Comparing machine learning algorithms for non-invasive detection and classification of failure in piezoresistive bone cement via electrical impedance tomography.

At an estimated cost of $8 billion annually in the United States, revision surgeries to total joint replacements represent a substantial financial burden to the health care system and a tremendous mental and physical burden on patients and their caretakers. Fixation failures, such as implant loosening, wear, and mechanical instability of the poly(methyl methacrylate) (PMMA) cement, which bonds the implant to the bone, are the main causes of long-term implant failure. Early and accurate diagnosis of cement failure is critical for developing novel therapeutic strategies and reducing the high risk of a misjudged revision. Unfortunately, prevailing imaging modalities, notably plain radiographs, struggle to detect the precursors of implant failure and are often interpreted incorrectly. Our prior work has shown that the modification of PMMA bone cement with low concentrations of conductive fillers makes it piezoresistive and therefore self-sensing. When combined with a conductivity imaging modality such as electrical impedance tomography (EIT), it is possible to monitor load transfer across the PMMA using cost-effective, physiologically benign, non-contact, and real-time electrical measurements. Despite the ability of EIT for monitoring load transfer across self-sensing PMMA bone cement, it is unable to accurately characterize failure mechanisms. Overcoming this challenge is critical to the success of this technology in practice. Therefore, we herein expand upon our previous results by integrating machine learning techniques with EIT for cement condition characterization with the goal of establishing the feasibility of even off-the-shelf machine learning algorithms to address this important problem. We survey a wide variety of different machine learning algorithms for application to this problem, including neural networks on voltage readings of an EIT phantom for tracking the spatial position of a sample, specifying defect orientation within a sample, and classifying defect types, including cracks and delaminations. In addition, we explore the utilization of principal component analysis (PCA) for pre-treating impedance signals in each of these problems. Within the tested algorithms, our results show clear advantages of neural networks, support vector machines, and K-nearest neighbor algorithms for interpreting EIT signals. We also show that PCA is an effective addition to machine learning. These preliminary results demonstrate that the combination of smart materials, EIT, and machine learning may be a powerful instrumentation tool for diagnosing the origin and evolution of mechanical failure in joint replacements.

Graduate Student Literature Review: Potential mechanisms of interaction between bacteria and the reproductive tract of dairy cattle.

Although the presence of bacteria has been characterized throughout the reproductive tracts of multiple species, how these bacteria may interact with the host has yet to be described. Previous reviews have described how pathogenic bacteria interact with the reproductive tract to cause infections such as metritis. This review aimed to summarize the knowledge related to pathogenic and nonpathogenic bacteria in various locations of the bovine reproductive tract and the possible mechanisms underlying host-microbe interactions during gametogenesis and early pregnancy. Lactic acid bacteria such as Lactobacillus seem to be beneficial in multiple areas of the reproductive tract: they have been associated with increased oocyte quality when in follicular fluid and secrete reactive oxygen species that are beneficial during placental angiogenesis. However, other bacteria, including Enterococcus, Staphylococcus, and Streptococcus, may modulate T helper cells that inhibit maternal recognition of pregnancy. Available data on the reproductive microbiome focus on variations in microbial communities and their associations with reproductive performance. However, research on these host-microbiome interactions may provide more insight on how bacteria affect fertility.

Varying dietary protein and fat elicits differential transcriptomic expression within stress response pathways in preweaned Holstein heifers.

Increases in milk replacer dietary energy subsequently increase growth and weight in preweaned dairy heifers. However, the underlying effects of dietary component increases on key functional pathways have yet to be fully investigated. Elucidating these relationships may provide insights into the mechanisms through which protein and fat are partitioned for tissue growth and metabolism. We hypothesized that genes within key growth and metabolic pathways would be differentially expressed between calves fed a protein- and fat-restricted diet and calves fed a protein- and fat-enhanced diet. The objectives of this study were to (1) identify genes differentially expressed between dietary restricted calves and enhanced calves and (2) determine the key regulatory pathways influenced by these genes. Preweaned Holstein heifers (n = 12; 6 ± 0.02 d of age) were randomly assigned to 1 of 2 milk replacer diets: enhanced (28.9% crude protein, 26.2% fat; n = 6) or restricted (20.9% crude protein, 19.8% fat; n = 6). Growth measures included average daily gain and gain-to-feed ratio. After 56 d, calves were killed for tissue collection. Samples from longissimus dorsi, adipose, and liver tissues were collected and RNA was isolated for RNA sequencing analysis. The MIXED procedure of SAS (SAS Institute Inc., Cary, NC) was used to evaluate relationships of growth with dietary energy. Fixed effects included date of collection and time (day). Random effects included sire and birth weight. The RNA sequencing analysis was performed using CLC Genomics Workbench (Qiagen, Germantown, MD), and the Robinson and Smith exact test was used to identify differentially expressed genes between diets. The Protein Analysis Through Evolutionary Relationships (PANTHER) database was then used to identify functional categories of differentially expressed genes. Enhanced calves had increased growth rates and feed efficiency compared with restricted calves (average daily gain = 0.76 and 0.22, respectively; gain-to-feed ratio = 0.10 and 0.06, respectively). There were 238 differentially expressed genes in adipose, 227 in longissimus dorsi, and 40 in liver. We identified 10 genes concordant among tissues. As expected, functional analyses suggested that the majority of genes were associated with metabolic or cellular processes, predominantly cell communication and cell cycle. Overall, it appears that varying levels of dietary protein and fat influence calf growth and development through metabolic processes, including oxidative phosphorylation and glyceroneogenesis. However, protein- and fat-restricted calves appeared to experience metabolic stress at a cellular level, as evidenced by an upregulation in stress response pathways, including genes in the p53 pathway. Calves could be fed at a higher level of protein and fat to decrease the prevalence of metabolic stress at the cellular level, but evidence indicating the presence of inflammatory stress and adipose fibrosis in enhanced calves prompts further investigation of the effects of milk replacer component levels.

Putative sigma(3) sites in mammalian brain have histamine H(1) receptor properties: evidence from ligand binding and distribution studies with the novel H(1) radioligand [(3)H]-(-)-trans-1-phenyl-3-aminotetralin.

A novel phenylaminotetralin (PAT) radioligand, [(3)H]-(1R, 3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene ([(3)H]-[-]-trans-H(2)-PAT), is shown here to label a saturable (B(max)=39+/-6 fmol/mg protein) population of sites with high affinity (K(d)=0.13+/-0.03 nM) in guinea pig brain. Consistent with previous studies which showed that PATs stimulate catecholamine (dopamine) synthesis in rat striatum, autoradiographic brain receptor mapping studies here indicate that [(3)H]-(-)-trans-H(2)-PAT-labeled sites are highly localized in catecholaminergic nerve terminal fields in hippocampus, nucleus accumbens, and striatum in guinea pig brain. Competition binding studies with a broad range of CNS receptor-active ligands and CNS radioreceptor screening assays indicate that the pharmacological binding profile of brain [(3)H]-(-)-trans-H(2)-PAT sites closely resembles histamine H(1)-type receptors. Comparative studies using the histamine H(1) antagonist radioligand, [(3)H]mepyramine, indicate that the H(1) ligand binding profile and guinea pig brain distribution of H(1) receptors and [(3)H]-(-)-trans-H(2)-PAT sites are nearly identical; moreover, both sites have about 40-fold stereoselective affinity for (-)- over (+)-trans-H(2)-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (sigma(3)) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H(1) receptors that can be stereoselectively labeled with [(3)H]-(-)-trans-H(2)-PAT.

1-Phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes and related derivatives as ligands for the neuromodulatory sigma 3 receptor: further structure-activity relationships.

A series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) previously was found to stimulate tyrosine hydroxylase activity and dopamine synthesis in rat brain through interaction with a novel sigma 3 receptor. Specifically, the trans-1R,3S-(-) isomer of H2-PAT showed highest affinity for sigma 3 receptors and also produced maximal stimulation of tyrosine hydroxylase activity and dopamine synthesis, as compared to the trans-1S,3R-(+) isomer. Affinity for sigma 3 receptors and functional potency at stimulating dopamine synthesis were attenuated either by altering the position or dimethyl substitution pattern of the amino group or by hydroxylating the tetralin aromatic ring. A preliminary binding model can accommodate many PAT analogs and several non-PATs with a wide range of affinities for the sigma 3 receptor. Here, we report the synthesis and evaluation of additional analogs in order to expand previous structure-activity relationship studies. Further molecular modifications include synthesis of 1-phenyl-1-methyl-3-amino, 1-phenyl-2-amino, 1-phenyl-3-(trimethylammoniumyl), and 1-phenyl-3-(phenylalkyl) analogs, as well as ring-expanded tetrahydrobenzocycloheptenes. In general, the above modifications decreased sigma 3 receptor affinity and, in some cases, caused a reversal of the sigma 3 binding selectivity of trans- versus cis-PATs found previously. Most analogs were selective for sigma 3 receptors and showed little or no affinity for either sigma 1/sigma 2 or dopamine D1, D2, and D3 receptors. N-Phenylalkyl substituents, such as N-phenylethyl, however, endowed the 1-phenyl-3-aminotetralins with enhanced sigma 1/sigma 2 and dopamine receptor affinity while decreasing sigma 3 affinity, thus abolishing sigma 3 selectivity.

Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.

Molecular modeling studies were carried out on a series of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (phenylaminotetralins, PATs), several PAT structural analogs, and various non-PAT ligands that demonstrate a range of affinities for a novel sigma 3 receptor linked to stimulation of tyrosine hydroxylase and dopamine synthesis in rodent brain. In an effort to develop a ligand-binding model for the sigma 3 receptor, a pharmacophore mapping program (DISCO) was used to identify structural features that are common to ligands that exhibit moderate to high binding affinity for sigma 3 sites. DISCO then was utilized to propose a common pharmacophoric region that included one low-energy conformation of each compound in the training set. The resulting alignment was utilized in a comparative molecular field analysis (CoMFA) study in an attempt to correlate the steric and electrostatic fields of the molecules with the respective binding affinities at the sigma 3 receptor. A suitably predictive model was obtained from the CoMFA analysis which will be employed in the development of additional PAT analogs that could potentially display high affinity and selectivity for the sigma 3 receptor. The excluded volumes which resulted from comparing molecular volumes of active and inactive compounds were visualized to examine the limits of steric tolerance imposed by the sigma 3 receptor.

Actions of (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) on dopamine synthesis in limbic and extrapyramidal regions of rat brain.

The proposed D3-selective ligand (+/-)-7-hydroxy-N,N-dipropylaminotetralin (7-OH-DPAT) inhibited tyrosine hydroxylase in vitro (IC50 = 0.6-0.7 microM) and dihydroxyphenylalanine (DOPA) accumulation in vivo (ID50 = 4.8-6.4 mg/kg) in two autoreceptor models in extrapyramidal and limbic tissue in rat forebrain, without consistent regional selectivity. Some limbic selectivity (ID50 = 10 vs. 29 mg/kg) was found in an in vivo model permitting expression of postsynaptic D3 and D2 receptor activity. The effects were partially blocked by S(-)-eticlopride alone, and fully after reserpine pretreatment. The results suggest that 7-OH-DPAT activates D3 or D2 autoreceptors, alters dopamine storage or release, and may interact with some limbic selectivity at postsynaptic D3 and D2 receptors as a partial agonist.

Synthesis and pharmacological evaluation of 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes as ligands for a novel receptor with sigma-like neuromodulatory activity.

Certain novel 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes (1-phenyl-3-aminotetralins, PATs) produced stimulation (ca. 30% above basal levels) of tyrosine hydroxylase (TH) activity at 0.1 microM concentrations in rodent brain tissue. This effect on TH was blocked by the putative sigma-receptor antagonist BMY-14802, suggesting involvement of a novel neuromodulatory sigma-like receptor. Within the new phenylaminotetralin series, a correlation was found between the ability to stimulate TH and the potency to compete for binding sites labeled by (+/-)-[3H]1-phenyl-3-(N,N-dimethylamino)-6-chloro-7-hydroxy-1,2,3,4- tetrahydronaphthalene ([3H](+/-)-4). trans-Catechol analogs had low affinity for [3H]4 sites, and although they inhibited TH activity, this effect was not blocked by known sigma or dopamine antagonists. Analogs with dihydroxy substituents (catechols), as well as nitrogen substituents larger than methyl, had little affinity for [3H]4 binding sites and did not significantly affect TH activity. The pharmacology of the [3H]4 binding site is unique from that of any known sigma or dopamine receptor, thus the effects appear to be mediated by a previously uncharacterized binding site/receptor. The site has stereoselectivity for the (1R,3S)-(-)-isomer of 1-phenyl-3-(N,N-dimethylamino)-1,2,3,4-tetrahydronaphthalene; this isomer is also more active at stimulating TH. Thus, certain 1-phenyl-3-amino-1,2,3,4-tetrahydronaphthalenes appear to be selective probes of a novel receptor type that mediates sigma-like neuromodulatory activity and may have pharmacotherapeutic utility in conditions in which modulation of dopamine function is important.