Flux balance models of metabolism generally utilize synthesis of biomass as the main determinant of intracellular fluxes. However, the biomass constraint alone is not sufficient to predict realistic ...fluxes in central heterotrophic metabolism of plant cells because of the major demand on the energy budget due to transport costs and cell maintenance. This major limitation can be addressed by incorporating transport steps into the metabolic model and by implementing a procedure that uses Pareto optimality analysis to explore the trade‐off between ATP and NADPH production for maintenance. This leads to a method for predicting cell maintenance costs on the basis of the measured flux ratio between the oxidative steps of the oxidative pentose phosphate pathway and glycolysis. We show that accounting for transport and maintenance costs substantially improves the accuracy of fluxes predicted from a flux balance model of heterotrophic Arabidopsis cells in culture, irrespective of the objective function used in the analysis. Moreover, when the new method was applied to cells under control, elevated temperature and hyper‐osmotic conditions, only elevated temperature led to a substantial increase in cell maintenance costs. It is concluded that the hyper‐osmotic conditions tested did not impose a metabolic stress, in as much as the metabolic network is not forced to devote more resources to cell maintenance.
Spt5 is the only known RNA polymerase-associated factor that is conserved in all three domains of life. We have solved the structure of the Methanococcus jannaschii Spt4/5 complex by X-ray ...crystallography, and characterized its function and interaction with the archaeal RNAP in a wholly recombinant in vitro transcription system. Archaeal Spt4 and Spt5 form a stable complex that associates with RNAP independently of the DNA-RNA scaffold of the elongation complex. The association of Spt4/5 with RNAP results in a stimulation of transcription processivity, both in the absence and the presence of the non-template strand. A domain deletion analysis reveals the molecular anatomy of Spt4/5--the Spt5 Nus-G N-terminal (NGN) domain is the effector domain of the complex that both mediates the interaction with RNAP and is essential for its elongation activity. Using a mutagenesis approach, we have identified a hydrophobic pocket on the Spt5 NGN domain as binding site for RNAP, and reciprocally the RNAP clamp coiled-coil motif as binding site for Spt4/5.
Dysregulation of the striatum and altered corticostriatal connectivity have been associated with psychotic disorders. Social anhedonia has been identified as a predictor for the development of ...schizophrenia spectrum disorders. The aim of the present study was to examine corticostriatal functional connectivity in individuals with high social anhedonia.
Twenty-one participants with high social anhedonia score and 30 with low social anhedonia score measured by the Chinese version of the Revised Social Anhedonia Scale were recruited from university undergraduates (age 17-21 years) to undergo resting-state functional MRI scans. Six subdivisions of the striatum in each hemisphere were defined as seeds. Voxel-wise functional connectivity analyses were conducted between each seed and the whole brain voxels, followed by repeated-measures ANOVA for the group effect.
Participants with high social anhedonia showed hyper-connectivity between the ventral striatum and the anterior cingulate cortex and the insula, and between the dorsal striatum and the motor cortex. Hypo-connectivity in participants with high social anhedonia was also observed between the ventral striatum and the posterior cingulate cortex. Partial correlation analyses further showed that the functional connectivity between the ventral striatum and the prefrontal cortex was associated with pleasure experience and emotional suppression.
Our findings suggest that altered corticostriatal connectivity can be found in participants with high levels of social anhedonia. Since social anhedonia has been considered a predictor for schizophrenia spectrum disorders, our results may provide novel evidence on the early changes in brain functional connectivity in at-risk individuals.
Respiration is a major contributor to net exchange of CO2 between plants and the atmosphere and thus an important aspect of the vegetation component of global climate change models. However, a ...mechanistic model of respiration is lacking, and so here we explore the potential for flux balance analysis (FBA) to predict cellular CO2 evolution rates. Metabolic flux analysis reveals that respiration is not always the dominant source of CO2, and that metabolic processes such as the oxidative pentose phosphate pathway (OPPP) and lipid synthesis can be quantitatively important. Moreover, there is considerable variation in the metabolic origin of evolved CO2 between tissues, species and conditions. Comparison of FBA‐predicted CO2 evolution profiles with those determined from flux measurements reveals that FBA is able to predict the metabolic origin of evolved CO2 in different tissues/species and under different conditions. However, FBA is poor at predicting flux through certain metabolic processes such as the OPPP and we identify the way in which maintenance costs are accounted for as a major area of improvement for future FBA studies. We conclude that FBA, in its standard form, can be used to predict CO2 evolution in a range of plant tissues and in response to environment.
Although respiration is a major contributor to the net exchange of
CO
2
between plants and the atmosphere, it would be desirable to take a holistic view of the network when modelling the process and to consider all the potential contributors to light‐independent
CO
2
balance. We argue that flux balance analysis of genome‐scale metabolic models offers a practicable tool for predictive modelling of net
CO
2
evolution. This is supported by the encouraging agreement that has been found between the experimental results obtained by metabolic flux analysis and the predictions of flux balance analysis. While there is scope for further improvement, particularly in the way in which flux balance analysis handles cell maintenance costs, its power is already sufficient to make useful predictions about the impact of environmental factors on
CO
2
production by plant tissues.
Neurological soft signs (NSS) have long been considered potential endophenotypes for schizophrenia. However, few studies have investigated the heritability and familiality of NSS. The present study ...examined the heritability and familiality of NSS in healthy twins and patient-relative pairs.
The abridged version of the Cambridge Neurological Inventory was administered to 267 pairs of monozygotic twins, 124 pairs of dizygotic twins, and 75 pairs of patients with schizophrenia and their non-psychotic first-degree relatives.
NSS were found to have moderate but significant heritability in the healthy twin sample. Moreover, patients with schizophrenia correlated closely with their first-degree relatives on NSS.
Taken together, the findings provide evidence on the heritability and familiality of NSS in the Han Chinese population.
Background
There is increasing use of anti‐osteoporotic agents (AOA) worldwide for prevention or management of patients with osteoporosis. However, there have been reports of severe cutaneous adverse ...reactions (SCAR) induced by AOA. A recent study showed weak association between HLA and strontium ranelate (SR)‐SCAR.
Objective
To characterize patients with AOA‐SCAR and investigate the HLA association and utility of in vitro diagnostic methods.
Methods
We enrolled 16 cases with AOA‐cutaneous adverse drug reactions (cADR), including SCAR (n = 10: 8 with Stevens–Johnson syndrome SJS and 2 with drug rash with eosinophilia and systemic symptoms DRESS) and maculopapular exanthema (MPE) (n = 6) from Taiwan and Hong Kong. We analysed the clinical characteristics, outcomes, HLA alleles and in vitro testing of AOA‐SCAR, and tolerability to alternative drugs. We further performed literature review and meta‐analysis on the HLA association of AOA‐SCAR.
Results
Our data showed strontium ranelate is the most common causality of AOA‐SCAR in Asian populations. There was no cross‐hypersensitivity of SR‐SCAR with other AOA. HLA genotyping showed that SR‐SJS was most significantly associated with HLA‐A*33:03 (Pc = 5.17 × 10−3, OR: 25.97, 95% CI: 3.08–219.33). Meta‐analysis showed that HLA‐A*33:03 was associated with SR‐SJS (P = 5.01 × 10−5; sensitivity: 85.7%) in Asians. The sensitivity of lymphocyte activation test (LAT) for identifying the culprit drug of SR‐SJS was 83.3%.
Conclusions
Strontium ranelate is identified as the most notorious AOA associated with SCAR. The HLA‐A*33:03 genetic allele and LAT testing may add benefits to the diagnosis of SR‐SCAR in patients whose reaction developed while taking multiple drugs.
Linked Commentary: T. Shiohara. J Eur Acad Dermatol Venereol 2021; 35: 567‐568. https://doi.org/10.1111/jdv.17138.
This paper investigates the loss characteristics of RF magnetic materials for power conversion applications in the 10 to 100 MHz range. A measurement method is proposed that provides a direct ...measurement of an inductor quality factor QL as a function of inductor current at RF frequencies, and enables indirect calculation of core loss as a function of flux density. Possible sources of error in measurement and calculation are evaluated and addressed. The proposed method is used to identify loss characteristics of several commercial RF magnetic-core materials. The loss characteristics of these materials, which have not previously been available, are illustrated and compared in tables and figures. The use of the method and data is demonstrated in the design of a magnetic-core inductor, which is applied in a 30-MHz inverter. The results of this paper are thus useful for the design of magnetic components for very high frequency applications.
Aims
To examine all‐cause and cause‐specific mortality in a population‐based cohort of people with early and late onset of Type 1 diabetes.
Methods
The Yorkshire Register of Diabetes in Children and ...Young People includes individuals with early (0–14 years) and late (15–29 years) Type 1 diabetes onset, diagnosed between 1978 and 2013. This register was linked to death certification data from the Office for National Statistics to calculate standardized mortality ratios, cumulative mortality curves using Kaplan–Meier survival estimates, and Cox regression modelling. Ethnicity was derived using Onomap. Deprivation status was classified using the Townsend index. The underlying cause of death in each case was clinically verified.
Results
There were 229 deaths in 5498 individuals with 100 959 person‐years of follow‐up. The overall standardized mortality ratio was 4.3 (95% CI 3.8 to 4.9). There were no significant differences in standardized mortality ratios according to age of onset, sex or deprivation status. The standardized mortality ratios were significantly higher for people of white ethnic origin 8.1 (95% CI 6.9 to 9.4) than for those of South‐Asian ethnic origin 3.4 (95% CI 1.7 to 6.4). The mortality risk was lower in those diagnosed in later years (2002 to 2013 for the early‐onset and 2006 to 2013 for the late‐onset group) compared with earlier years (1991 to 1997 for the early‐onset and 1991 to 1997 for the late‐onset group) for both onset groups hazard ratio 0.13 (95% CI 0.05 to 0.33) vs 0.24 (95% CI 0.07 to 0.81). Mortality risk improved over time for chronic complications in the early‐onset group only, but there was no improvement in either onset group with regard to acute complications.
Conclusions
An excess of deaths in the population with Type 1 diabetes remains. Although the all‐cause mortality risk has fallen over time, no improvement has been found in the mortality risk associated with acute complications.
What's new?
Population‐based registers have shown decreasing mortality in early‐onset (age <15 years) Type 1 diabetes, but analysis of mortality in late‐onset (age 15–29 years) is lacking.
The Yorkshire Register of Diabetes in Children and Young People is the largest sub‐national population‐based dataset in the UK (5498 individuals with 100 959 person‐years of follow‐up). We found that all‐cause mortality had fallen over time, but there was no improvement in mortality rates for deaths attributable to acute complications for either onset group.
We highlight the importance of clinical verification of death certification data for accurate reporting of cause‐specific mortality.
Patients with schizophrenia have intact ability to experience emotion, but empirical evidence suggests that they fail to translate emotional salience into effortful behaviour. Previous research in ...patients with chronic schizophrenia suggests that working memory is important in integrating emotion and behaviour. This study aimed to examine avolition and anhedonia in patients with first-episode schizophrenia and clarify the role of working memory in emotion-behaviour coupling.
We recruited 72 participants with first-episode schizophrenia and 61 healthy controls, and used a validated emotion-inducing behavioural paradigm to measure participants' affective experiences and how experienced emotion coupled with behaviour. Participants were given the opportunity to expend effort to increase or decrease their exposure to emotion-inducing photographs. Participants with schizophrenia having poor working memory were compared with those with intact working memory in their liking and emotion-behaviour coupling.
Patients with first-episode schizophrenia experienced intact 'in-the-moment' emotion, but their emotion was less predictive of the effort expended, compared with controls. The emotion-behaviour coupling was significantly weaker in patients with schizophrenia with poor working memory than in those with intact working memory. However, compared with controls, patients with intact working also showed substantial emotion-behaviour decoupling.
Our findings provide strong evidence for emotion-behaviour decoupling in first-episode schizophrenia. Although working memory deficits contribute to defective translation of liking into effortful behaviour, schizophrenia alone affects emotion-behaviour coupling.
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