DNA is subject to many endogenous and exogenous insults that impair DNA replication and proper chromosome segregation. DNA double-strand breaks (DSBs) are one of the most toxic of these lesions and ...must be repaired to preserve chromosomal integrity. Eukaryotes are equipped with several different, but related, repair mechanisms involving homologous recombination, including single-strand annealing, gene conversion, and break-induced replication. In this review, we highlight the chief sources of DSBs and crucial requirements for each of these repair processes, as well as the methods to identify and study intermediate steps in DSB repair by homologous recombination.
Theoretical accounts suggest heightened uncertainty about the state of the world underpin aberrant belief updates, which in turn increase the risk of developing a persecutory delusion. However, this ...raises the question as to how an agent’s uncertainty may relate to the precise phenomenology of paranoia, as opposed to other qualitatively different forms of belief. We tested whether the same population (n = 693) responded similarly to non-social and social contingency changes in a probabilistic reversal learning task and a modified repeated reversal Dictator game, and the impact of paranoia on both. We fitted computational models that included closely related parameters that quantified the rigidity across contingency reversals and the uncertainty about the environment/partner. Consistent with prior work we show that paranoia was associated with uncertainty around a partner’s behavioural policy and rigidity in harmful intent attributions in the social task. In the non-social task we found that pre-existing paranoia was associated with larger decision temperatures and commitment to suboptimal cards. We show relationships between decision temperature in the non-social task and priors over harmful intent attributions and uncertainty over beliefs about partners in the social task. Our results converge across both classes of model, suggesting paranoia is associated with a general uncertainty over the state of the world (and agents within it) that takes longer to resolve, although we demonstrate that this uncertainty is expressed asymmetrically in social contexts. Our model and data allow the representation of sociocognitive mechanisms that explain persecutory delusions and provide testable, phenomenologically relevant predictions for causal experiments.
Convection-Enhanced Delivery Mehta, A. M.; Sonabend, A. M.; Bruce, J. N.
Neurotherapeutics,
04/2017, Volume:
14, Issue:
2
Journal Article, Book Review
Peer reviewed
Open access
Convection-enhanced delivery (CED) is a promising technique that generates a pressure gradient at the tip of an infusion catheter to deliver therapeutics directly through the interstitial spaces of ...the central nervous system. It addresses and offers solutions to many limitations of conventional techniques, allowing for delivery past the blood–brain barrier in a targeted and safe manner that can achieve therapeutic drug concentrations. CED is a broadly applicable technique that can be used to deliver a variety of therapeutic compounds for a diversity of diseases, including malignant gliomas, Parkinson’s disease, and Alzheimer’s disease. While a number of technological advances have been made since its development in the early 1990s, clinical trials with CED have been largely unsuccessful, and have illuminated a number of parameters that still need to be addressed for successful clinical application. This review addresses the physical principles behind CED, limitations in the technique, as well as means to overcome these limitations, clinical trials that have been performed, and future developments.
We search for signatures of gravitational lensing in the binary black hole events detected by Advanced LIGO and Virgo during their first two observational runs. In particular, we look for three ...effects: (1) evidence of lensing magnification in the individual signals due to galaxy lenses, (2) evidence of multiple images due to strong lensing by galaxies, and (3) evidence of wave optics effects due to point-mass lens. We find no compelling evidence of any of these signatures in the observed gravitational wave signals. However, as the sensitivities of gravitational wave detectors improve in the future, detecting lensed events may become quite likely.
Fabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes ...have been described "Classic" and "late onset" which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations.
In this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients.
N215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non-N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non-N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non-N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals' life time exposure to lyso-Gb3 (calculated as lyso-Gb3*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001).
These results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group.
Summary
Objective
To review the efficacy, safety, and clinical applicability of liraglutide for weight management from phase III clinical trials.
Methods
A search of the English language literature ...was performed using PubMed search terms: “liraglutide”, “glucagon‐like peptide‐1 receptor agonist”, and “randomized clinical trial”. Articles and bibliographies relevant to the subject were reviewed and additional references known to the authors were included.
Results
Five randomized, placebo‐controlled trials of liraglutide for weight management were identified. In addition to recommended diet and physical activity, liraglutide consistently resulted in a 4 to 6 kg weight loss, with a greater proportion of patients achieving at least 5 and 10% weight loss compared with placebo. The most common adverse effects were gastrointestinal and primarily occurred early in the treatment course. Comparative data suggest that weight loss with liraglutide is greater than that seen with orlistat or lorcaserin, but slightly less that seen with phentermine/topiramate. Liraglutide 1.8 mg was recently shown to have cardiovascular benefit in a large outcomes trial; applicability of these results for the 3.0 mg formulation in a more diverse weight loss population at high cardiovascular risk is not currently known. Barriers to real‐world clinical use as a first‐line agent include gastrointestinal side effects, high cost, and need for injection.
Conclusions
Liraglutide helps to induce and sustain weight loss in patients with obesity. Its efficacy is comparable to other available agents but it offers the unique benefit of improved glycemic control. Additional studies are needed to determine its long term efficacy and safety profile.
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die ...within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.
Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute ...rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue.
We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection.
The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m
of body-surface area before transplantation to 62 ml per minute per 1.73 m
after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m
in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys.
Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).
A class of wormhole solutions is constructed that has restricted polar degrees of freedom to achieve a gateway-like configuration. This compels the use of distribution-valued metrics and connections, ...which further compels the use of neutrix product of distributions, to define distribution-valued curvature, the Einstein tensor, and other relevant quantities. The solution requires a space–time with non-Riemannian effects like nonmetricity to be consistent and well defined, due to the nonassociativity of the neutrix product. Finally, the ideal gateway configuration where the negative energy requirement is zero is derived.
There is growing concern about possible cognitive consequences of COVID-19, with reports of ‘Long COVID’ symptoms persisting into the chronic phase and case studies revealing neurological problems in ...severely affected patients. However, there is little information regarding the nature and broader prevalence of cognitive problems post-infection or across the full spread of disease severity.
We sought to confirm whether there was an association between cross-sectional cognitive performance data from 81,337 participants who between January and December 2020 undertook a clinically validated web-optimized assessment as part of the Great British Intelligence Test, and questionnaire items capturing self-report of suspected and confirmed COVID-19 infection and respiratory symptoms.
People who had recovered from COVID-19, including those no longer reporting symptoms, exhibited significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression and anxiety. The deficits were of substantial effect size for people who had been hospitalised (N = 192), but also for non-hospitalised cases who had biological confirmation of COVID-19 infection (N = 326). Analysing markers of premorbid intelligence did not support these differences being present prior to infection. Finer grained analysis of performance across sub-tests supported the hypothesis that COVID-19 has a multi-domain impact on human cognition.
Interpretation. These results accord with reports of ‘Long Covid’ cognitive symptoms that persist into the early-chronic phase. They should act as a clarion call for further research with longitudinal and neuroimaging cohorts to plot recovery trajectories and identify the biological basis of cognitive deficits in SARS-COV-2 survivors.
Funding. AH is supported by the UK Dementia Research Institute Care Research and Technology Centre and Biomedical Research Centre at Imperial College London. WT is supported by the EPSRC Centre for Doctoral Training in Neurotechnology. SRC is funded by a Wellcome Trust Clinical Fellowship 110,049/Z/15/Z. JMB is supported by Medical Research Council (MR/N013700/1). MAM, SCRW and PJH are, in part, supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London
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