Investigating the causes and consequences of intraspecific trait variation (ITV) in plants is not novel, as it has long been recognized that such variation shapes biotic and abiotic interactions. ...While evolutionary and population biology have extensively investigated ITV, only in the last 10 years has interest in ITV surged within community and comparative ecology.
Despite this recent interest, still lacking are thorough descriptions of ITV's extent, the spatial and temporal structure of ITV, and stronger connections between ITV and community and ecosystem properties. Our primary aim in this review is to synthesize the recent literature and ask: (1) How extensive is intraspecific variation in traits across scales, and what underlying mechanisms drive this variation? (2) How does this variation impact higher-order ecological processes (e.g. population dynamics, community assembly, invasion, ecosystem productivity)? (3) What are the consequences of ignoring ITV and how can these be mitigated? and (4) What are the most pressing research questions, and how can current practices be modified to suit our research needs? Our secondary aim is to target diverse and underrepresented traits and plant organs, including anatomy, wood, roots, hydraulics, reproduction and secondary chemistry. In addressing these aims, we showcase papers from the Special Issue.
Plant ITV plays a key role in determining individual and population performance, species interactions, community structure and assembly, and ecosystem properties. Its extent varies widely across species, traits and environments, and it remains difficult to develop a predictive model for ITV that is broadly applicable. Systematically characterizing the sources (e.g. ontogeny, population differences) of ITV will be a vital step forward towards identifying generalities and the underlying mechanisms that shape ITV. While the use of species means to link traits to higher-order processes may be appropriate in many cases, such approaches can obscure potentially meaningful variation. We urge the reporting of individual replicates and population means in online data repositories, a greater consideration of the mechanisms that enhance and constrain ITV's extent, and studies that span sub-disciplines.
The descent of the westerly phase of the quasi‐biennial oscillation (QBO) in equatorial stratospheric zonal wind was interrupted by the development of easterlies near 40 hPa (~23 km altitude) in ...early 2016. We use tropical meteorological analyses of wind and temperature to describe in detail the special circumstances by which equatorward‐propagating planetary waves produced this unprecedented disruption in the QBO. Our findings show that the subtropical easterly jet in the winter lower stratosphere during the 2015–2016 winter was anomalously weak owing to (1) the timing of the QBO relative to the annual cycle and (2) an extreme El Niño event. The weak jet allowed an unusually large flux of westward momentum to propagate from the extratropical Northern Hemisphere to the equator near the 40 hPa level. Consequently, the QBO westerlies at that level experienced sustained easterly acceleration from extratropical wave breaking, leading to the observed wind reversal.
Key Points
The disruption of the quasi‐biennial oscillation in early 2016 was caused by extratropical Rossby wave breaking
Stratospheric subtropical easterlies were anomalously weak due to combined effects from an extreme El Niño and annual variability
Westerlies in the Northern Hemisphere subtropics allowed Rossby waves to propagate from the midlatitudes to the equator and break there
A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal ...cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging (MRI) to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine-induced increase in hippocampal Glx (glutamate+glutamine; F=3.76; P=0.04), a decrease in fronto-temporal (t=4.92, P
<0.05, k
=2198, x=-30, y=52, z=14) and temporo-parietal functional connectivity (t=5.07, P
<0.05, k
=6094, x=-28, y=-36, z=-2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting-state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.
To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth.
Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, ...the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion.
Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness.
Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance.
For primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.
Mechanisms that control the activation of antigen-specific immune responses in vivo are poorly understood. It has been suggested that the initiation of adaptive immune responses is controlled by ...innate immune recognition. Mammalian Toll-like receptors play an essential role in innate immunity by recognizing conserved pathogen-associated molecular patterns and initiating the activation of NF-kappaB and other signaling pathways through the adapter protein, MyD88. Here we show that MyD88-deficient mice have a profound defect in the activation of antigen-specific T helper type 1 (TH1) but not TH2 immune responses. These results suggest that distinct pathways of the innate immune system control activation of the two effector arms of adaptive immunity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glioblastoma multiforme (GBM) is a particularly aggressive brain tumor and remains a clinically devastating disease. Despite innovative therapies for the treatment of GBM, there has been no ...significant increase in patient survival over the past decade. Enzymes that control epigenetic alterations are of considerable interest as targets for cancer therapy because of their critical roles in cellular processes that lead to oncogenesis. Several inhibitors of histone deacetylases (HDACs) have been developed and tested in GBM with moderate success. We found that treatment of GBM cells with HDAC inhibitors caused the accumulation of histone methylation, a modification removed by the lysine specific demethylase 1 (LSD1). This led us to examine the effects of simultaneously inhibiting HDACs and LSD1 as a potential combination therapy. We evaluated induction of apoptosis in GBM cell lines after combined inhibition of LSD1 and HDACs. LSD1 was inhibited by targeted short hairpin RNA or pharmacological means and inhibition of HDACs was achieved by treatment with either vorinostat or PCI-24781. Caspase-dependent apoptosis was significantly increased (>2-fold) in LSD1-knockdown GBM cells treated with HDAC inhibitors. Moreover, pharmacologically inhibiting LSD1 with the monoamine oxidase inhibitor tranylcypromine, in combination with HDAC inhibitors, led to synergistic apoptotic cell death in GBM cells; this did not occur in normal human astrocytes. Taken together, these results indicate that LSD1 and HDACs cooperate to regulate key pathways of cell death in GBM cell lines but not in normal counterparts, and they validate the combined use of LSD1 and HDAC inhibitors as a therapeutic approach for GBM.
The aim of this study was to establish the relative safety and balance of risks for antidepressant treatment in older people. The study objectives were to (1) determine relative and absolute risks of ...predefined adverse events in older people with depression, comparing classes of antidepressant drugs tricyclic and related antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other antidepressants and commonly prescribed individual drugs with non-use of antidepressant drugs; (2) directly compare the risk of adverse events for SSRIs with TCAs; (3) determine associations with dose and duration of antidepressant medication; (4) describe patterns of antidepressant use in older people with depression; and (5) estimate costs of antidepressant medication and primary care visits.
A cohort study of patients aged 65 years and over diagnosed with depression.
The study was based in 570 general practices in the UK supplying data to the QResearch database.
Patients diagnosed with a new episode of depression between the ages of 65 and 100 years, from 1 January 1996 to 31 December 2007. Participants were followed up until 31 December 2008.
The exposure of interest was treatment with antidepressant medication. Antidepressant drugs were grouped into the major classes and commonly prescribed individual drugs were identified.
There were 13 predefined outcome measures: all-cause mortality, sudden cardiac death, suicide, attempted suicide/self-harm, myocardial infarction, stroke/transient ischaemic attack (TIA), falls, fractures, upper gastrointestinal bleeding, epilepsy/seizures, road traffic accidents, adverse drug reactions and hyponatraemia.
In total, 60,746 patients were included in the study cohort. Of these, 54,038 (89.0%) received at least one prescription for an antidepressant during follow-up. The associations with the adverse outcomes were significantly different between the classes of antidepressant drugs for seven outcomes. SSRIs were associated with the highest adjusted hazard ratios (HRs) for falls 1.66, 95% confidence interval (CI) 1.58 to 1.73 and hyponatraemia (1.52, 95% CI 1.33 to 1.75), and the group of other antidepressants was associated with the highest HRs for all-cause mortality (1.66, 95% CI 1.56 to 1.77), attempted suicide/self-harm (5.16, 95% CI 3.90 to 6.83), stroke/TIA (1.37, 95% CI 1.22 to 1.55), fracture (1.63, 95% CI 1.45 to 1.83) and epilepsy/seizures (2.24, 95% CI 1.60 to 3.15) compared with when antidepressants were not being used. TCAs did not have the highest HR for any of the outcomes. There were also significantly different associations between the individual drugs for seven outcomes, with trazodone, mirtazapine and venlafaxine associated with the highest rates for several of these outcomes. The mean incremental cost (for all antidepressant prescriptions) ranged between £51.58 (amitriptyline) and £641.18 (venlafaxine) over the 5-year post-diagnosis period.
This study found associations between use of antidepressant drugs and a number of adverse events in older people. There was no evidence that SSRIs or drugs in the group of other antidepressants were associated with a reduced risk of any of the adverse outcomes compared with TCAs; however, they may be associated with an increased risk for certain outcomes. Among individual drugs trazodone, mirtazapine and venlafaxine were associated with the highest rates for some outcomes. Indication bias and residual confounding may explain some of the study findings. The risks of prescribing antidepressants need to be weighed against the potential benefits of these drugs.
The National Institute for Health Research Health Technology Assessment programme.
Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction.
The purpose of this ...study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification.
Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years).
In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005).
Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine.
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