The cloning of the glutamate-gated ion channels of the brain revealed an unexpected level of complexity: there are many different genes that encode distinct subunits of the receptor/channel complex ...and an even larger number of possible receptor subunit combinations. Many—nearly all—of these gene products are expressed in the retina, and the questions that we face today are: how are they used and why are there so many? Answers to these questions will be found at several levels. At the level of transcription, we have learned that different sets of subunits are expressed by different retinal neurons. Little is known about the transcriptional control of these genes, so it remains to be determined whether these patterns of expression reflect the need for different gene products in different retinal neurons or whether these patterns of expression reflect the functional constraints of gene expression. Another level of complexity is caused by alternative splicing, and here we report that at least four and possibly all eight of the different NMDAR1 transcripts are present in the mouse retina. The consequences of this alternative splicing are poorly understood, but antibodies directed against the two different possible C-termini of NMDAR1 label many of the same cell types. It is possible that these different splice variants are combined to generate the channels. While immunohistochemistry provides us with a glimpse of the subunit proteins, much remains to be learned about their half-life within a retinal cell, their intracellular trafficking, their regulation at the synapse, and the proteins associated with their cytoplasmic domains. An approach we have taken towards studying the dynamic properties of receptor subunits has been to fuse them to the cDNA encoding the jellyfish Green Fluorescent Protein. This makes it possible to follow functional subunits in transfected cells over time and to begin to measure the mobility of the protein.
Reduced kidney function is related to brain atrophy and higher risk of dementia. It is not known whether kidney impairment is associated with higher levels of circulating amyloid-β and brain ...amyloid-β deposition, which could contribute to elevated risk of dementia.
To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition.
This cross-sectional study was performed within the community-based Atherosclerosis Risk in Communities (ARIC) Study cohort. We used estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C levels and urine albumin-to-creatinine ratio (ACR) to assess kidney function. Amyloid positivity was defined as a standardized uptake value ratios > 1.2 measured with florbetapir positron emission tomography (PET) (n = 340). Plasma amyloid-β1 - 40 and amyloid-β1 - 42 were measured using a fluorimetric bead-based immunoassay (n = 2,569).
Independent of demographic and cardiovascular risk factors, a doubling of ACR was associated with 1.10 (95% CI: 1.01,1.20) higher odds of brain amyloid positivity, but not eGFR (odds ratio per 15 ml/min/1.73 m2 lower eGFR: 1.08; 95% CI: 0.95,1.23). A doubling of ACR was associated with a higher level of plasma amyloid-β1 - 40 (standardized difference: 0.12; 95% CI: 0.09,0.14) and higher plasma amyloid-β1 - 42 (0.08; 95% CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-β1 - 40 (0.36; 95% CI: 0.33,0.39) and higher amyloid-β1 - 42 (0.32; 95% CI: 0.29,0.35).
Low clearance of amyloid-β and elevated brain amyloid positivity may link impaired kidney function with elevated risk of dementia. kidney function should be considered in interpreting amyloid biomarker results in clinical and research setting.
In spite of the remarkable success of current preventive efforts, periodontitis remains one of the most prevalent diseases of mankind. The objective of this workshop was to review critical scientific ...evidence and develop recommendations to improve: (i) plaque control at the individual and population level (oral hygiene), (ii) control of risk factors, and (iii) delivery of preventive professional interventions.
Discussions were informed by four systematic reviews covering aspects of professional mechanical plaque control, behavioural change interventions to improve self-performed oral hygiene and to control risk factors, and assessment of the risk profile of the individual patient. Recommendations were developed and graded using a modification of the GRADE system using evidence from the systematic reviews and expert opinion.
Key messages included: (i) an appropriate periodontal diagnosis is needed before submission of individuals to professional preventive measures and determines the selection of the type of preventive care; (ii) preventive measures are not sufficient for treatment of periodontitis; (iii) repeated and individualized oral hygiene instruction and professional mechanical plaque (and calculus) removal are important components of preventive programs; (iv) behavioural interventions to improve individual oral hygiene need to set specific Goals, incorporate Planning and Self monitoring (GPS approach); (v) brief interventions for risk factor control are key components of primary and secondary periodontal prevention; (vi) the Ask, Advise, Refer (AAR) approach is the minimum standard to be used in dental settings for all subjects consuming tobacco; (vii) validated periodontal risk assessment tools stratify patients in terms of risk of disease progression and tooth loss.
Consensus was reached on specific recommendations for the public, individual dental patients and oral health care professionals with regard to best action to improve efficacy of primary and secondary preventive measures. Some have implications for public health officials, payers and educators.
Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of ...metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR,
1
H NMR,
13
C NMR,
13
C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC
50
at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC
50
values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.
Communicated by Ramaswamy H. Sarma
Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity ...of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC.
We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU.
Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value PPV 19·7%, 95% CI 16·2–23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% 95% CI 77·9–82·0 vs 64·0% 61·4–66.4) while maintaining sensitivity (99·0% 94·4–100·0 vs 100·0% 96·3–100·0; PPV 19·7%, 16·3–23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6–41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2–84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4–100·0).
An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours.
European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.
It is increasingly recognised that collecting patient reported outcome measures (PROMs) data is an important part of healthcare and should be considered alongside traditional clinical assessments. As ...part of a more holistic view of healthcare provision, there has been an increased drive to implement PROM collection as part of routine clinical care in hepatology. This drive has resulted in an increase in the number of PROMs currently developed to be used in various liver conditions. However, the development and validation of a new PROM is time-consuming and costly. Therefore, before deciding to develop a new PROM, researchers should consider identifying existing PROMs to assess their appropriateness and, if necessary, make adaptations to existing PROMs to ensure their rigour when used with the target population. Little is written in the literature on how to identify and adapt the existing PROMs in hepatology. This article aims to provide a summary of the current literature and guidance regarding identifying and adapting existing PROMs in clinical practice.
A new family of cyclometallated gold(III) thiolato complexes based on pyrazine‐centred pincer ligands has been prepared, (C^Npz^C)AuSR, where C^Npz^C=2,6‐bis(4‐ButC6H4)pyrazine dianion and R=Ph (1), ...C6H4tBu‐4 (2), 2‐pyridyl (3), 1‐naphthyl (1‐Np, 4), 2‐Np (5), quinolinyl (Quin, 6), 4‐methylcoumarinyl (Coum, 7) and 1‐adamantyl (8). The complexes were isolated as yellow to red solids in high yields using mild synthetic conditions. The single‐crystal X‐ray structures revealed that the colour of the deep‐red solids is associated with the formation of a particular type of short (3.2–3.3 Å) intermolecular pyrazine⋅⋅⋅pyrazine π‐interactions. In some cases, yellow and red crystal polymorphs were formed; only the latter were emissive at room temperature. Combined NMR and UV/Vis techniques showed that the supramolecular π‐stacking interactions persist in solution and give rise to intense deep‐red photoluminescence. Monomeric molecules show vibronically structured green emissions at low temperature, assigned to ligand‐based 3IL(C^N^C) triplet emissions. By contrast, the unstructured red emissions correlate mainly with a 3LLCT(SR→{(C^Npz^C)2}) charge transfer transition from the thiolate ligand to the π⋅⋅⋅π dimerized pyrazine. Unusually, the π‐interactions can be influenced by sample treatment in solution, such that the emissions can switch reversibly from red to green. To our knowledge this is the first report of aggregation‐enhanced emission in gold(III) chemistry.
Gold(III) thiolates based on 2,6‐diarylpyrazine pincer ligands are a new class of luminescent gold compounds. Their photoemissions depend strongly on supramolecular interactions and involve a bimolecular emissive state.
Antarctic extreme events Siegert, Martin J.; Bentley, Mike J.; Atkinson, Angus ...
Frontiers in environmental science,
08/2023, Letnik:
11
Journal Article
Recenzirano
Odprti dostop
There is increasing evidence that fossil-fuel burning, and consequential global heating of 1.1°C to date, has led to the increased occurrence and severity of extreme environmental events. It is well ...documented how such events have impacted society outside Antarctica through enhanced levels of rainfall and flooding, heatwaves and wildfires, drought and water/food shortages and episodes of intense cooling. Here, we briefly examine evidence for extreme events in Antarctica and the Southern Ocean across a variety of environments and timescales. We show how vulnerable natural Antarctic systems are to extreme events and highlight how governance and environmental protection of the continent must take them into account. Given future additional heating of at least 0.4°C is now unavoidable (to contain heating to the “Paris Agreement 1.5°C” scenario), and may indeed be higher unless drastic action is successfully taken on reducing greenhouse gas emissions to net zero by mid-Century, we explain it is virtually certain that future Antarctic extreme events will be more pronounced than those observed to date.
Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with ...subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, 967 participants completed 14-day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with <100% AF during electrocardiographic monitoring) was associated with lower white matter fractional anisotropy (-0.25 SDs 95% CI, -0.44 to -0.07) and greater prevalence of microbleeds (prevalence ratio: 1.42 95% CI, 1.12-1.79). Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.
Despite its declining prevalence during the past few decades, tobacco use remains one of the most significant public health issues of the 1990s. Environmental and policy interventions are among the ...most cost-effective approaches to control tobacco use and prevent cardiovascular diseases. In this article, the authors review and offer to state and local health departments and other public health partners a summary of recommended policy and environmental interventions that have either reduced or show potential to reduce tobacco use. Priority recommendations include clean indoor air policies, restrictions on tobacco advertising and promotion, policies limiting youth access to tobacco, comprehensive school health programs, and excise taxes and other economic incentives. Many of these recommendations should be integrated with other health promotion interventions to also improve nutrition and physical activity. The authors also highlight several successful interventions and strategies used to establish policies at the state and local levels.
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