Publications

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6-10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72-168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide ( = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide ( = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions ( = 14) versus uninjured white matter ( = 24) in subjects receiving placebo ( = 20) or glyburide ( = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA]

The essential oil were extracted from the leaf of (Hemsl.) Yang by a hydrothermal method and then analyzed by gas chromatography-mass spectrometry. The leaf oil mainly included -copaene (5.44%), -muurolene (7.32%), -cadinene (11.44%), 1s-calamenene (5.18%). (Hemsl.) Yang leaf essential oil had significant inhibitory activity against and , the potential antitumor activity towards leukemia, breast, and colon cancer cell lines was good. (Hemsl.) Yang leaf essential oil had weaker activity on the four tested bacteria, it exhibited a certain role in promoting glucose uptake by adipocytes.

Ketamine is increasingly being used as a therapeutic for treatment-resistant depression (TRD), yet the effects of ketamine on the human brain remain largely unknown. This pilot study employed diffusion magnetic resonance imaging (dMRI) to examine relationships between ketamine treatment and white matter (WM) microstructure, with the aim of increasing the current understanding of ketamine’s neural mechanisms of action in humans. Longitudinal dMRI data were acquired from 13 individuals with TRD two hours prior to (pre-infusion), and four hours following (post-infusion), an intravenous ketamine infusion. Free-water imaging was employed to quantify cerebrospinal fluid-corrected mean fractional anisotropy (FA) in 15 WM bundles pre- and post-infusion. Analyses revealed that higher pre-infusion FA in the left cingulum bundle and the left superior longitudinal fasciculus was associated with greater depression symptom improvement 24 h post-ketamine. Moreover, four hours after intravenous administration of ketamine, FA rapidly increased in numerous WM bundles in the brain; this increase was significantly associated with 24 h symptom improvement in select bundles. Overall, the results of this preliminary study suggest that WM properties, as measured by dMRI, may have a potential impact on clinical improvement following ketamine. Ketamine administration additionally appears to be associated with rapid WM diffusivity changes, suggestive of rapid changes in WM microstructure. This study thus points to pre-treatment WM structure as a potential factor associated with ketamine’s clinical efficacy, and to post-treatment microstructural changes as a candidate neuroimaging marker of ketamine’s cellular mechanisms.

Although there is no universal definition for texture, the concept in various forms is nevertheless widely used and a key element of visual perception to analyze images in different fields. The present work’s main idea relies on the assumption that there exist representative samples, which we refer to as references as well, i.e., "good or bad" samples that represent a given dataset investigated in a particular data analysis problem. These representative samples need to be accounted for when designing predictive models with the aim of improving their performance. In particular, based on a selected subset of texture gray-level co-occurrence matrices (GLCMs) from the training cohort, we propose new representative spatial texture features, which we incorporate into a supervised image classification pipeline. The pipeline relies on the support vector machine (SVM) algorithm along with Bayesian optimization and the Wasserstein metric from optimal mass transport (OMT) theory. The selection of the best, "good and bad," GLCM references is considered for each classification label and performed during the training phase of the SVM classifier using a Bayesian optimizer. We assume that sample fitness is defined based on closeness (in the sense of the Wasserstein metric) and high correlation (Spearman’s rank sense) with other samples in the same class. Moreover, the newly defined spatial texture features consist of the Wasserstein distance between the optimally selected references and the remaining samples. We assessed the performance of the proposed classification pipeline in diagnosing the corona virus disease 2019 (COVID-19) from computed tomographic (CT) images.

Self-assembly of amphiphilic polymers into micelles is an archetypical example of a "self-confined" system due to the formation of micellar cores with dimensions of a few nanometers. In this work, we investigate the chain packing and resulting shape of C -PEO micelles with semicrystalline cores using small/wide-angle X-ray scattering (SAXS/WAXS), contrast-variation small-angle neutron scattering (SANS), and nuclear magnetic resonance spectroscopy (NMR). Interestingly, the -alkyl chains adopt a rotator-like conformation and pack into prolate ellipses (axial ratio ϵ ≈ 0.5) in the "crystalline" region and abruptly arrange into a more spheroidal shape (ϵ ≈ 0.7) above the melting point. We attribute the distorted spherical shape above the melting point to thermal fluctuations and intrinsic rigidity of the -alkyl blocks. We also find evidence for a thin dehydrated PEO layer (=1 nm) close to the micellar core. The results provide substantial insight into the interplay between crystallinity and molecular packing in confinement and the resulting overall micellar shape.

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta, total tau, and phosphorylated tau as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta levels (effect = - 0.5, p = 9.2 × 10). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta (R = 2.29%; p = 2.5 × 10). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta levels (p = 7.3 × 10). Two-sample Mendelian Randomization revealed that CSF amyloid beta plays a role in Parkinson’s disease (p = 1.4 × 10) and age at onset (p = 7.6 × 10), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta (p = 3.8 × 10), higher mean cortical binding potentials (p = 5.8 × 10), and higher Braak amyloid beta score (p = 4.4 × 10). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta, and APOE.

UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase (LpxC), the zinc metalloenzyme catalyzing the first committed step of lipid A biosynthesis in Gram-negative bacteria, has been a target for antibacterial drug discovery for many years. All inhibitor chemotypes reaching an advanced preclinical stage and clinical phase 1 have contained terminal hydroxamic acid, and none have been successfully advanced due, in part, to safety concerns, including hemodynamic effects. We hypothesized that the safety of LpxC inhibitors could be improved by replacing the terminal hydroxamic acid with a different zinc-binding group. After choosing an N-hydroxyformamide zinc-binding group, we investigated the structure-activity relationship of each part of the inhibitor scaffold with respect to Pseudomonas aeruginosa and Escherichia coli LpxC binding affinity, in vitro antibacterial potency and pharmacological properties. We identified a novel, potency-enhancing hydrophobic binding interaction for an LpxC inhibitor. We demonstrated in vivo efficacy of one compound in a neutropenic mouse E. coli infection model. Another compound was tested in a rat hemodynamic assay and was found to have a hypotensive effect. This result demonstrated that replacing the terminal hydroxamic acid with a different zinc-binding group was insufficient to avoid this previously recognized safety issue with LpxC inhibitors.

Hand gestures are an integral part of social interactions and communication. Several imaging studies in healthy subjects and lesion studies in patients with apraxia suggest the praxis network for gesture production, involving mainly left inferior frontal, posterior parietal and temporal regions. However, little is known about the structural connectivity underlying gesture production. We recruited 41 healthy participants and 39 patients with schizophrenia. All participants performed a gesture production test, the Test of Upper Limb Apraxia, and underwent diffusion tensor imaging. We hypothesized that gesture production is associated with structural network connectivity as well as with tract integrity. We defined the praxis network as an undirected graph comprised of 13 bilateral regions of interest and derived measures of local and global structural connectivity and tract integrity from Finsler geometry. We found an association of gesture deficit with reduced global and local efficiency of the praxis network. Furthermore, reduced tract integrity, for example in the superior longitudinal fascicle, arcuate fascicle or corpus callosum were related to gesture deficits. Our findings contribute to the understanding of structural correlates of gesture production as they first present diffusion tensor imaging data in a combined sample of healthy subjects and a patient cohort with gestural deficits.

Fiber tracking produces large tractography datasets that are tens of gigabytes in size consisting of millions of streamlines. Such vast amounts of data require formats that allow for efficient storage, transfer, and visualization. We present TRAKO, a new data format based on the Graphics Layer Transmission Format (glTF) that enables immediate graphical and hardware-accelerated processing. We integrate a state-of-the-art compression technique for vertices, streamlines, and attached scalar and property data. We then compare TRAKO to existing tractography storage methods and provide a detailed evaluation on eight datasets. TRAKO can achieve data reductions of over 28x without loss of statistical significance when used to replicate analysis from previously published studies.