario, GapC1 genes uniquely found in photosynthetic alveolates, photosynthetic stramenopiles, haptophytes, and cryptopyhytes are not necessarily a character vertically inherited from a common ancestor