Integrated multi‐omics analysis supports role of lysophosphatidylcholine and related glycerophospholipids in the Lotus japonicus–Glomus intraradices mycorrhizal symbiosis

Interaction of plant roots with arbuscular mycorrhizal fungi (AMF) is a complex trait resulting in cooperative interactions among the two symbionts including bidirectional exchange of resources. To study arbuscular mycorrhizal symbiosis (AMS) trait variation in the model plant Lotus japonicus, we performed an integrated multi‐omics analysis with a focus on plant and fungal phospholipid (PL) metabolism and biological significance of lysophosphatidylcholine (LPC). Our results support the role of LPC as a bioactive compound eliciting cellular and molecular response mechanisms in Lotus. Evidence is provided for large interspecific chemical diversity of LPC species among mycorrhizae with related AMF species. Lipid, gene expression and elemental profiling emphasize the Lotus–Glomus intraradices interaction as distinct from other arbuscular mycorrhizal (AM) interactions. In G. intraradices, genes involved in fatty acid (FA) elongation and biosynthesis of unsaturated FAs were enhanced, while in Lotus, FA synthesis genes were up‐regulated during AMS. Furthermore, FAS protein localization to mitochondria suggests FA biosynthesis and elongation may also occur in AMF. Our results suggest the existence of interspecific partitioning of PL resources for generation of LPC and novel candidate bioactive PLs in the Lotus–G. intraradices symbiosis. Moreover, the data advocate research with phylogenetically diverse Glomeromycota species for a broader understanding of the molecular underpinnings of AMS.     

NONSULFATED SULFAKININ CHANGES METABOLIC PARAMETERS OF INSECT FAT BODY MITOCHONDRIA

We investigated the effect of neuropeptide, the nonsulfated sulfakinin (SK) Zopat‐SK‐1 (pETSDDYGHLRFa) on the mitochondrial oxidative metabolism in the Zophobas atratus larval fat body. Mitochondria were isolated from beetle fat bodies 2 and 24 h after hormone injection. The administration of 20 pmol of Zopat‐SK‐1 to feeding larvae led to decreased mitochondrial oxidative activities in larval fat body. Diminished activities of citrate synthase and the cytochrome pathway, that is, nonphosphorylating and phosphorylating respiration during succinate oxidation, were observed. However, the effect of Zopat‐SK‐1 was more pronounced in fat body of insects after 24 h since hormone application. In hormone‐treated larval fat bodies, mitochondrial respiration was decreased at the level of respiratory chain and the TCA cycle as well as at the level of mitochondrial biogenesis, as indicated by decreased activities of mitochondrial marker enzymes in fat body homogenates. The inhibition of succinate oxidation may indicate the role of Zopat‐SK‐1 in the regulation of mitochondrial complex II activity. Moreover, decreased respiratory chain activity was accompanied by the reduced activity of mitochondrial energy‐dissipating pathway, uncoupling protein 4. The observed decrease in mitochondrial oxidative metabolism may reflect the Zopat‐SK‐1‐induced reduction in the metabolic rate of larval fat body linked to actual energetic demands of animal.     

The Oldest Cranium of <Emphasis Type="Italic">Sinomastodon</Emphasis> (Proboscidea,Gomphotheriidae), Discovered in the Uppermost Miocene of Southwestern China: Implications for the Origin and Migration of This Taxon

The origin of the Old World brevirostrine gomphotheriid taxon Sinomastodon has been debated intensively. The discovery of the oldest known Sinomastodon cranium, reported herein, supports its endemic origin and contradicts the prevalent theory of its North America origin. The new cranium was discovered from the Shuitangba locality, southwestern China, and is dated at about 6.5–6.0 Ma, corresponding to the latest Miocene. The new specimen shows distinct characters from the other species of Sinomastodon and was therefore named Sinomastodon praeintermedius, sp. nov. Newly discovered, isolated Sinomastodon-like teeth from the upper Miocene to the lower Pleistocene of southwestern China and Southeast Asia indicate a long evolution of Sinomastodon endemically. Remains of this species are frequently accompanied by those of stegodontid species. These two groups may have had a similar migration route, invading northern China and Japan during the latest Miocene, and retreating or becoming extinct from the Palearctic realm by the end of the Pliocene. The migrations of proboscideans may have been sparked by major paleoenviromental changes, i.e., the strengthened summer monsoon beginning in the late Miocene (~7–8 Ma) and global cooling due to the expansion of ice sheets from the middle Pliocene to the early Pleistocene. The new finding reveals a close relationship of the early Pliocene fauna of northern China and the latest Miocene fauna of southwestern China, and thus provides novel insight into the origin and components of Pliocene fauna in northern China.     

Implementing international osteoarthritis treatment guidelines in primary health care: study protocol for the SAMBA stepped wedge cluster randomized controlled trial

Background

Previous research indicates that people with osteoarthritis (OA) are not receiving the recommended and optimal treatment. Based on international treatment recommendations for hip and knee OA and previous research, the SAMBA model for integrated OA care in Norwegian primary health care has been developed. The model includes physiotherapist (PT) led patient OA education sessions and an exercise programme lasting 8–12 weeks. This study aims to assess the effectiveness, feasibility, and costs of a tailored strategy to implement the SAMBA model.

Methods/design

A cluster randomized controlled trial with stepped wedge design including an effect, process, and cost evaluation will be conducted in six municipalities (clusters) in Norway. The municipalities will be randomized for time of crossover from current usual care to the implementation of the SAMBA model by a tailored strategy. The tailored strategy includes interactive workshops for general practitioners (GPs) and PTs in primary care covering the SAMBA model for integrated OA care, educational material, educational outreach visits, feedback, and reminder material. Outcomes will be measured at the patient, GP, and PT levels using self-report, semi-structured interviews, and register based data. The primary outcome measure is patient-reported quality of care (OsteoArthritis Quality Indicator questionnaire) at 6-month follow-up. Secondary outcomes include referrals to PT, imaging, and referrals to the orthopaedic surgeon as well as participants’ treatment satisfaction, symptoms, physical activity level, body weight, and self-reported and measured lower limb function. The actual exposure to the tailor made implementation strategy and user experiences will be measured in a process evaluation. In the economic evaluation, the difference in costs of usual OA care and the SAMBA model for integrated OA care will be compared with the difference in health outcomes and reported by the incremental cost-effectiveness ratio (ICER).

Discussion

The results from the present study will add to the current knowledge on tailored strategies, which aims to improve the uptake of evidence-based OA care recommendations and improve the quality of OA care in primary health care. The new knowledge can be used in national and international initiatives designed to improve the quality of OA care.

Trial registration

ClinicalTrials.gov NCT02333656

     

Dynamics of Urinary Calprotectin after Renal Ischaemia

Background: Urinary calprotectin has been identified as a promising biomarker for acute kidney injury. To date, however, the time-dependent changes of this parameter during acute kidney injury remain elusive. The aim of the present work was to define the time-course of urinary calprotectin secretion after ischaemia/reperfusion-induced kidney injury in comparison to neutrophil gelatinase—associated lipocalin, thereby monitoring the extent of tubular damage in nephron sparing surgery for kidney tumours. Methods: The study population consisted of 42 patients. Thirty-two patients underwent either open or endoscopic nephron sparing surgery for kidney tumours. During the surgery, the renal arterial pedicle was clamped with a median ischaemic time of 13 minutes (interquartile range, 4.5–20.3 minutes) in 26 patients. Ten retro-peritoneoscopic living donor nephrectomy patients and 6 nephron sparing surgery patients in whom the renal artery was not clamped served as controls. Urinary calprotectin and neutrophil gelatinase—associated lipocalin concentrations were repeatedly measured by enzyme-linked immunosorbent assay and assessed according to renal function parameters. Results: Urinary concentrations of calprotectin and neutrophil gelatinase—associated lipocalin increased significantly after ischaemia/reperfusion injury, whereas concentrations remained unchanged after nephron sparing surgery without ischaemia/reperfusion injury and after kidney donation. Calprotectin and neutrophil gelatinase—associated lipocalin levels were significantly increased 2 and 8 hours, respectively, post-ischaemia. Both proteins reached maximal concentrations after 48 hours, followed by a subsequent persistent decrease. Maximal neutrophil gelatinase—associated lipocalin and calprotectin concentrations were 9-fold and 69-fold higher than their respective baseline values. The glomerular filtration rate was only transiently impaired at the first post-operative day after ischaemia/reperfusion injury (p = 0.049). Conclusion: Calprotectin and neutrophil gelatinase—associated lipocalin can be used to monitor clinical and sub-clinical tubular damage after nephron sparing surgery for kidney tumours. Urinary calprotectin concentrations start rising within 2 hours after ischaemia/reperfusion-induced kidney injury.     

The epigenetics of CHARGE syndrome

In biology, we continue to appreciate the fact that the DNA sequence alone falls short when attempting to explain the intricate inheritance patterns for complex traits. This is particularly true for human disorders that appear to have simple genetic causes. The study of epigenetics, and the increased access to the epigenetic profiles of different tissues has begun to shed light on the genetic complexity of many basic biological processes, both physiological and pathological. Epigenetics refers to heritable changes in gene expression that are not due to alterations in the DNA sequence. Various mechanisms of epigenetic regulation exist, including DNA methylation and histone modification. The identification, and increased understanding of key players and mechanisms of epigenetic regulation have begun to provide significant insight into the underlying origins of various human genetic disorders. One such disorder is CHARGE syndrome (OMIM #214800), which is a leading cause of deaf-blindness worldwide. A majority of CHARGE syndrome cases are caused by haploinsufficiency for the CHD7 gene, which encodes an ATP-dependent chromatin remodeling protein involved in the epigenetic regulation of gene expression. The CHD7 protein has been highly conserved throughout evolution, and research into the function of CHD7 homologs in multiple model systems has increased our understanding of this family of proteins, and epigenetic mechanisms in general. Here we provide a review of CHARGE syndrome, and discuss the epigenetic functions of CHD7 in humans and CHD7 homologs in model organisms.     

Family psychoeducation for major depressive disorder – study protocol for a randomized controlled trial

BackgroundMajor depressive disorder has been shown to affect many domains of family life including family functioning. Conversely, the influence of the family on the course of the depression, including the risk of relapse, is one reason for targeting the family in interventions. The few studies conducted within this area indicate that family psychoeducation as a supplement to traditional treatment can effectively reduce the risk of relapse in patients with major depression as well as being beneficial for the relatives involved. However, the evidence is currently limited. This study will investigate the effect of family psychoeducation compared to social support on the course of the illness in patients with major depressive disorder.Method/designThe study is designed as a dual center, two-armed, observer-blinded, randomized controlled trial. Relatives are randomized to participate in one of two conditions: either four sessions of manualized family psychoeducation or four sessions in a social support group led by a health care professional. Patients will not participate in the groups and will continue their treatment as usual. A total of 100 patients, each accompanied by one relative, will be recruited primarily from two outpatient clinics in the Capital Region of Denmark.The primary outcome is the occurrence of depressive relapse at 9-month follow-up defined as a score ≥7 on the Hamilton six-item subscale. Secondary outcomes will include time to relapse.DiscussionIt is hoped that the results from this study will help to clarify the mechanisms behind any beneficial changes due to family psychoeducation and provide information on the long-term effect of this intervention for both patient and relatives. If the results are positive, the family psychoeducation program may be suitable for implementation within a clinical setting.

Trial registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02348827","term_id":"NCT02348827"}}NCT02348827, registered 5 January 2015.     

Variable Temperature Stress in the Nematode Caenorhabditis elegans (Maupas) and Its Implications for Sensitivity to an Additional Chemical Stressor

A wealth of studies has investigated how chemical sensitivity is affected by temperature, however, almost always under different constant rather than more realistic fluctuating regimes. Here we compared how the nematode Caenorhabditis elegans responds to copper at constant temperatures (8–24°C) and under fluctuation conditions of low (±4°C) and high (±8°C) amplitude (averages of 12, 16, 20°C and 16°C respectively). The DEBkiss model was used to interpret effects on energy budgets. Increasing constant temperature from 12–24°C reduced time to first egg, life-span and population growth rates consistent with temperature driven metabolic rate change. Responses at 8°C did not, however, accord with this pattern (including a deviation from the Temperature Size Rule), identifying a cold stress effect. High amplitude variation and low amplitude variation around a mean temperature of 12°C impacted reproduction and body size compared to nematodes kept at the matching average constant temperatures. Copper exposure affected reproduction, body size and life-span and consequently population growth. Sensitivity to copper (EC₅₀ values), was similar at intermediate temperatures (12, 16, 20°C) and higher at 24°C and especially the innately stressful 8°C condition. Temperature variation did not increase copper sensitivity. Indeed under variable conditions including time at the stressful 8°C condition, sensitivity was reduced. DEBkiss identified increased maintenance costs and increased assimilation as possible mechanisms for cold and higher copper concentration effects. Model analysis of combined variable temperature effects, however, demonstrated no additional joint stressor response. Hence, concerns that exposure to temperature fluctuations may sensitise species to co-stressor effects seem unfounded in this case.     

Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development: Results from the Danish Calmette Study - A Randomised Clinical Trial

ObjectivesTo assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development.DesignThis is a pre-specified secondary outcome from a randomised, clinical trial.SettingMaternity units and paediatric wards at three university hospitals in Denmark.ParticipantsChildren born at gestational age (GA) 32 weeks and above. All women planning to give birth at the three sites were invited during the recruitment period. Out of 4262 randomised children, 144 were premature (GA < 37 weeks). There were 2129 children (71 premature) randomised to BCG and 2133 randomised (73 premature) to the control group.InterventionsBCG vaccination 0.05 ml was given intradermally in the upper left arm at the hospital within seven days of birth. Children in the control group did not receive any intervention. Parents were not blinded to allocation.ResultsThe mean difference in ASQ score at 12 months adjusted for age and prematurity was -0.7 points (BCG vs. control, 95% confidence interval; -3.7 to 2.4), p = 0.67, corresponding to an effect size of Cohen’s d = -0.015 (-0.082 to 0.052). The mean difference in ASQ score for premature children at 22 months was -7.8 points (-20.6 to 5.0, p = 0.23), d = -0.23 (-0.62 to 0.15).ConclusionsA negative non-specific effect of BCG vaccination at birth on psychomotor development was excluded in term children.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01694108","term_id":"NCT01694108"}}NCT01694108     

Inter-Fraction Tumor Volume Response during Lung Stereotactic Body Radiation Therapy Correlated to Patient Variables

PurposeAnalyze inter-fraction volumetric changes of lung tumors treated with stereotactic body radiation therapy (SBRT) and determine if the volume changes during treatment can be predicted and thus considered in treatment planning.ResultsAll tumors studied experienced volume change during treatment. Tumor increased in volume by an average of 15% and regressed by an average of 11%. The overall volume increase during treatment is contained within the planning target volume (PTV) for all tumors. Larger tumors increased in volume more than smaller tumors during treatment (q = 0.0029). The volume increase on CBCT was correlated to the treatment planning gross target volume (GTV) as well as internal target volumes (ITV) (q = 0.0085 and q = 0.0039 respectively) and could be predicted for tumors with a GTV less than 22 mL. The volume increase was correlated to the integral dose (ID) in the ITV at every fraction (q = 0.0049). The peak inter-fraction volume occurred at an earlier fraction in younger patients (q = 0.0122).ConclusionsWe introduced a new analysis method to follow inter-fraction tumor volume changes and determined that the observed changes during lung SBRT treatment are correlated to the initial tumor volume, integral dose (ID), and patient age. Furthermore, the volume increase during treatment of tumors less than 22mL can be predicted during treatment planning. The volume increase remained significantly less than the overall PTV expansion, and radiation re-planning was therefore not required for the purpose of tumor control. The presence of the studied correlations suggests that the observed volumetric changes may reflect some underlying biologic process rather than random fluctuations.