Multiple determinants of lifespan memory differences

Memory problems are among the most common complaints as people grow older. Using structural equation modeling of commensurate scores of anterograde memory from a large (N = 315), population-derived sample (www.cam-can.org), we provide evidence for three memory factors that are supported by distinct brain regions and show differential sensitivity to age. Associative memory and item memory are dramatically affected by age, even after adjusting for education level and fluid intelligence, whereas visual priming is not. Associative memory and item memory are differentially affected by emotional valence, and the age-related decline in associative memory is faster for negative than for positive or neutral stimuli. Gray-matter volume in the hippocampus, parahippocampus and fusiform cortex, and a white-matter index for the fornix, uncinate fasciculus and inferior longitudinal fasciculus, show differential contributions to the three memory factors. Together, these data demonstrate the extent to which differential ageing of the brain leads to differential patterns of memory loss

Evaluating Models of the Ageing BOLD Response

Neural activity cannot be directly observed using fMRI; rather it must be inferred from the hemodynamic responses that neural activity causes. Solving this inverse problem is made possible through the use of forward models, which generate predicted hemodynamic responses given hypothesised underlying neural activity. Commonly-used hemodynamic models were developed to explain data from healthy young participants; however, studies of ageing and dementia are increasingly shifting the focus toward elderly populations. We evaluated the validity of a range of hemodynamic models across the healthy adult lifespan: from basis sets for the linear convolution models commonly used to analyse fMRI studies, to more advanced models including nonlinear fitting of a parameterised hemodynamic response function (HRF) and nonlinear fitting of a biophysical generative model (hemodynamic modelling, HDM). Using an exceptionally large sample of participants, and a sensorimotor task optimized for detecting the shape of the BOLD response to brief stimulation, we first characterised the effects of age on descriptive features of the response (e.g., peak amplitude and latency). We then compared these to features from more complex nonlinear models, fit to four regions of interest engaged by the task, namely left auditory cortex, bilateral visual cortex, left (contralateral) motor cortex and right (ipsilateral) motor cortex. Finally, we validated the extent to which parameter estimates from these models have predictive validity, in terms of how well they predict age in cross-validated multiple regression. We conclude that age-related differences in the BOLD response can be captured effectively by models with three free parameters. Furthermore, we show that biophysical models like the HDM have predictive validity comparable to more common models, while additionally providing insights into underlying mechanisms, which go beyond descriptive features like peak amplitude or latency, and include estimation of nonlinear effects. Here, the HDM revealed that most of the effects of age on the BOLD response could be explained by an increased rate of vasoactive signal decay and decreased transit rate of blood, rather than changes in neural activity per se. However, in the absence of other types of neural/hemodynamic data, unique interpretation of HDM parameters is difficult from fMRI data alone, and some brain regions in some tasks (e.g., ipsilateral motor cortex) can show responses that are more difficult to capture using current models

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

The effect of condensable minor components on the gas separation performance of polymeric membranes for carbon dioxide capture

AbstractPolymeric membranes as a carbon dioxide capture technology have a number of advantages over other approaches, including their low cost, high performance separation, ease of synthesis, as well as mechanical and thermal stability. However, condensable components in flue gas, in particular water, undergo competitively adsorption with carbon dioxide within the membranes, resulting in a reduction in CO2 permeability. Furthermore, on a longer timescale plasticization of the membrane can occur, turning the glassy polymer to a more rubbery state, which alters both gas permeability and selectivity. Here, the impact of water on three glassy polymeric membranes are studied; polysulfone, Matrimid and 6FDA-TMPDA (a polyimide). The purpose of this work is to model the behavior of gas separation membranes under humid conditions that mimic real flue gas. This will assist in analyzing the performance of glassy gas separation membranes in planned CO2 capture trials on both pre- and post-combustion carbon capture.Upon exposure to water in the feed, all three membranes, Matrimid, polysulfone and 6FDA-TMPDA experience reduced CO2 permeability indicative of competitive adsorption. Over a longer timescale, both polysulfone and 6FDA-TMPDA recover some of the loss in permeability performance, due to plasticization by water. Matrimid displays no plasticization behavior

Desilication of concentrated alkali solution by novel desilication reagent calcium hydroferrocarbonate: Part III. Standard thermodynamics investigation of desilication reaction using hydroferrite desilication reagents

The property of lower soda and alumina contents of iron hydrogarnet can reduce the loss of soda and alumina in Bayer and Sub-molten salt process. Thus, the economic efficiency of alumina production could be improved. How to solve the effective formation of iron hydrogarnet in concentrated caustic aluminate solution and its cycle in the digestion process has become an important research topic. The base of hydroferrire desilication agents (calcium hydroferrite CHF, calcium hydroferrocarbonate CHFC, calcium hydroferrosulfate CHFS) were synthesized, the desilication experiments and desilication products (DSPs) were characterized, the results show that the hydroandradite and aluminum-hydroandradite are the main components in DSPs. The free energy of synthesis reaction of desilication agents and desilication reaction in concentrated caustic solution was investigated using the complex silicate theory. The investigation shows that CHFC has the better desilication performance for hydroferrite desilication agents. The free energy of desilication reaction in concentrated caustic solution using hydroandradite is affected by the initial silica coefficient, the reacted silica coefficient of DSPs, and the reaction temperature. From the point of view of thermodynamics, the substitution reaction between aluminum to iron that occurred in the concentrated caustic aluminosilicate solution main occurs when the higher initial silica coefficient of hydroandradite and the higher alumina coefficient of reaction product