GPU Accelerated Discrete Element Method (DEM) Molecular Dynamics for Conservative, Faceted Particle Simulations

Faceted shapes, such as polyhedra, are commonly found in systems of nanoscale, colloidal, and granular particles. Many interesting physical phenomena, like crystal nucleation and growth, vacancy motion, and glassy dynamics are challenging to model in these systems because they require detailed dynamical information at the individual particle level. Within the granular materials community the Discrete Element Method has been used extensively to model systems of anisotropic particles under gravity, with friction. We provide an implementation of this method intended for simulation of hard, faceted nanoparticles, with a conservative Weeks-Chandler-Andersen (WCA) interparticle potential, coupled to a thermodynamic ensemble. This method is a natural extension of classical molecular dynamics and enables rigorous thermodynamic calculations for faceted particles

Tuning Mesoscopic Self-Assembly Behavior via Nano Building-Block Interactions and Architecture.

Using molecular dynamics (MD) computer simulations we show that a variety of complex, technologically relevant phases emerge from tuning aspects of nanoparticle architecture and interactions. In doing so, we demonstrate that nanoparticles can be thought of as building-blocks in larger scale assemblies over which we can tune nearly every aspect of the structure for specific applications such as photonics, photovoltaics, or catalysis. We highlight three specific case studies - polymer/nanoparticle composite building-block assemblies, star polymer microdroplets, and amino-acid coated nanoparticles with embedded dipoles that form rods of preferred chirality. In all cases predictions from simulations are used to either guide building-block assembly or to offer detailed insight into structures that were not previously understood. Additionally, we establish general, domain-agnostic mesophase behavior, as well as hypothesize synthesis and assembly strategies to target highly specific structures for any given application.PhDMaterials Science and EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113306/1/rmarson_1.pd

A comparison of HMGB1 concentrations between cerebrospinal fluid and blood in patients with neurological disease

AIMS: To determine whether a correlation exists between paired cerebrospinal fluid (CSF) and serum levels of a novel inflammatory biomarker, high-mobility group box 1 (HMGB1), in different neurological conditions. METHODS: HMGB1 was measured in the serum and CSF of 46 neurological patients (18 idiopathic intracranial hypertension [IIH], 18 neurological infection/inflammation [NII] and 10 Rasmussen's encephalitis [RE]). RESULTS: Mean serum (± SD) HMGB1 levels were 1.43 ± 0.54, 25.28 ± 27.9 and 1.89 ± 1.49 ng/ml for the patients with IIH, NII and RE, respectively. Corresponding mean (± SD) CSF levels were 0.35 ± 0.22, 4.48 ± 6.56 and 2.24 ± 2.35 ng/ml. Both CSF and serum HMGB1 was elevated in NII. Elevated CSF HMGB1 was demonstrated in RE. There was no direct correlation between CSF and serum levels of HMGB1. CONCLUSION: Serum HMGB1 cannot be used as a surrogate measure for CSF levels. CSF HMGB1 was elevated in NII and RE, its role as a prognostic/stratification biomarker needs further study

Genetic Disease and Therapy

Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment

Standardized Outcomes in Nephrology-Transplantation: A Global Initiative to Develop a Core Outcome Set for Trials in Kidney Transplantation.

BACKGROUND: Although advances in treatment have dramatically improved short-term graft survival and acute rejection in kidney transplant recipients, long-term graft outcomes have not substantially improved. Transplant recipients also have a considerably increased risk of cancer, cardiovascular disease, diabetes, and infection, which all contribute to appreciable morbidity and premature mortality. Many trials in kidney transplantation are short-term, frequently use unvalidated surrogate endpoints, outcomes of uncertain relevance to patients and clinicians, and do not consistently measure and report key outcomes like death, graft loss, graft function, and adverse effects of therapy. This diminishes the value of trials in supporting treatment decisions that require individual-level multiple tradeoffs between graft survival and the risk of side effects, adverse events, and mortality. The Standardized Outcomes in Nephrology-Transplantation initiative aims to develop a core outcome set for trials in kidney transplantation that is based on the shared priorities of all stakeholders. METHODS: This will include a systematic review to identify outcomes reported in randomized trials, a Delphi survey with an international multistakeholder panel (patients, caregivers, clinicians, researchers, policy makers, members from industry) to develop a consensus-based prioritized list of outcome domains and a consensus workshop to review and finalize the core outcome set for trials in kidney transplantation. CONCLUSIONS: Developing and implementing a core outcome set to be reported, at a minimum, in all kidney transplantation trials will improve the transparency, quality, and relevance of research; to enable kidney transplant recipients and their clinicians to make better-informed treatment decisions for improved patient outcomes

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

A Marxian Review of Gerontological Literature

A major concern for the sociology of aging and social gerontology is the lack of theoretical rigor. In particular, Birren and Bengtson (1988) describe all of social gerontology as data-rich but theory-poor. In an effort to deal with the lack of theory, this essay reviews the general social gerontology literature from a Marxian perspective. The findings suggest that the Marxian framework can illuminate aspects of social gerontology hitherto left unexamined in both the academic and applied arenas