Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan

Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.

Persistence of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the androgen 17β-trenbolone.

The aim of the present study was to investigate the effects of the androgenic endocrine disruptor 17β-trenbolone on the sexual development of zebrafish (Danio rerio) with special emphasis on the question of whether adverse outcomes of developmental exposure are reversible or persistent. An exposure scenario including a recovery phase was chosen to assess the potential reversibility of androgenic effects. Zebrafish were exposed to environmentally relevant concentrations of 17β-trenbolone (1 ng/L-30 ng/L) from fertilization until completion of gonad sexual differentiation (60 d posthatch). Thereafter, exposure was either followed by 40 d of recovery in clean water or continued until 100 d posthatch, the age when zebrafish start being able to reproduce. Fish exposed for 100 d to 10 ng/L or 30 ng/L 17β-trenbolone were masculinized at different biological effect levels, as evidenced from a concentration-dependent shift of the sex ratio toward males as well as a significantly increased maturity of testes. Gonad morphological masculinization occurred in parallel with decreased vitellogenin concentrations in both sexes. Changes of brain aromatase (cyp19b) mRNA expression showed no consistent trend with respect to either exposure duration or concentration. Gonad morphological masculinization as well as the decrease of vitellogenin persisted after depuration over 40 d in clean water. This lack of recovery suggests that androgenic effects on sexual development of zebrafish are irreversible.

Reversibility of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the estrogen 17α-ethinylestradiol.

The aim of the present study was to investigate the persistence of the feminizing effects of discontinued 17α-ethinylestradiol (EE2) exposure on zebrafish (Danio rerio). An exposure scenario covering the sensitive phase of sexual differentiation, as well as final gonad maturation was chosen to examine the estrogenic effects on sexual development of zebrafish. Two exposure scenarios were compared: continuous exposure to environmentally relevant concentrations (0.1-10 ng/L EE2) up to 100 days post-hatch (dph) and developmental exposure up to 60 dph, followed by 40 days of depuration in clean water. The persistence of effects was investigated at different biological organization levels from mRNA to population-relevant endpoints to cover a broad range of important parameters. EE2 had a strong feminizing and inhibiting effect on the sexual development of zebrafish. Brain aromatase (cyp19b) mRNA expression showed no clear response, but vitellogenin levels were significantly elevated, gonad maturation and body growth were inhibited in both genders, and sex ratios were skewed towards females and undifferentiated individuals. To a large extent, all of these effects were reversed after 40 days of recovery, leading to the conclusion that exposure to the estrogen EE2 results in very strong, but reversible underdevelopment and feminization of zebrafish. The present study is the first to show this reversibility at different levels of organization, which gives better insight into the mechanistic basis of estrogenic effects in zebrafish.

Rivalry of homeostatic and sensory-evoked emotions: dehydration attenuates olfactory disgust and its neural correlates

Neural correlates have been described for emotions evoked by states of homeostatic imbalance (e.g. thirst, hunger, and breathlessness) and for emotions induced by external sensory stimulation (such as fear and disgust). However, the neurobiological mechanisms of their interaction, when they are experienced simultaneously, are still unknown. We investigated the interaction on the neurobiological and the perceptional level using subjective ratings, serum parameters, and functional magnetic resonance imaging (fMRI) in a situation of emotional rivalry, when both a homeostatic and a sensory-evoked emotion were experienced at the same time. Twenty highly dehydrated male subjects rated a disgusting odor as significantly less repulsive when they were thirsty. On the neurobiological level, we found that this reduction in subjective disgust during thirst was accompanied by a significantly reduced neural activity in the insular cortex, a brain area known to be considerably involved in processing of disgust. Furthermore, during the experience of disgust in the satiated condition, we observed a significant functional connectivity between brain areas responding to the disgusting odor, which was absent during the stimulation in the thirsty condition. These results suggest interference of conflicting emotions: An acute homeostatic imbalance can attenuate the experience of another emotion evoked by the sensory perception of a potentially harmful external agent. This finding offers novel insights with regard to the behavioral relevance of biologically different types of emotions, indicating that some types of emotions are more imperative for behavior than others. As a general principle, this modulatory effect during the conflict of homeostatic and sensory-evoked emotions may function to safeguard survival.

Measuring Intensity of End of Life Care: A Systematic Review.

BACKGROUND Many studies have measured the intensity of end of life care. However, no summary of the measures used in the field is currently available. OBJECTIVES To summarise features, characteristics of use and reported validity of measures used for evaluating intensity of end of life care. METHODS This was a systematic review according to PRISMA guidelines. We performed a comprehensive literature search in Ovid Medline, Embase, The Cochrane Library of Systematic Reviews and reference lists published between 1990-2014. Two reviewers independently screened titles, abstracts, full texts and extracted data. Studies were eligible if they used a measure of end of life care intensity, defined as all quantifiable measures describing the type and intensity of medical care administered during the last year of life. RESULTS A total of 58 of 1590 potentially eligible studies met our inclusion criteria and were included. The most commonly reported measures were hospitalizations (n = 44), intensive care unit admissions (n = 39) and chemotherapy use (n = 27). Studies measured intensity of care in different timeframes ranging from 48 hours to 12 months. The majority of studies were conducted in cancer patients (n = 31). Only 4 studies included information on validation of the measures used. None evaluated construct validity, while 3 studies considered criterion and 1 study reported both content and criterion validity. CONCLUSIONS This review provides a synthesis to aid in choosing intensity of end of life care measures based on their previous use but simultaneously highlights the crucial need for more validation studies and consensus in the field.

Dimensions of Global Change in African Mountains: The Example of Mount Kenya

This paper discusses the effects of global change in African mountains, with the example of Mount Kenya. The geographical focus is the northwestern, semi-arid foot zone of the mountain (Laikipia District). Over the past 50 years, this area has experienced rapid and profound transformation, the respective processes of which are all linked to global change. The main driving forces behind these processes have been political and economic in nature. To these an environmental change factor has been added in recent years – climate change. After introducing the area of research, the paper presents three dimensions of global change that are manifested in the region and largely shape its development: Socio-political change, economic change, environmental change. For the regions northwest of Mount Kenya, climate models predict important changes in rainfall distribution that will have a profound impact on freshwater availability and management. The results presented here are based on research undertaken northwest of Mount Kenya within the framework of a series of long-term Kenyan-Swiss research programmes that began in the early 1980s.

Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation

Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.

Depletion of regulatory T cells augments a vaccine-induced T effector cell response against the liver-stage of malaria but fails to increase memory

Regulatory T cells (T(reg)) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4(+)CD25(+) T(reg) were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3(+)CD25(-) T(reg). To obtain more insights in the specific function of T(reg) during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when T(reg) are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.

Reevaluation of the MASTER-2009 MLI and H-10 Debris Modeling

The current paper is an excerpt from the doctoral thesis ”Multi-Layer Insulation as Contribution to Orbital Debris”written at the Institute of Aerospace Systems of the Technische Universit ̈at of Braunschweig. The Multi-Layer In-sulation (MLI) population included in ESA’s MASTER-2009 (M eteoroid and Space-Debris Terrestrial Environment Reference) software is based on models for two mechanisms: One model simulates the release of MLI debris during fragmentation events while another estimates the continuo us release of larger MLI pieces due to aging related deterioration of the material. The aim of the thesis was to revise the MLI models from the base up followed by a re-validation of the simulated MLI debris population. The validation is based on comparison to measurement data of the GEO and GTO debris environment obtained by the Astronomical Institute of the University of Bern (AIUB) using ESA’s Space Debris Telescope (ESASDT), the 1-m Zeiss telescope located at the Optical Ground Station (OGS) at the Teide Observatory at Tenerife, Spain. The re-validation led to the conclusion that MLI may cover a much smaller portion of the observed objects than previously published. Further investigation of the resulting discrepancy revealed that the contribution of altogether nine known Ariane H-10 upper stage explosion events which occurred between 1984 and 2002 has very likely been underestimated in past simulations.

Home-based versus clinic-based specimen collection in the management of Chlamydia trachomatis and Neisseria gonorrhoeae infections

BACKGROUND Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are the most frequent causes of bacterial sexually transmitted infections (STIs). Management strategies that reduce losses in the clinical pathway from infection to cure might improve STI control and reduce complications resulting from lack of, or inadequate, treatment. OBJECTIVES To assess the effectiveness and safety of home-based specimen collection as part of the management strategy for Chlamydia trachomatis and Neisseria gonorrhoeae infections compared with clinic-based specimen collection in sexually-active people. SEARCH METHODS We searched the Cochrane Sexually Transmitted Infections Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS on 27 May 2015, together with the World Health Organization International Clinical Trials Registry (ICTRP) and ClinicalTrials.gov. We also handsearched conference proceedings, contacted trial authors and reviewed the reference lists of retrieved studies. SELECTION CRITERIA Randomized controlled trials (RCTs) of home-based compared with clinic-based specimen collection in the management of C. trachomatis and N. gonorrhoeae infections. DATA COLLECTION AND ANALYSIS Three review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We contacted study authors for additional information. We resolved any disagreements through consensus. We used standard methodological procedures recommended by Cochrane. The primary outcome was index case management, defined as the number of participants tested, diagnosed and treated, if test positive. MAIN RESULTS Ten trials involving 10,479 participants were included. There was inconclusive evidence of an effect on the proportion of participants with index case management (defined as individuals tested, diagnosed and treated for CT or NG, or both) in the group with home-based (45/778, 5.8%) compared with clinic-based (51/788, 6.5%) specimen collection (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.60 to 1.29; 3 trials, I² = 0%, 1566 participants, moderate quality). Harms of home-based specimen collection were not evaluated in any trial. All 10 trials compared the proportions of individuals tested. The results for the proportion of participants completing testing had high heterogeneity (I² = 100%) and were not pooled. We could not combine data from individual studies looking at the number of participants tested because the proportions varied widely across the studies, ranging from 30% to 96% in home group and 6% to 97% in clinic group (low-quality evidence). The number of participants with positive test was lower in the home-based specimen collection group (240/2074, 11.6%) compared with the clinic-based group (179/967, 18.5%) (RR 0.72, 95% CI 0.61 to 0.86; 9 trials, I² = 0%, 3041 participants, moderate quality). AUTHORS' CONCLUSIONS Home-based specimen collection could result in similar levels of index case management for CT or NG infection when compared with clinic-based specimen collection. Increases in the proportion of individuals tested as a result of home-based, compared with clinic-based, specimen collection are offset by a lower proportion of positive results. The harms of home-based specimen collection compared with clinic-based specimen collection have not been evaluated. Future RCTs to assess the effectiveness of home-based specimen collection should be designed to measure biological outcomes of STI case management, such as proportion of participants with negative tests for the relevant STI at follow-up.

Optimization of Optical Follow-up Strategies Based on Covariance Analysis

An in-depth study, using simulations and covariance analysis, is performed to identify the optimal sequence of observations to obtain the most accurate orbit propagation. The accuracy of the results of an orbit determination/ improvement process depends on: tracklet length, number of observations, type of orbit, astrometric error, time interval between tracklets and observation geometry. The latter depends on the position of the object along its orbit and the location of the observing station. This covariance analysis aims to optimize the observation strategy taking into account the influence of the orbit shape, of the relative object-observer geometry and the interval between observations.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy.

BACKGROUND Febrile neutropenia (FN) and other infectious complications are some of the most serious treatment-related toxicities of chemotherapy for cancer, with a mortality rate of 2% to 21%. The two main types of prophylactic regimens are granulocyte (macrophage) colony-stimulating factors (G(M)-CSF) and antibiotics, frequently quinolones or cotrimoxazole. Current guidelines recommend the use of colony-stimulating factors when the risk of febrile neutropenia is above 20%, but they do not mention the use of antibiotics. However, both regimens have been shown to reduce the incidence of infections. Since no systematic review has compared the two regimens, a systematic review was undertaken. OBJECTIVES To compare the efficacy and safety of G(M)-CSF compared to antibiotics in cancer patients receiving myelotoxic chemotherapy. SEARCH METHODS We searched The Cochrane Library, MEDLINE, EMBASE, databases of ongoing trials, and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 to December 2015). We planned to include both full-text and abstract publications. Two review authors independently screened search results. SELECTION CRITERIA We included randomised controlled trials (RCTs) comparing prophylaxis with G(M)-CSF versus antibiotics for the prevention of infection in cancer patients of all ages receiving chemotherapy. All study arms had to receive identical chemotherapy regimes and other supportive care. We included full-text, abstracts, and unpublished data if sufficient information on study design, participant characteristics, interventions and outcomes was available. We excluded cross-over trials, quasi-randomised trials and post-hoc retrospective trials. DATA COLLECTION AND ANALYSIS Two review authors independently screened the results of the search strategies, extracted data, assessed risk of bias, and analysed data according to standard Cochrane methods. We did final interpretation together with an experienced clinician. MAIN RESULTS In this updated review, we included no new randomised controlled trials. We included two trials in the review, one with 40 breast cancer patients receiving high-dose chemotherapy and G-CSF compared to antibiotics, a second one evaluating 155 patients with small-cell lung cancer receiving GM-CSF or antibiotics.We judge the overall risk of bias as high in the G-CSF trial, as neither patients nor physicians were blinded and not all included patients were analysed as randomised (7 out of 40 patients). We considered the overall risk of bias in the GM-CSF to be moderate, because of the risk of performance bias (neither patients nor personnel were blinded), but low risk of selection and attrition bias.For the trial comparing G-CSF to antibiotics, all cause mortality was not reported. There was no evidence of a difference for infection-related mortality, with zero events in each arm. Microbiologically or clinically documented infections, severe infections, quality of life, and adverse events were not reported. There was no evidence of a difference in frequency of febrile neutropenia (risk ratio (RR) 1.22; 95% confidence interval (CI) 0.53 to 2.84). The quality of the evidence for the two reported outcomes, infection-related mortality and frequency of febrile neutropenia, was very low, due to the low number of patients evaluated (high imprecision) and the high risk of bias.There was no evidence of a difference in terms of median survival time in the trial comparing GM-CSF and antibiotics. Two-year survival times were 6% (0 to 12%) in both arms (high imprecision, low quality of evidence). There were four toxic deaths in the GM-CSF arm and three in the antibiotics arm (3.8%), without evidence of a difference (RR 1.32; 95% CI 0.30 to 5.69; P = 0.71; low quality of evidence). There were 28% grade III or IV infections in the GM-CSF arm and 18% in the antibiotics arm, without any evidence of a difference (RR 1.55; 95% CI 0.86 to 2.80; P = 0.15, low quality of evidence). There were 5 episodes out of 360 cycles of grade IV infections in the GM-CSF arm and 3 episodes out of 334 cycles in the cotrimoxazole arm (0.8%), with no evidence of a difference (RR 1.55; 95% CI 0.37 to 6.42; P = 0.55; low quality of evidence). There was no significant difference between the two arms for non-haematological toxicities like diarrhoea, stomatitis, infections, neurologic, respiratory, or cardiac adverse events. Grade III and IV thrombopenia occurred significantly more frequently in the GM-CSF arm (60.8%) compared to the antibiotics arm (28.9%); (RR 2.10; 95% CI 1.41 to 3.12; P = 0.0002; low quality of evidence). Neither infection-related mortality, incidence of febrile neutropenia, nor quality of life were reported in this trial. AUTHORS' CONCLUSIONS As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Failure of fixed orthodontic retainers: A systematic review

OBJECTIVE To evaluate the risk of failure of fixed orthodontic retention protocols. DATA Screening for inclusion eligibility, quality assessment of studies and data extraction was performed independently by two authors. SOURCES The electronic databases MEDLINE, EMBASE and CENTRAL were searched with no restrictions on publication date or language using detailed strategies. The main outcome assessed was bond failure. STUDY SELECTION Twenty-seven studies satisfied the inclusion criteria. Randomised controlled trials and prospective studies were evaluated according to the Cochrane risk of bias tool. Retrospective studies were graded employing the predetermined criteria of Bondemark. RESULTS Nine randomised controlled trials, four of which were of low quality, were identified. Six studies had a prospective design and all were of low quality. Twelve studies were retrospective. The quality of trial reporting was poor in general. Four studies assessing glass-fibre retainers, three RCTs and one prospective, reported bond failures from 11 to 71%, whereas twenty studies evaluating multistranded retainers – nine RCTs, two prospective and nine retrospective – reported failures ranging from 12 to 50%. One comparison was performed, multistranded wires vs. polyehtylene woven ribbon (RR: 1.74; 95% CI: 0.45, 6.73; p=0.42). CONCLUSION The quality of the available evidence is low. No conclusive evidence was found in order to guide orthodontists in the selection of the best protocol. CLINICAL SIGNIFICANCE Although fixed orthodontic retainers have been used for years in clinical practice, the selection of the best treatment protocol still remains a subjective issue. The available studies, and their synthesis, cannot provide reliable evidence in this field.

An Assessment of the Risk of Bias in Randomized Controlled Trial Reports Published in Prosthodontic and Implant Dentistry Journals

PURPOSE The objective of this study was to assess the risk of bias of randomized controlled trials (RCTs) published in prosthodontic and implant dentistry journals. MATERIALS AND METHODS The last 30 issues of 9 journals in the field of prosthodontic and implant dentistry (Clinical Implant Dentistry and Related Research, Clinical Oral Implants Research, Implant Dentistry, International Journal of Oral & Maxillofacial Implants, International Journal of Periodontics and Restorative Dentistry, International Journal of Prosthodontics, Journal of Dentistry, Journal of Oral Rehabilitation, and Journal of Prosthetic Dentistry) were hand-searched for RCTs. Risk of bias was assessed using the Cochrane Collaboration's risk of bias tool and analyzed descriptively. RESULTS From the 3,667 articles screened, a total of 147 RCTs were identified and included. The number of published RCTs increased with time. The overall distribution of a high risk of bias assessment varied across the domains of the Cochrane risk of bias tool: 8% for random sequence generation, 18% for allocation concealment, 41% for masking, 47% for blinding of outcome assessment, 7% for incomplete outcome data, 12% for selective reporting, and 41% for other biases. CONCLUSION The distribution of high risk of bias for RCTs published in the selected prosthodontic and implant dentistry journals varied among journals and ranged from 8% to 47%, which can be considered as substantial.