Force Characterization and Manufacturing of a Dynamic Unilateral Clubfoot Brace

Clubfoot is a musculoskeletal birth defect that is characterized by an inward twisting of an infant’s feet. The current method for correction involves several casts and a bilateral boots-and-bar maintenance brace. This method of maintenance requires 5 years of bracing and has issues with compliance, comfort, and social stigma. CURE International in Kijabe, Kenya is currently using the boots-and-bar brace but is interested in implementing a design that reduces these concerns. Mr. Jerald Cunningham, CPO, designed and is utilizing a unilateral clubfoot maintenance brace, the Cunningham Brace, which he expects will reduce treatment time to 2-3 years, lessen the social stigma, and increase the child’s mobility. However, there is not enough published research on its biomechanics and patient success rates to confirm his findings. The Collaboratory Cunningham Clubfoot Brace project seeks to validate the effectiveness of this design and increase accessibility through force testing and standardized manufacturing. We are working on measuring the biomechanical forces created and applied by the brace with a series of force sensors that are attached to the child’s brace. In addition, a new wrapping process for manufacturing the Cunningham Brace is being developed to increase the productivity and reproducibility of brace manufacturing in Kenya. Along with a clinical study that was started in Kenya, this testing and manufacturing will allow for further understanding of the effectiveness of the Cunningham Brace and provide more research for the medical community for it to potentially be accepted as an alternative clubfoot maintenance brace.https://mosaic.messiah.edu/engr2020/1014/thumbnail.jp

LPS from P. gingivalis

Objective. Oral inflammatory pathologies are linked to increased oxidative stress, thereby partly explaining their relevance in the etiology of systemic disorders. The purpose of this work was to determine the degree to which LPS from Porphyromonas gingivalis, the primary pathogen related to oral inflammation, altered gingival mitochondrial function and reactive oxygen species generation. Methods. Human gingival fibroblast (HGF-1) cells were treated with lipopolysaccharide of P. gingivalis. Mitochondrial function was determined via high-resolution respirometry. Results. LPS-treated HGF-1 cells had significantly higher mitochondrial complex IV and higher rates of mitochondrial respiration. However, this failed to translate into greater ATP production, as ATP production was paradoxically diminished with LPS treatment. Nevertheless, production of the reactive H2O2 was elevated with LPS treatment. Conclusions. LPS elicits an increase in gingival cell mitochondria content, with a subsequent increase in reactive oxygen species production (i.e., H2O2), despite a paradoxical reduction in ATP generation. These findings provide an insight into the nature of oxidative stress in oral inflammatory pathologies

Prediction of survival of HPV16-negative, p16-negative oral cavity cancer patients using a 13-gene signature: A multicenter study using FFPE samples

Objectives: To WA the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer. Materials and Methods: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease. Results: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent. Conclusions: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients

Deconstructing compassionate conservation

Compassionate conservation focuses on 4 tenets: first, do no harm; individuals matter; inclusivity of individual animals; and peaceful coexistence between humans and animals. Recently, compassionate conservation has been promoted as an alternative to conventional conservation philosophy. We believe examples presented by compassionate conservationists are deliberately or arbitrarily chosen to focus on mammals; inherently not compassionate; and offer ineffective conservation solutions. Compassionate conservation arbitrarily focuses on charismatic species, notably large predators and megaherbivores. The philosophy is not compassionate when it leaves invasive predators in the environment to cause harm to vastly more individuals of native species or uses the fear of harm by apex predators to terrorize mesopredators. Hindering the control of exotic species (megafauna, predators) in situ will not improve the conservation condition of the majority of biodiversity. The positions taken by so-called compassionate conservationists on particular species and on conservation actions could be extended to hinder other forms of conservation, including translocations, conservation fencing, and fertility control. Animal welfare is incredibly important to conservation, but ironically compassionate conservation does not offer the best welfare outcomes to animals and is often ineffective in achieving conservation goals. Consequently, compassionate conservation may threaten public and governmental support for conservation because of the limited understanding of conservation problems by the general public

The Immune Landscape of Undifferentiated Pleomorphic Sarcoma

INTRODUCTION: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. MATERIAL AND METHODS: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. RESULTS: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p\u3c0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p\u3c0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p\u3c0.0001) and DFS (p\u3c0.001). CONCLUSION: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS

Sarcomeric Pattern Formation by Actin Cluster Coalescence

Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells

Characterization of killer immunoglobulin-like receptor genetics and comprehensive genotyping by pyrosequencing in rhesus macaques

<p>Abstract</p> <p>Background</p> <p>Human killer immunoglobulin-like receptors (KIRs) play a critical role in governing the immune response to neoplastic and infectious disease. Rhesus macaques serve as important animal models for many human diseases in which KIRs are implicated; however, the study of KIR activity in this model is hindered by incomplete characterization of <it>KIR </it>genetics.</p> <p>Results</p> <p>Here we present a characterization of <it>KIR </it>genetics in rhesus macaques (<it>Macaca mulatta)</it>. We conducted a survey of <it>KIRs </it>in this species, identifying 47 novel full-length <it>KIR </it>sequences. Using this expanded sequence library to build upon previous work, we present evidence supporting the existence of 22 <it>Mamu-KIR </it>genes, providing a framework within which to describe macaque <it>KIRs</it>. We also developed a novel pyrosequencing-based technique for <it>KIR </it>genotyping. This method provides both comprehensive <it>KIR </it>genotype and frequency estimates of transcript level, with implications for the study of <it>KIRs </it>in all species.</p> <p>Conclusions</p> <p>The results of this study significantly improve our understanding of macaque <it>KIR </it>genetic organization and diversity, with implications for the study of many human diseases that use macaques as a model. The ability to obtain comprehensive KIR genotypes is of basic importance for the study of KIRs, and can easily be adapted to other species. Together these findings both advance the field of macaque KIRs and facilitate future research into the role of KIRs in human disease.</p

Don't Fall Off the Adaptation Cliff: When Asymmetrical Fitness Selects for Suboptimal Traits

The cliff-edge hypothesis introduces the counterintuitive idea that the trait value associated with the maximum of an asymmetrical fitness function is not necessarily the value that is selected for if the trait shows variability in its phenotypic expression. We develop a model of population dynamics to show that, in such a system, the evolutionary stable strategy depends on both the shape of the fitness function around its maximum and the amount of phenotypic variance. The model provides quantitative predictions of the expected trait value distribution and provides an alternative quantity that should be maximized (“genotype fitness”) instead of the classical fitness function (“phenotype fitness”). We test the model's predictions on three examples: (1) litter size in guinea pigs, (2) sexual selection in damselflies, and (3) the geometry of the human lung. In all three cases, the model's predictions give a closer match to empirical data than traditional optimization theory models. Our model can be extended to most ecological situations, and the evolutionary conditions for its application are expected to be common in nature

A foundation model for atomistic materials chemistry

Machine-learned force fields have transformed the atomistic modelling of materials by enabling simulations of ab initio quality on unprecedented time and length scales. However, they are currently limited by: (i) the significant computational and human effort that must go into development and validation of potentials for each particular system of interest; and (ii) a general lack of transferability from one chemical system to the next. Here, using the state-of-the-art MACE architecture we introduce a single general-purpose ML model, trained on a public database of 150k inorganic crystals, that is capable of running stable molecular dynamics on molecules and materials. We demonstrate the power of the MACE-MP-0 model - and its qualitative and at times quantitative accuracy - on a diverse set problems in the physical sciences, including the properties of solids, liquids, gases, chemical reactions, interfaces and even the dynamics of a small protein. The model can be applied out of the box and as a starting or "foundation model" for any atomistic system of interest and is thus a step towards democratising the revolution of ML force fields by lowering the barriers to entry.Comment: 119 pages, 63 figures, 37MB PD