The molecular mechanisms involved in the aging of collagen and consequent increase in mechanical strength and stiffness occur in a series of enzymic and non‐enzymic intermolecular cross‐links. The ...enzymic mechanism involves divalent aldimine intermolecular cross‐links derived from the reaction of aldehydes which then mature to trivalent cross‐links and further stabilize the collagen fiber and is now well known. Recent studies have demonstrated that the rate of turnover and level of telopeptide lysyl hydroxylation modifies the nature of the cross‐link and hence the mechanical strength of the fiber.
The slow turnover of mature collagen subsequently allows accumulation of the products of the adventitious non‐enzymic reaction of glucose with the lysines in the triple helix to form glucosyl lysine and its Amadori product, that is, the Maillard reaction. These products are subsequently oxidized to a complex series of advanced glycation end‐products, some of which are intermolecular cross‐links between the triple helices rendering the fiber too stiff for optimal functioning of the collagen fibers, and consequently of the particular tissue involved. The glycation reactions following maturation are true aging processes, and attempts at their specific inhibition involve competitive inhibition of the Maillard reaction and chemical cleavage of the glycation cross‐links.
It is clear that the nature of the age‐related cross‐links and hence tissue strength depends on the rate of turnover of the collagen. An examination of the particular effect of strenuous exercise on the rate of turnover of collagen and hence cross‐linking in different tissues could lead to a better understanding of optimal sports training regimes.
Global climate change has increased flooding events, which affect both natural vegetation dynamics and crop productivity. The flooded environment is lethal for most plant species because it restricts ...gas exchange and induces an energy and carbon crisis. Flooding survival strategies have been studied in Oryza sativa, a cultivated monocot. However, our understanding of plant adaptation to natural flood-prone environments remains scant, even though wild plants represent a valuable resource of tolerance mechanisms that could be used to generate stress-tolerant crops. Here we identify mechanisms that mediate the distinct flooding survival strategies of two related wild dicot species: Rumex palustris and Rumex acetosa. Whole transcriptome sequencing and metabolite profiling reveal flooding-induced metabolic reprogramming specific to R. acetosa. By contrast, R. palustris uses the early flooding signal ethylene to increase survival by regulating shade avoidance and photomorphogenesis genes to outgrow submergence and by priming submerged plants for future low oxygen stress. These results provide molecular resolution of flooding survival strategies of two species occupying distinct hydrological niches. Learning how these contrasting flood adaptive strategies evolved in nature will be instrumental for the development of stress-tolerant crop varieties that deliver enhanced yields in a changing climate.
The aim of this work was to evaluate colorectal cancer (CRC) outcomes after 'low' (sub-threshold) faecal immunochemical test (FIT) results in symptomatic patients tested in primary care.
This work ...comprised a retrospective audit of 35 289 patients with FIT results who had consulted their general practitioner with lower gastrointestinal symptoms and had subsequent CRC diagnoses. The Rapid Colorectal Cancer Diagnosis pathway was introduced in November 2017 to allow incorporation of FIT into clinical practice. The local '4F' protocol combined FIT results with blood tests and digital rectal examination (DRE): FIT, full blood count, ferritin and finger DRE. The outcome used was detection rates of CRC, missed CRC and time to diagnosis in local 4F protocols for patients with a subthreshold faecal haemoglobin (fHb) result compared with thresholds of 10 and 20 μg Hb/g faeces.
A single threshold of 10 μg Hb/g faeces identifies a population in whom the risk of CRC is 0.2%, but this would have missed 63 (10.5%) of 599 CRCs in this population. The Nottingham 4F protocol would have missed fewer CRCs 42 of 599 (7%) despite using a threshold of 20 μg Hb/g faeces for patients with normal blood tests. Subthreshold FIT results in patients subsequently diagnosed with a palpable rectal tumour yielded the longest delays in diagnosis.
A combination of FIT with blood results and DRE (the 4F protocol) reduced the risk of missed or delayed diagnosis. Further studies on the impact of such protocols on the diagnostic accuracy of FIT are expected. The value of adding blood tests to FIT may be restricted to specific parts of the fHb results spectrum.
Dye-based protein determination assays are widely used to estimate protein concentration, however various reports suggest that the response is dependent on the composition and sequence of the ...protein, limiting confidence in the resulting concentration estimates. In this study a diverse set of model proteins representing various sizes of protein and covalent modifications, some typical of biopharmaceuticals have been used to assess the utility of dye-based protein concentration assays. The protein concentration assays (Bicinchoninic acid (BCA), Bradford, 3-(4-carboxybenzoyl)quinoline-2-carboxaldehyde (CBQCA), DC, Fluorescamine and Quant-i) were compared to the 'gold standard' assay, quantitative amino acid analysis (AAA). The assays that displayed the lowest variability between proteins, BCA and DC, also generated improved estimates when BSA was used as a standard, when compared to AAA derived concentrations. Assays read out by absorbance tended to display enhanced robustness and repeatability, whereas the fluorescence based assays had wider quantitation ranges and lower limits of detection. Protein modification, in the form of glycosylation and PEGylation, and the addition of excipients, were found to affect the estimation of protein concentration for some of the assays when compared to the unmodified protein. We discuss the suitability and limitations of the selected assays for the estimation of protein concentration in biopharmaceutical applications.
The general mechanism of chemical sensing is based on molecular recognition linked to different transduction strategies based on electrochemical, optical, gravimetric or thermal effects that can ...convert the signal to digital information. Electrochemical sensors support accurate, fast, and inexpensive analytical methods with the advantages of being easily embedded and integrated into electronics, and having the greatest potential impact in the areas of healthcare, environmental monitoring (e.g. electronic noses), food packaging and many other applications (E. Bakker and Y. Qin, Anal. Chem., 2006, 78, 3965). Nanoscale electrochemical biosensors offer a new scope and opportunity in analytical chemistry. The reduction in the size of electrochemical biosensors to nanoscale dimensions expands their analytical capability, allowing the exploration of nanoscopic domains, measurements of local concentration profiles, detection in microfluidic systems and in vivo monitoring of neurochemical events by detection of stimulated dopamine release (R. Kennedy, L. Huang, M. Atkinson and P. Dush, Anal. Chem., 1993, 65, 1882). This article reviews both state of art developments in electrochemical nanosensing, and the industrial outlook.
Background and methods: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4:1, suggesting ...that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs (ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. Results: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male–male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male–male and 74 male–female/female–female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male–female/female–female ASP (MLS = 2.62 v 0.00, for non-male and male–male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 (paternal MLS = 1.46 at ∼112 cM, and maternal MLS = 1.83 at ∼135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 (maternal MLS = 1.99 at ∼30 cM; paternal MLS = 0.02). Conclusion: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism.
Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from ...a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least partly genetic.
Ordinal genome-wide association study of suicidality in the UK Biobank cohort comparing: ‘no suicidality’ controls (N = 83,557); ‘thoughts that life was not worth living’ (N = 21,063); ‘ever contemplated self-harm’ (N = 13,038); ‘act of deliberate self-harm in the past’ (N = 2498); and ‘previous suicide attempt’ (N = 2666).
We identified three novel genome-wide significant loci for suicidality (on chromosomes nine, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81).
These findings provide new information about genetic variants relating to increased risk of suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level.
UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217). MRC Doctoral Training Programme Studentship at the University of Glasgow (MR/K501335/1). MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh. UKRI Innovation Fellowship (MR/R024774/1).
A
bstract
The
Neutrino Experiment with a Xenon TPC
(NEXT) searches for the neutrinoless double-beta (0
νββ
) decay of
136
Xe using high-pressure xenon gas TPCs with electroluminescent amplification. ...A scaled-up version of this technology with about 1 tonne of enriched xenon could reach in less than 5 years of operation a sensitivity to the half-life of 0
νββ
decay better than 10
27
years, improving the current limits by at least one order of magnitude. This prediction is based on a well-understood background model dominated by radiogenic sources. The detector concept presented here represents a first step on a compelling path towards sensitivity to the parameter space defined by the inverted ordering of neutrino masses, and beyond.
Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK ...Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h
SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.
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