Two for One: Diffusion Models and Force Fields for Coarse-Grained Molecular Dynamics

Coarse-grained (CG) molecular dynamics enables the study of biological processes at temporal and spatial scales that would be intractable at an atomistic resolution. However, accurately learning a CG force field remains a challenge. In this work, we leverage connections between score-based generative models, force fields and molecular dynamics to learn a CG force field without requiring any force inputs during training. Specifically, we train a diffusion generative model on protein structures from molecular dynamics simulations, and we show that its score function approximates a force field that can directly be used to simulate CG molecular dynamics. While having a vastly simplified training setup compared to previous work, we demonstrate that our approach leads to improved performance across several small- to medium-sized protein simulations, reproducing the CG equilibrium distribution, and preserving dynamics of all-atom simulations such as protein folding events

Analysis of graft survival in a trial of stem cell transplant in ALS

Objective The first US Food and Drug Administration–approved clinical trial to treat amyotrophic lateral sclerosis ( ALS ) with neural stem cell–based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord–derived neural stem cells ( HSSC s) transplanted into the spinal cord in patients with ALS . Methods Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real‐time PCR methods ( qPCR ). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells. Results Genomic DNA from donor HSSC s was identified in all cases, comprising 0.67–5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a “nest” of cells identified on H&E staining were XY ‐positive by FISH , confirming donor origin. A subset of XY ‐positive cells labeled for the neuronal marker NeuN and stem cell marker SOX 2. Interpretation This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSC s survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109593/1/acn3134.pd

Increased Adiposity, Dysregulated Glucose Metabolism and Systemic Inflammation in Galectin-3 KO Mice

PMCID: PMC3579848This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Near-bed and surface flow division patterns in experimental river bifurcations

Understanding channel bifurcation mechanics is of great importance for predicting and managing multichannel river processes and avulsion in distributary river deltas. To date, research on river channel bifurcations has focused on factors determining the stability and evolution of bifurcations. It has recently been shown that, theoretically, the nonlinearity of the relation between sediment transport and flow discharge causes one of the two distributaries of a (slightly) asymmetrical bifurcation to grow and the other to shrink. The positive feedback introduced by this effect results in highly asymmetrical bifurcations. However, there is a lack of detailed insight into flow dynamics within river bifurcations, the consequent effect on bed load flux through bifurcating channels, and thus the impact on bifurcation stability over time. In this paper, three key parameters (discharge ratio, width-to-depth ratio, and bed roughness) were varied in order to examine the secondary flow field and its effect on flow partitioning, particularly near-bed and surface flow, at an experimental bifurcation. Discharge ratio was controlled by varying downstream water levels. Flow fields were quantified using both particle image velocimetry and ultrasonic Doppler velocity profiling. Results show that a bifurcation induces secondary flow cells upstream of the bifurcation. In the case of unequal discharge ratio, a strong increase in the secondary flow near the bed causes a larger volume of near-bed flow to enter the dominant channel compared to surface and depth-averaged flow. However, this effect diminishes with larger width-to-depth ratio and with increased bed roughness. The flow structure and division pattern will likely have a stabilizing effect on river channel bifurcations. The magnitude of this effect in relation to previously identified destabilizing effects is addressed by proposing an adjustment to a widely used empirical bed load nodal-point partition equation. Our finding implies that river bifurcations can be stable under a wider range of conditions than previously thought. Key Points Secondary flow in symmetrical bifurcations causes strong near-bed flow curvature A disproportional amount of near-bed flow enters the dominant downstream channel Flow curvature adds a stabilizing feedback on bifurcation evolution

Strategy for Treating Motor Neuron Diseases Using a Fusion Protein of Botulinum Toxin Binding Domain and Streptavidin for Viral Vector Access: Work in Progress

Although advances in understanding of the pathogenesis of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) have suggested attractive treatment strategies, delivery of agents to motor neurons embedded within the spinal cord is problematic. We have designed a strategy based on the specificity of botulinum toxin, to direct entry of viral vectors carrying candidate therapeutic genes into motor neurons. We have engineered and expressed fusion proteins consisting of the binding domain of botulinum toxin type A fused to streptavidin (SAv). This fusion protein will direct biotinylated viral vectors carrying therapeutic genes into motor nerve terminals where they can enter the acidified endosomal compartments, be released and undergo retrograde transport, to deliver the genes to motor neurons. Both ends of the fusion proteins are shown to be functionally intact. The binding domain end binds to mammalian nerve terminals at neuromuscular junctions, ganglioside GT1b (a target of botulinum toxin), and a variety of neuronal cells including primary chick embryo motor neurons, N2A neuroblastoma cells, NG108-15 cells, but not to NG CR72 cells, which lack complex gangliosides. The streptavidin end binds to biotin, and to a biotinylated Alexa 488 fluorescent tag. Further studies are in progress to evaluate the delivery of genes to motor neurons in vivo, by the use of biotinylated viral vectors

Measurement of the inelastic pp cross-section at a centre-of-mass energy of 13TeV

The cross-section for inelastic proton-proton collisions at a centre-of-mass energy of 13TeV is measured with the LHCb detector. The fiducial cross-section for inelastic interactions producing at least one prompt long-lived charged particle with momentum p > 2 GeV/c in the pseudorapidity range 2 < η < 5 is determined to be ϭ acc = 62:2 ± 0:2 ± 2:5mb. The first uncertainty is the intrinsic systematic uncertainty of the measurement, the second is due to the uncertainty on the integrated luminosity. The statistical uncertainty is negligible. Extrapolation to full phase space yields the total inelastic proton-proton cross-section ϭ inel = 75:4 ± 3:0 ± 4:5mb, where the first uncertainty is experimental and the second due to the extrapolation. An updated value of the inelastic cross-section at a centre-of-mass energy of 7TeV is also reported