The protozoan parasite Trypanosoma brucei has a complex digenetic lifecycle between a mammalian host and an insect vector, and adaption of its proteome between lifecycle stages is essential to its ...survival and virulence. We have optimized a procedure for growing Trypanosoma brucei procyclic form cells in conditions suitable for stable isotope labeling by amino acids in culture (SILAC) and report a comparative proteomic analysis of cultured procyclic form and bloodstream form T. brucei cells. In total we were able to identify 3959 proteins and quantify SILAC ratios for 3553 proteins with a false discovery rate of 0.01. A large number of proteins (10.6%) are differentially regulated by more the 5-fold between lifecycle stages, including those involved in the parasite surface coat, and in mitochondrial and glycosomal energy metabolism. Our proteomic data is broadly in agreement with transcriptomic studies, but with significantly larger fold changes observed at the protein level than at the mRNA level.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An enhancement in Brillouin light scattering of optical photons with magnons is demonstrated in magneto-optical whispering gallery mode resonators tuned to a triple-resonance point. This occurs when ...both the input and output optical modes are resonant with those of the whispering gallery resonator, with a separation given by the ferromagnetic resonance frequency. The identification and excitation of specific optical modes allows us to gain a clear understanding of the mode-matching conditions. A selection rule due to wave vector matching leads to an intrinsic single-sideband excitation. Strong suppression of one sideband is essential for one-to-one frequency mapping in coherent optical-to-microwave conversion.
Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ...'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Seagrass ecosystems are inherently dynamic, responding to environmental change across a range of scales. Habitat requirements of seagrass are well defined, but less is known about their ability to ...resist disturbance. Specific means of recovery after loss are particularly difficult to quantify. Here we assess the resistance and recovery capacity of 12 seagrass genera. We document four classic trajectories of degradation and recovery for seagrass ecosystems, illustrated with examples from around the world. Recovery can be rapid once conditions improve, but seagrass absence at landscape scales may persist for many decades, perpetuated by feedbacks and/or lack of seed or plant propagules to initiate recovery. It can be difficult to distinguish between slow recovery, recalcitrant degradation, and the need for a window of opportunity to trigger recovery. We propose a framework synthesizing how the spatial and temporal scales of both disturbance and seagrass response affect ecosystem trajectory and hence resilience.
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•Degradation of seagrass ecosystems can reverse rapidly when conditions improve.•In other cases, seagrass loss is recalcitrant, or persists for many decades.•Ecosystem trajectory depends on timescales of disturbance, resistance and recovery.•Resistance and recovery capacity are quantified and compared for 12 seagrass genera.
Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data ...connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment.
The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines.
Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy–treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated.
Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
Objective
To investigate whether people with subjective memory complaints (SMC) but no objective deficits are at increased risk of developing mild cognitive impairment (MCI) and dementia.
Method
...Major electronic databases were searched till 03/2014, and a meta‐analysis was conducted using inception cohort studies.
Results
Across 28 studies, there were 29 723 unique individuals (14 714 with SMC and 15 009 without SMC) (mean 71.6 years) followed on average for 4.8 years through to dementia. The annual conversion rate (ACR) of SMC to dementia was 2.33% (95% CI = 1.93%–2.78%) a relative risk (RR) of 2.07 (95% CI = 1.76–2.44) compared with those without SMC (n = 15 009). From 11 studies the ACR of developing MCI was 6.67% (95% CI = 4.70–8.95%). In long‐term studies over 4 years, 14.1% (9.67–19.1%) of people with SMC developed dementia and 26.6% (95% CI = 5.3–39.7) went on to develop MCI. The ACR from SMC to dementia and MCI were comparable in community and non‐community settings.
Conclusion
Older people with SMC but no objective complaints are twice as likely to develop dementia as individuals without SMC. Approximately 2.3% and 6.6% of older people with SMC will progress to dementia and MCI per year.
Altered glycosylation patterns of plasma proteins are associated with autoimmune disorders and pathogenesis of various cancers. Elucidating glycoprotein microheterogeneity and relating subtle changes ...in the glycan structural repertoire to changes in protein–protein, or protein–small molecule interactions, remains a significant challenge in glycobiology. Here, we apply mass spectrometry-based approaches to elucidate the global and site-specific microheterogeneity of two plasma proteins: α1-acid glycoprotein (AGP) and haptoglobin (Hp). We then determine the dissociation constants of the anticoagulant warfarin to different AGP glycoforms and reveal how subtle N-glycan differences, namely, increased antennae branching and terminal fucosylation, reduce drug-binding affinity. Conversely, similar analysis of the haptoglobin–hemoglobin (Hp–Hb) complex reveals the contrary effects of fucosylation and N-glycan branching on Hp–Hb interactions. Taken together, our results not only elucidate how glycoprotein microheterogeneity regulates protein–drug/protein interactions but also inform the pharmacokinetics of plasma proteins, many of which are drug targets, and whose glycosylation status changes in various disease states.
1. Environmental flows is now a widely accepted term that covers the quantity, timing, duration, frequency and quality of water flows required to sustain freshwater, estuarine and near-shore ...ecosystems and the human livelihoods and well-being that depend on them. 2. The Water Framework Directive (WFD) of the European Union does not use the term environmental flows explicitly, but requires member states to achieve good ecological status (GES) in all waterbodies, which is assessed by reference to aquatic biology. Nevertheless, it is accepted that ecologically appropriate hydrological regimes are necessary to meet this status. Implementing environmental flows will be a key measure for restoring and managing river ecosystems. 3. The WFD explicitly requires stakeholder involvement, but this has been interpreted as largely a dissemination exercise by national government agencies. Stakeholders are no longer involved in negotiation over ecological objectives as these are pre-set in the WFD. However, stakeholders may be more involved in reviewing standards and agreeing to measures to restore river ecosystems to the status required by the WFD. 4. The U.K. has undertaken two major projects to set environmental standards for water resources (i) to define water abstraction limits that maintain a healthy river ecosystem and (ii) to define ecologically appropriate flow releases from reservoirs. 5. Implementation of environmental flows remains a major issue, but new ideas such as time-limited licences and licence trading are being tried.
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