Hippocampal subfield volumetry: differential pattern of atrophy in different forms of genetic frontotemporal dementia

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD. OBJECTIVES: We aimed to investigate hippocampal subfield volumes in genetic FTD. METHODS: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1(3.4) years; 29 with MAPT, 28 with C9orf72, and 18 with GRN mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes. RESULTS: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24–27%, p < 0.0005). For C9orf72, the CA4, CA1, and dentate gyrus regions (8–11%, p < 0.0005), and for GRN the presubiculum and subiculum (10–14%, p < 0.0005) showed the largest differences from controls. CONCLUSIONS: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability

Tidal stream resource characterisation in progressive versus standing wave systems

© 2018 The Author(s) Characterisations of the tidal stream resource and its variability over various timescales are crucial for the development of the tidal stream energy industry. To date, no research has compared resource sensitivity in standing wave (when peak currents occur midway between high and low water) and progressive wave (where peak currents occur at high and low water) tidal systems. Here, we compare the flow regimes of standing wave versus progressive wave systems and the associated variations in tidal stream power with applications to device deployment options (floating-platform turbines versus bottom-mounted turbines). We use a validated 3D numerical model (ROMS) of a globally-significant tidal energy shelf sea region (Irish Sea), to test the hypotheses that the influence on potential extractable energy, and suitability for different devices, may be markedly different between these contrasting systems. Power density was also calculated and compared for floating versus bottom-mounted devices using in-situ current data (ADCPs) obtained from a standing wave site and a progressive wave site. We show that progressive wave systems are characterised by velocity-asymmetry over a tidal cycle (i.e. stronger peak flows at high water than at low water), leading to power-asymmetry. Such power asymmetry was shown to have more of an effect on floating device technology, where an assumed turbine depth tracks the sea surface, in contrast to bottom-mounted technology, where the hub height is fixed at a certain position above the sea bed. Shallow, high-flow regions where tidal range is large contained up to 2.5% more power density from bottom-mounted compared with floating turbines; however, there were areas where floating devices were exposed to higher mean currents over a tidal cycle. Standing wave systems, where flow asymmetry is minimised, did not particularly favour either technology. The results highlight the requirement for detailed resource assessments to consider the vertical plane, and are applicable to all potential tidal stream energy sites

Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α

Many functional aspects of the protein kinase p38α have been illustrated by more than three hundred structures determined in the presence of reducing agents. These structures correspond to free forms and complexes with activators, substrates, and inhibitors. Here we report the conformation of an oxidized state with an intramolecular disulfide bond between Cys119 and Cys162 that is conserved in vertebrates. The structure of the oxidized state does not affect the conformation of the catalytic site, but alters the docking groove by partially unwinding and displacing the short αD helix due to the movement of Cys119 towards Cys162. The transition between oxidized and reduced conformations provides a mechanism for fine-tuning p38α activity as a function of redox conditions, beyond its activation loop phosphorylation. Moreover, the conformational equilibrium between these redox forms reveals an unexplored cleft for p38α inhibitor design that we describe in detail.© 2023. The Author(s)

Mitochondrial echoes of first settlement and genetic continuity in El Salvador

Background: From Paleo-Indian times to recent historical episodes, the Mesoamerican isthmus played an important role in the distribution and patterns of variability all around the double American continent. However, the amount of genetic information currently available on Central American continental populations is very scarce. In order to shed light on the role of Mesoamerica in the peopling of the New World, the present study focuses on the analysis of the mtDNA variation in a population sample from El Salvador. Methodology/Principal Findings: We have carried out DNA sequencing of the entire control region of the mitochondrial DNA (mtDNA) genome in 90 individuals from El Salvador. We have also compiled more than 3,985 control region profiles from the public domain and the literature in order to carry out inter-population comparisons. The results reveal a predominant Native American component in this region: by far, the most prevalent mtDNA haplogroup in this country (at ~90%) is A2, in contrast with other North, Meso- and South American populations. Haplogroup A2 shows a star-like phylogeny and is very diverse with a substantial proportion of mtDNAs (45%; sequence range 16090–16365) still unobserved in other American populations. Two different Bayesian approaches used to estimate admixture proportions in El Salvador shows that the majority of the mtDNAs observed come from North America. A preliminary founder analysis indicates that the settlement of El Salvador occurred about 13,400±5,200 Y.B.P.. The founder age of A2 in El Salvador is close to the overall age of A2 in America, which suggests that the colonization of this region occurred within a few thousand years of the initial expansion into the Americas. Conclusions/Significance: As a whole, the results are compatible with the hypothesis that today's A2 variability in El Salvador represents to a large extent the indigenous component of the region. Concordant with this hypothesis is also the observation of a very limited contribution from European and African women (~5%). This implies that the Atlantic slave trade had a very small demographic impact in El Salvador in contrast to its transformation of the gene pool in neighbouring populations from the Caribbean facade

DeepReg: a deep learning toolkit for medical image registration

Image fusion is a fundamental task in medical image analysis and computer-assisted intervention. Medical image registration, computational algorithms that align different images together (Hill et al., 2001), has in recent years turned the research attention towards deep learning. Indeed, the representation ability to learn from population data with deep neural networks has opened new possibilities for improving registration generalisability by mitigating difficulties in designing hand-engineered image features and similarity measures for many realworld clinical applications (Fu et al., 2020; Haskins et al., 2020). In addition, its fast inference can substantially accelerate registration execution for time-critical tasks. DeepReg is a Python package using TensorFlow (Abadi et al., 2015) that implements multiple registration algorithms and a set of predefined dataset loaders, supporting both labelledand unlabelled data. DeepReg also provides command-line tool options that enable basic and advanced functionalities for model training, prediction and image warping. These implementations, together with their documentation, tutorials and demos, aim to simplify workflows for prototyping and developing novel methodology, utilising latest development and accessing quality research advances. DeepReg is unit tested and a set of customised contributor guidelines are provided to facilitate community contributions. A submission to the MICCAI Educational Challenge has utilised the DeepReg code and demos to explore the link between classical algorithms and deep-learning-based methods (Montana Brown et al., 2020), while a recently published research work investigated temporal changes in prostate cancer imaging, by using a longitudinal registration adapted from the DeepReg code (Yang et al., 2020)

Parameter identification problems in the modelling of cell motility

We present a novel parameter identification algorithm for the estimation of parameters in models of cell motility using imaging data of migrating cells. Two alternative formulations of the objective functional that measures the difference between the computed and observed data are proposed and the parameter identification problem is formulated as a minimisation problem of nonlinear least squares type. A Levenberg–Marquardt based optimisation method is applied to the solution of the minimisation problem and the details of the implementation are discussed. A number of numerical experiments are presented which illustrate the robustness of the algorithm to parameter identification in the presence of large deformations and noisy data and parameter identification in three dimensional models of cell motility. An application to experimental data is also presented in which we seek to identify parameters in a model for the monopolar growth of fission yeast cells using experimental imaging data. Our numerical tests allow us to compare the method with the two different formulations of the objective functional and we conclude that the results with both objective functionals seem to agree

Citrobacter freundii infection after acute necrotizing pancreatitis in a patient with a pancreatic pseudocyst: a case report

<p>Abstract</p> <p>Introduction</p> <p>Infections are the most frequent and severe complications of acute necrotizing pancreatitis with a mortality rate of up to 80 percent. Although experimental and clinical studies suggest that the microbiologic source of pancreatic infection could be enteric, information in this regard is controversial.</p> <p>Case presentation</p> <p>We describe a <it>Citrobacter freundii </it>isolation by endoscopy ultrasound fine needle aspiration in a 80-year-old Caucasian man with pancreatic pseudocyst after acute necrotizing pancreatitis.</p> <p>Conclusion</p> <p>Our case report confirms that this organism can be recovered in patients with a pancreatic pseudocyst. On-site cytology feedback was crucial to the successful outcome of this case as immediate interpretation of the fine needle aspiration sample directed the appropriate cultures and, ultimately, the curative therapy. To the best of our knowledge, this is the first reported case of isolated pancreatic <it>C. freundii </it>diagnosed by endoscopy ultrasound fine needle aspiration.</p