For nearly a century, we have known that brain photoreceptors regulate avian seasonal biology. Two photopigments, vertebrate ancient opsin (VA) and neuropsin (OPN5), provide possible molecular ...substrates for these photoreceptor pathways. VA fulfills many criteria for providing light input to the reproductive response, but a functional link has yet to be demonstrated. This study examined the role of VA and OPN5 in the avian photoperiodic response of Japanese quail (Coturnix japonica). Non-breeding male quail were housed under short days (6L:18D) and received an intracerebroventricular infusion of adeno-associated viral vectors with shRNAi that selectively inhibited either VA or OPN5. An empty viral vector acted as a control. Quail were then photostimulated (16L:8D) to stimulate gonadal growth. Two long days significantly increased pituitary thyrotrophin-stimulating hormone β-subunit (TSHβ) and luteinizing hormone β-subunit (LHβ) mRNA of VA shRNAi treated quail compared to controls. Furthermore, at one week there was a significant increase, compared to controls, in both hypothalamic gonadotrophin releasing hormone-I (GnRH-I) mRNA and paired testicular mass in VA shRNAi birds. Opn5 shRNAi facilitated the photoinduced increase in TSHβ mRNA at 2 days, but no other differences were identified compared to controls. Contrary to our expectations, the silencing of deep brain photoreceptors enhanced the response of the reproductive axis to photostimulation rather than preventing it. In addition, we show that VA opsin plays a dominant role in the light-dependent neuroendocrine control of seasonal reproduction in birds. Together our findings suggest the photoperiodic response involves at least two photoreceptor types and populations working together with VA opsin playing a dominant role.
•VA opsin and neuropsin RNAi silencing impact photoinduced activation of the reproductive axis in quail.•VA opsin RNAi increased testes mass after 7 long days and induced acute changes in some pituitary secretagogues.•Neuropsin RNAi only effected TSHβ gene expression.•Non-visual opsin photoreceptors appear to exert their effect at multiple points in the regulation of the reproductive axis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The release of over 4500 Gt (gigatonnes) of carbon at the Paleocene–Eocene boundary provides the closest geological analog to modern anthropogenic CO2 emissions. The cause(s) of and responses to the ...resulting Paleocene–Eocene Thermal Maximum (PETM) and attendant carbon isotopic excursion (CIE) remain enigmatic and intriguing despite over 30 years of intense study. CIE records from the deep sea are generally thin due to its short duration and slow sedimentation rates, and they are truncated due to corrosive bottom waters dissolving carbonate sediments. In contrast, PETM coastal plain sections along the US mid-Atlantic margin are thick, generally having an expanded record of the CIE. Drilling here presents an opportunity to study the PETM onset to a level of detail that could transform our understanding of this important event. Previous drilling in this region provided important insights, but existing cores are either depleted or contain stratigraphic gaps. New core material is needed for well-resolved marine climate records. To plan new drilling, members of the international scientific community attended a multi-staged, hybrid scientific drilling workshop in 2022 designed to maximize not only scientifically and demographically diverse participation but also to protect participants' health and safety during the global pandemic and to reduce our carbon footprint. The resulting plan identified 10 sites for drill holes that would penetrate the Cretaceous–Paleogene (K–Pg) boundary, targeting the pre-onset excursion (POE), the CIE onset, the rapidly deposited Marlboro Clay that records a very thick CIE body, and other Eocene hyperthermals. The workshop participants developed several primary scientific objectives related to investigating the nature and the cause(s) of the CIE onset as well as the biotic effects of the PETM on the paleoshelf. Additional objectives focus on the evidence for widespread wildfires and changes in the hydrological cycle, shelf morphology, and sea level during the PETM as well as the desire to study both underlying K–Pg sediments and overlying post-Eocene records of extreme hyperthermal climate events. All objectives address our overarching research question: what was the Earth system response to a rapid carbon cycle perturbation?
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Home delivery and late and infrequent attendance at antenatal care (ANC) are responsible for substantial avoidable maternal and pediatric morbidity and mortality in sub-Saharan Africa. This ...cluster-randomized trial aimed to determine the impact of a community health worker (CHW) intervention on the proportion of women who (i) visit ANC fewer than 4 times during their pregnancy and (ii) deliver at home.
As part of a 2-by-2 factorial design, we conducted a cluster-randomized trial of a home-based CHW intervention in 2 of 3 districts of Dar es Salaam from 18 June 2012 to 15 January 2014. Thirty-six wards (geographical areas) in the 2 districts were randomized to the CHW intervention, and 24 wards to the standard of care. In the standard-of-care arm, CHWs visited women enrolled in prevention of mother-to-child HIV transmission (PMTCT) care and provided information and counseling. The intervention arm included additional CHW supervision and the following additional CHW tasks, which were targeted at all pregnant women regardless of HIV status: (i) conducting home visits to identify pregnant women and refer them to ANC, (ii) counseling pregnant women on maternal health, and (iii) providing home visits to women who missed an ANC or PMTCT appointment. The primary endpoints of this trial were the proportion of pregnant women (i) not making at least 4 ANC visits and (ii) delivering at home. The outcomes were assessed through a population-based household survey at the end of the trial period. We did not collect data on adverse events. A random sample of 2,329 pregnant women and new mothers living in the study area were interviewed during home visits. At the time of the survey, the mean age of participants was 27.3 years, and 34.5% (804/2,329) were pregnant. The proportion of women who reported having attended fewer than 4 ANC visits did not differ significantly between the intervention and standard-of-care arms (59.1% versus 60.7%, respectively; risk ratio RR: 0.97; 95% CI: 0.82-1.15; p = 0.754). Similarly, the proportion reporting that they had attended ANC in the first trimester did not differ significantly between study arms. However, women in intervention wards were significantly less likely to report having delivered at home (3.9% versus 7.3%; RR: 0.54; 95% CI: 0.30-0.95; p = 0.034). Mixed-methods analyses of additional data collected as part of this trial suggest that an important reason for the lack of effect on ANC outcomes was the perceived high economic burden and inconvenience of attending ANC. The main limitations of this trial were that (i) the outcomes were ascertained through self-report, (ii) the study was stopped 4 months early due to a change in the standard of care in the other trial that was part of the 2-by-2 factorial design, and (iii) the sample size of the household survey was not prespecified.
A home-based CHW intervention in urban Tanzania significantly reduced the proportion of women who reported having delivered at home, in an area that already has very high uptake of facility-based delivery. The intervention did not affect self-reported ANC attendance. Policy makers should consider piloting, evaluating, and scaling interventions to lessen the economic burden and inconvenience of ANC.
ClinicalTrials.gov NCT01932138.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The high-latitude oceans are key areas of carbon and heat exchange between
the atmosphere and the ocean. As such, they are a focus of both modern
oceanographic and palaeoclimate research. However, ...most palaeoclimate
proxies that could provide a long-term perspective are based on calcareous
organisms, such as foraminifera, that are scarce or entirely absent in
deep-sea sediments south of 50∘ S in the Southern Ocean and north
of 40∘ N in the North Pacific. As a result, proxies need to be
developed for the opal-based organisms (e.g. diatoms) found at these high
latitudes, which dominate the biogenic sediments recovered from these
regions. Here we present a method for the analysis of the boron (B) content
and isotopic composition (δ11B) of diatom opal. We apply it for
the first time to evaluate the relationship between seawater pH, δ11B and B concentration (B) in the frustules of the diatom
Thalassiosira weissflogii, cultured across a range of carbon dioxide partial pressure (pCO2) and
pH values. In agreement with existing data, we find that the B
of the cultured diatom frustules increases with increasing pH (Mejía et al.,
2013). δ11B shows a relatively well defined negative trend with
increasing pH, completely distinct from any other biomineral previously
measured. This relationship not only has implications for the magnitude of
the isotopic fractionation that occurs during boron incorporation into opal,
but also allows us to explore the potential of the boron-based proxies for
palaeo-pH and palaeo-CO2 reconstruction in high-latitude marine
sediments that have, up until now, eluded study due to the lack of suitable
carbonate material.
Six ruminally cannulated steers (average BW = 791 ± 71 kg) were used in a replicated 3 × 3 Latin square experiment to determine the effects of roughage type on rumination, fiber mat characteristics, ...and rumen fermentation variables. Three roughages were included at 7% (DM basis) in a steam flaked corn-based diet: cotton burrs (CB), wheat silage (WS), or corn stalks (CS). Steers were fitted with a sensory collar to record rumination behaviors in 2-h intervals at the beginning of the experiment. Each 30-d period consisted of 7 d of recovery, 14 d of diet adaptation, 7 d of rumination data collection (daily and bi-hourly average rumination), 1 d of rumen fluid collection, and 1 d of rumen evacuations. In situ degradation of individual roughages was determined for 4 d after period 3 evacuations. During rumen evacuations, ruminal contents were removed; the rumen fiber mat (RF) was separated from the liquid portion with a 2-mm sieve, weighed, and a subsample was dried. Data were analyzed using the MIXED procedure of SAS with steer as the experimental unit and roughage (CB, WS, and CS) as the main effect. Dry matter intake (DMI) was not different for CB and WS (P = 0.25) and greatest for steers consuming CS diet (P ≤ 0.01). Roughage type did not influence the weight of the RF dry matter (%; DM; P = 0.92), RF weight (P = 0.69), or RF:DMI ratio (P = 0.29). Daily rumination (min/d) did not differ among roughages (P = 0.40), but min of rumination/kg of DMI was greatest for CS (18.0 min), min/kg of NDF was greatest for WS (89.8 min; P = 0.02), and min/kg of peNDF was greatest for CS (132.4 min; P ≤ 0.01). Wheat silage had the greatest percentage of soluble and degradable DM. Rumen fiber mat did not differ for roughages, although rumination min/kg of DMI and peNDF was greatest for steers consuming CS and WS. In situ degradation determined that CB-R and CS-R had the greatest percentage of ruminal undegraded DM. Based on the objective of the experiment, roughage type did not influence daily rumination or fiber mat characteristics.
Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced bronchoconstriction, remain ...poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for hyaluronan) or inter-α-trypsin inhibitor (molecule that facilitates hyaluronan binding) show similar elevations in hyaluronan but are protected from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan mediates ozone-induced AHR, which is dependent on the fragment size and both CD44 and inter-α-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Dysfunction of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunit and deficits in synaptic plasticity are implicated in schizophrenia and sleep and ...circadian rhythm disruption. To investigate the role of GluA1 in circadian and sleep behaviour, we used wheel-running, passive-infrared, and video-based home-cage activity monitoring to assess daily rest-activity profiles of GluA1-knockout mice (Gria1
). We showed that these mice displayed various circadian abnormalities, including misaligned, fragmented, and more variable rest-activity patterns. In addition, they showed heightened, but transient, behavioural arousal to light→dark and dark→light transitions, as well as attenuated nocturnal-light-induced activity suppression (negative masking). In the hypothalamic suprachiasmatic nuclei (SCN), nocturnal-light-induced cFos signals (a molecular marker of neuronal activity in the preceding ~1-2 h) were attenuated, indicating reduced light sensitivity in the SCN. However, there was no change in the neuroanatomical distribution of expression levels of two neuropeptides-vasoactive intestinal peptide (VIP) and arginine vasopressin (AVP)-differentially expressed in the core (ventromedial) vs. shell (dorsolateral) SCN subregions and both are known to be important for neuronal synchronisation within the SCN and circadian rhythmicity. In the motor cortex (area M1/M2), there was increased inter-individual variability in cFos levels during the evening period, mirroring the increased inter-individual variability in locomotor activity under nocturnal light. Finally, in the spontaneous odour recognition task GluA1 knockouts' short-term memory was impaired due to enhanced attention to the recently encountered familiar odour. These abnormalities due to altered AMPA-receptor-mediated signalling resemble and may contribute to sleep and circadian rhythm disruption and attentional deficits in different modalities in schizophrenia.
Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their ...underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
: Pharmacokinetic/pharmacodynamic (PK/PD) modelling can be used to characterize the relationship between dose regimen of opioids, plasma concentration and effect of opioids, which in turn can lead ...to more rational treatment regimens of pain. The aim of this study was to investigate the concentration–effect relationship for transdermal buprenorphine and fentanyl in experimentally induced pain. Twenty‐two healthy volunteers were randomized to receive transdermal patches with fentanyl (25 μg/hr, 72 hr), buprenorphine (20 μg/hr, 144 hr) or placebo. The experimental pain tests were pressure at the tibial bone, cutaneous thermal stimulation, cold pressor test (conditioning stimulus (3 ± 0.3°C cold water), nerve growth factor–induced muscle soreness and intradermal capsaicin‐induced hyperalgesia and allodynia. Experiments were carried out at baseline, 24, 48, 72 and 144 hr after application of patches. Time‐course of placebo was described first and was afterwards added to the description of the time‐courses of buprenorphine and fentanyl. This was either described by zero (no drug effect), linear or Emax model concentration–effect relationships. Time‐dependent changes in pain measures in the placebo arm were described by linear or quadratic functions. The time‐course of fentanyl and buprenorphine plasma concentrations was complex but could be represented by cubic spline interpolation in the models. Buprenorphine significantly attenuated bone‐associated pain, heat pain, nerve growth factor–induced soreness and cold pressor pain. Fentanyl significantly attenuated cold pressor pain for the administered dose regimens. Although the PK/PD relationship for both drugs could be described with similar models, tissue‐differentiated analgesic effects between buprenorphine and fentanyl was shown.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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