X-ray tomography is an invaluable tool in biomedical imaging. It can deliver the three-dimensional internal structure of entire organisms as well as that of single cells, and even gives access to ...quantitative information, crucially important both for medical applications and for basic research. Most frequently such information is based on X-ray attenuation. Phase contrast is sometimes used for improved visibility but remains significantly harder to quantify. Here we describe an X-ray computed tomography technique that generates quantitative high-contrast three-dimensional electron density maps from phase contrast information without reverting to assumptions of a weak phase object or negligible absorption. This method uses a ptychographic coherent imaging approach to record tomographic data sets, exploiting both the high penetration power of hard X-rays and the high sensitivity of lensless imaging. As an example, we present images of a bone sample in which structures on the 100 nm length scale such as the osteocyte lacunae and the interconnective canalicular network are clearly resolved. The recovered electron density map provides a contrast high enough to estimate nanoscale bone density variations of less than one per cent. We expect this high-resolution tomography technique to provide invaluable information for both the life and materials sciences.
Candidemia and Invasive Candidiasis McCarty, Todd P; White, Cameron M; Pappas, Peter G
Infectious disease clinics of North America,
06/2021, Letnik:
35, Številka:
2
Journal Article
Recenzirano
Invasive candidiasis (IC) is a collective term that refers to a group of infectious syndromes caused by a variety of species of Candida, 6 of which cause most cases globally. Candidemia is probably ...the most commonly recognized syndrome associated with IC; however, Candida can cause invasive infection of any organ, especially visceral organs, vasculature, bones and joints, the eyes and central nervous system. Targeted prevention and empirical therapy are important interventions for patients at high risk for IC, and the current approach should be based on a combination of clinical risk factors and non-culture-based diagnostics, when available.
SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning ...prospectively characterizes the impacts of mutations on these biochemical properties, enabling rapid assessment of new mutations seen during viral surveillance. However, the effects of mutations can change as the virus evolves, requiring updated deep mutational scans. We determined the impacts of all single amino acid mutations in the Omicron BA.1 and BA.2 RBDs on ACE2-binding affinity, RBD folding, and escape from binding by the LY-CoV1404 (bebtelovimab) monoclonal antibody. The effects of some mutations in Omicron RBDs differ from those measured in the ancestral Wuhan-Hu-1 background. These epistatic shifts largely resemble those previously seen in the Alpha variant due to the convergent epistatically modifying N501Y substitution. However, Omicron variants show additional lineage-specific shifts, including examples of the epistatic phenomenon of entrenchment that causes the Q498R and N501Y substitutions present in Omicron to be more favorable in that background than in earlier viral strains. In contrast, the Omicron substitution Q493R exhibits no sign of entrenchment, with the derived state, R493, being as unfavorable for ACE2 binding in Omicron RBDs as in Wuhan-Hu-1. Likely for this reason, the R493Q reversion has occurred in Omicron sub-variants including BA.4/BA.5 and BA.2.75, where the affinity buffer from R493Q reversion may potentiate concurrent antigenic change. Consistent with prior studies, we find that Omicron RBDs have reduced expression, and identify candidate stabilizing mutations that ameliorate this deficit. Last, our maps highlight a broadening of the sites of escape from LY-CoV1404 antibody binding in BA.1 and BA.2 compared to the ancestral Wuhan-Hu-1 background. These BA.1 and BA.2 deep mutational scanning datasets identify shifts in the RBD mutational landscape and inform ongoing efforts in viral surveillance.
On the age of the β Pictoris moving group Mamajek, Eric E; Bell, Cameron P. M
Monthly notices of the Royal Astronomical Society,
12/2014, Letnik:
445, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Binks & Jeffries and Malo et al. have recently reported Li depletion boundary (LDB) ages for the β Pictoris moving group (BPMG) which are twice as old as the oft-cited kinematic age of ∼12 Myr. In ...this study, we present (1) a new evaluation of the internal kinematics of the BPMG using the revised Hipparcos astrometry and best available published radial velocities, and assess whether a useful kinematic age can be derived, and (2) derive an isochronal age based on the placement of the A-, F-, and G-type stars in the colour–magnitude diagram (CMD). We explore the kinematics of the BPMG looking at velocity trends along Galactic axes, and conducting traceback analyses assuming linear trajectories, epicyclic orbit approximation, and orbit integration using a realistic gravitational potential. None of the methodologies yield a kinematic age with small uncertainties using modern velocity data. Expansion in the Galactic X and Y directions is significant only at the 1.7σ and 2.7σ levels, and together yields an overall kinematic age with a wide range (13–58 Myr; 95 per cent CL). The A-type members are all on the zero-age main sequence, suggestive of an age of >20 Myr, and the loci of the CMD positions for the late-F- and G-type pre-main-sequence BPMG members have a median isochronal age of 22 Myr (± 3 Myr statistical, ±1 Myr systematic) when considering four sets of modern theoretical isochrones. The results from recent LDB and isochronal age analyses are now in agreement with a median BPMG age of 23 ± 3 Myr (overall 1σ uncertainty, including ±2 Myr statistical and ±2 Myr systematic uncertainties).
Objective
Randomized clinical trials have shown that aerobic exercise attenuates motor symptom progression in Parkinson's disease, but the underlying neural mechanisms are unclear. Here, we ...investigated how aerobic exercise influences disease‐related functional and structural changes in the corticostriatal sensorimotor network, which is involved in the emergence of motor deficits in Parkinson's disease. Additionally, we explored effects of aerobic exercise on tissue integrity of the substantia nigra, and on behavioral and cerebral indices of cognitive control.
Methods
The Park‐in‐Shape trial is a single‐center, double‐blind randomized controlled trial in 130 Parkinson's disease patients who were randomly assigned (1:1 ratio) to aerobic exercise (stationary home trainer) or stretching (active control) interventions (duration = 6 months). An unselected subset from this trial (exercise, n = 25; stretching, n = 31) underwent resting‐state functional and structural magnetic resonance imaging (MRI), and an oculomotor cognitive control task (pro‐ and antisaccades), at baseline and at 6‐month follow‐up.
Results
Aerobic exercise, but not stretching, led to increased functional connectivity of the anterior putamen with the sensorimotor cortex relative to the posterior putamen. Behaviorally, aerobic exercise also improved cognitive control. Furthermore, aerobic exercise increased functional connectivity in the right frontoparietal network, proportionally to fitness improvements, and it reduced global brain atrophy.
Interpretation
MRI, clinical, and behavioral results converge toward the conclusion that aerobic exercise stabilizes disease progression in the corticostriatal sensorimotor network and enhances cognitive performance. ANN NEUROL 2022;91:203–216
April is Child Abuse Awareness month, even during the coronavirus disease 2019 (COVID-19) pandemic. Social isolation, the public health measure now in place across the world, is also a proven risk ...factor for child abuse. Other risks include stress, uncertain access to food and housing, and worries about making ends meet. Owing to the current COVID-19 pandemic, we recognize that parents and caregivers feel overwhelmed with these stresses. They may be experiencing job loss, childcare struggles, and schedule changes.
There has been considerable recent progress in protein structure prediction using deep neural networks to predict inter-residue distances from amino acid sequences
. Here we investigate whether the ...information captured by such networks is sufficiently rich to generate new folded proteins with sequences unrelated to those of the naturally occurring proteins used in training the models. We generate random amino acid sequences, and input them into the trRosetta structure prediction network to predict starting residue-residue distance maps, which, as expected, are quite featureless. We then carry out Monte Carlo sampling in amino acid sequence space, optimizing the contrast (Kullback-Leibler divergence) between the inter-residue distance distributions predicted by the network and background distributions averaged over all proteins. Optimization from different random starting points resulted in novel proteins spanning a wide range of sequences and predicted structures. We obtained synthetic genes encoding 129 of the network-'hallucinated' sequences, and expressed and purified the proteins in Escherichia coli; 27 of the proteins yielded monodisperse species with circular dichroism spectra consistent with the hallucinated structures. We determined the three-dimensional structures of three of the hallucinated proteins, two by X-ray crystallography and one by NMR, and these closely matched the hallucinated models. Thus, deep networks trained to predict native protein structures from their sequences can be inverted to design new proteins, and such networks and methods should contribute alongside traditional physics-based models to the de novo design of proteins with new functions.
Liver transplantation for alcoholic hepatitis Im, Gene Y.; Cameron, Andrew M.; Lucey, Michael R.
Journal of hepatology,
February 2019, 2019-02-00, 20190201, Letnik:
70, Številka:
2
Journal Article
Recenzirano
Odprti dostop
While liver transplantation (LT) has become a standard therapy for life-threatening alcohol related cirrhosis, LT as a treatment for severe alcoholic hepatitis (AH) has remained a taboo owing to ...concerns about the limited organ supply and the risk that the AH liver recipient will return to harmful drinking. The adoption of a 6-month abstinence requirement (the so-called ‘6-month rule’) by many centres made AH a contraindication to LT. Given the high short-term mortality of severe AH, the lack of effective medical therapies and an increasing recognition that the 6-month rule unfairly excluded otherwise favourable candidates, a seminal European pilot study of LT for AH was performed. The success of the European study, which has been corroborated in retrospective analyses from the United States, represented a paradigm shift in therapy for highly selected patients with severe AH who are not responding to medical therapy. However, prospective studies are urgently needed to resolve the controversies that still surround the criteria for selection of patients with AH for LT and the long-term outcomes of the associated alcohol use disorder.
The study of phenomena such as protein folding and conformational changes in molecules is a central theme in chemical physics. Molecular dynamics (MD) simulation is the primary tool for the study of ...transition processes in biomolecules, but it is hampered by a huge timescale gap between the processes of interest and atomic vibrations that dictate the time step size. Therefore, it is imperative to combine MD simulations with other techniques in order to quantify the transition processes taking place on large timescales. In this work, the diffusion map with Mahalanobis kernel, a meshless approach for approximating the Backward Kolmogorov Operator (BKO) in collective variables, is upgraded to incorporate standard enhanced sampling techniques, such as metadynamics. The resulting algorithm, which we call the target measure Mahalanobis diffusion map (tm-mmap), is suitable for a moderate number of collective variables in which one can approximate the diffusion tensor and free energy. Imposing appropriate boundary conditions allows use of the approximated BKO to solve for the committor function and utilization of transition path theory to find the reactive current delineating the transition channels and the transition rate. The proposed algorithm, tm-mmap, is tested on the two-dimensional Moro-Cardin two-well system with position-dependent diffusion coefficient and on alanine dipeptide in two collective variables where the committor, the reactive current, and the transition rate are compared to those computed by the finite element method (FEM). Finally, tm-mmap is applied to alanine dipeptide in four collective variables where the use of finite elements is infeasible.
Aluminosilicate zeolites are traditionally used in high-temperature applications at low water vapour pressures where the zeolite framework is generally considered to be stable and static. ...Increasingly, zeolites are being considered for applications under milder aqueous conditions. However, it has not yet been established how neutral liquid water at mild conditions affects the stability of the zeolite framework. Here, we show that covalent bonds in the zeolite chabazite (CHA) are labile when in contact with neutral liquid water, which leads to partial but fully reversible hydrolysis without framework degradation. We present ab initio calculations that predict novel, energetically viable reaction mechanisms by which Al-O and Si-O bonds rapidly and reversibly break at 300 K. By means of solid-state NMR, we confirm this prediction, demonstrating that isotopic substitution of
O in the zeolitic framework occurs at room temperature in less than one hour of contact with enriched water.
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