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David Hutchinson,1,2 Judith Müller,3 Joseph E McCarthy,4 Yurii K Gun’ko,4,5 Navin Kumar Verma,6 Xuezhi Bi,7 Luisana Di Cristo,8 Laura Kickham,8 Dania Movia,8 Adriele Prina-Mello,5,8 Yuri Volkov5,8,9 1Royal Cornwall Hospital NHS Trust, Treliske, 2University of Exeter Medical School Cornwall, UK; 3University of Basel, Basel, Switzerland; 4School of Chemistry, 5Advanced Materials for BioEngineering Research Centre (AMBER), Trinity College Dublin, Dublin, Ireland; 6Lee Kong Chian School of Medicine, Nanyang Technological University, 7Bioprocessing Technology Institute, A*STAR Graduate Academy, Singapore; 8Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland; 9International Laboratory of Magnetically Controlled Nanosystems for Theranostics of Oncological and Cardiovascular Diseases, ITMO University, St. Petersburg, Russia Objective: The objective of the study was to determine whether the cadmium-derived materials induce intracellular protein citrullination. Methods: Human A549 lung epithelial cells were exposed to cadmium in soluble and nanoparticulate forms represented by cadmium chloride (CdCl2) and cadmium oxide (CdO), respectively, and their combinations with ultrafine carbon black (ufCB) produced by high temperature combustion, imitating cigarette burning. Protein citrullination in cell lysates was analyzed by Western immunoblotting and verified by immunofluorescent confocal microscopy. Target citrullinated proteins were identified by proteomic analysis. Results: CdO, ufCB and its combination with CdCl2 and CdO after high temperature combustion induced protein citrullination in cultured human lung epithelial cells, as detected by immunoblotting with anti-citrullinated protein antibody. Cytokeratins of type II (1, 2, 5, 6A, 6B and 77) and type I (9, 10) were identified as major intracellular citrullination targets. Immunofluorescent staining confirmed the localization of citrullinated proteins both in the cytoplasm and cell nuclei. Conclusion: Cadmium oxide nanoparticle exposure facilitated post-translational citrullination of proteins. Keywords: cadmium, COPD, nanoparticles, cytokeratins, citrullination, autoimmunity, proteomics

Abstract Background Label-free quantitative proteomics holds a great deal of promise for the future study of both medicine and biology. However, the data generated is extremely intricate in its correlation structure, and its proper analysis is complex. There are issues with missing identifications. There are high levels of correlation between many, but not all, of the peptides derived from the same protein. Additionally, there may be systematic shifts in the sensitivity of the machine between experiments or even through time within the duration of a single experiment. Results We describe a hierarchical model for analyzing unbiased, label-free proteomics data which utilizes the covariance of peptide expression across samples as well as MS/MS-based identifications to group peptides—a strategy we call metaprotein expression modeling. Our metaprotein model acknowledges the possibility of misidentifications, post-translational modifications and systematic differences between samples due to changes in instrument sensitivity or differences in total protein concentration. In addition, our approach allows us to validate findings from unbiased, label-free proteomics experiments with further unbiased, label-free proteomics experiments. Finally, we demonstrate the clinical/translational utility of the model for building predictors capable of differentiating biological phenotypes as well as for validating those findings in the context of three novel cohorts of patients with Hepatitis C. Conclusions Mass-spectrometry proteomics is quickly becoming a powerful tool for studying biological and translational questions. Making use of all of the information contained in a particular set of data will be critical to the success of those endeavors. Our proposed model represents an advance in the ability of statistical models of proteomic data to identify and utilize correlation between features. This allows validation of predictors without translation to targeted assays in addition to informing the choice of targets when it is appropriate to generate those assays.

Abstract Background Several studies have noted that genetic variants of SCARB1, a lipoprotein receptor involved in reverse cholesterol transport, are associated with serum lipid levels in a sex-dependent fashion. However, the mechanism underlying this gene by sex interaction has not been explored. Methods We utilized both epidemiological and molecular methods to study how estrogen and gene variants interact to influence SCARB1 expression and lipid levels. Interaction between 35 SCARB1 haplotype-tagged polymorphisms and endogenous estradiol levels was assessed in 498 postmenopausal Caucasian women from the population-based Rancho Bernardo Study. We further examined associated variants with overall and SCARB1 splice variant (SR-BI and SR-BII) expression in 91 human liver tissues using quantitative real-time PCR. Results Several variants on a haplotype block spanning intron 11 to intron 12 of SCARB1 showed significant gene by estradiol interaction affecting serum lipid levels, the strongest for rs838895 with HDL-cholesterol (p = 9.2 × 10-4) and triglycerides (p = 1.3 × 10-3) and the triglyceride:HDL cholesterol ratio (p = 2.7 × 10-4). These same variants were associated with expression of the SR-BI isoform in a sex-specific fashion, with the strongest association found among liver tissue from 52 young women Conclusions Estrogen and SCARB1 genotype may act synergistically to regulate expression of SCARB1 isoforms and impact serum levels of HDL cholesterol and triglycerides. This work highlights the importance of considering sex-dependent effects of gene variants on serum lipid levels.

Background: The human peripheral nervous system embodies anatomical, physiologic, and diagnostic perplexities that remain unexplained. Yet in the course of human history, there are no mechanisms, such as computed tomography (CT) or radiography, by which to image the peripheral nervous system in vivo using a contrast agent that is identified by ionizing radiation, which would aid in surgical navigation, diagnostic radiology, and basic science thereof., Methods: A novel class of contrast was created by linking iodine to lidocaine. The radiodensity of 0.5% experimental contrast molecule was compared with a control of 1% lidocaine by placing 1.5-mL aliquots of each liquid into centrifuge tubes and performing micro-computed tomography (micro-CT) synchronously under identical settings. Physiologic binding to the sciatic nerve was evaluated by injecting 10 mg of the experimental contrast and 10 mg of the control into the contralateral sciatic nerve, and documenting loss of hindlimb function and recovery. In vivo visualization of the sciatic nerve was evaluated by injecting 10 mg of experimental contrast or control into either sciatic nerve and imaging the hindlimbs under identical conditions using micro-CT., Results: The mean Hounsfield unit of the contrast was 56.09 compared with -0.48 for control (116-fold increase, P = .0001). Hindlimb paresis revealed similar degree of paresis, baseline recovery, and time to recovery. In vivo enhancement between the contralateral sciatic nerves was similar., Conclusion: Iodinated lidocaine offers a viable mechanism for in vivo peripheral nerve imaging using CT; however, it requires modification to improve in vivo radiodensity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The sensory-collapse test (formerly the scratch-collapse test) is a physical examination finding describing a momentary inhibition of external shoulder rotation following light stimulation of an injured nerve in the ipsilateral limb. Similar to other physical examination tests designed to interrogate nerve compression, such as the Phalen or Tinel tests, its test characteristics demonstrate variation. There remains speculation about the test's existence and anatomic basis. The literature of mammalian reflex physiology was reviewed with an emphasis on the sensory pathways from the upper extremity, the extrapyramidal system, and newly discovered pathways and concepts of nociception. A clear reflex pathway is described connecting the stimulus within an injured nerve through the afferent pathways in the fasciculus cuneatus in the spinal cord directly to the lateral reticulospinal tract, resulting in the inhibition of extensor muscles in the proximal limb (eg, shoulder) and activation of the limb flexors by acting upon alpha and gamma motor neurons. The sensory-collapse test represents a reflex pathway that teleologically provides a mechanism to protect an injured nerve by withdrawal toward the trunk and away from the noxious environment., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Borrelia burgdorferi (Bb), the causative agent of Lyme disease, establishes a long-term infection and leads to disease manifestations that are the result of host immune responses to the pathogen. Inflammatory manifestations resolve spontaneously despite continued bacterial presence, suggesting inflammatory cells become less responsive over time. This is mimicked by in vitro repeated stimulations, resulting in tolerance, a phenotypic subset of innate immune memory. We performed comparative transcriptional analysis of macrophages in acute and memory states and identified sets of Tolerized, Hyper-Induced, Secondary-Induced and Hyper-Suppressed genes resulting from memory induction, revealing previously unexplored networks of genes affected by cellular re-programming. Tolerized gene families included inflammatory mediators and interferon related genes as would be predicted by the attenuation of inflammation over time. To better understand how cells mediate inflammatory hypo-responsiveness, we focused on genes that could mediate maintenance of suppression, such as Hyper-Induced genes which are up-regulated in memory states. These genes were notably enriched in stress pathways regulated by anti-inflammatory modulators. We examined one of the most highly expressed negative regulators of immune pathways during primary stimulation, Aconitate decarboxylase 1 (Acod1), and tested its effects during in vivo infection with Bb. As predicted by our in vitro model, we show its inflammation-suppressive downstream effects are sustained during in vivo long-term infection with Bb, with a specific role in Lyme carditis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Petnicki-Ocwieja et al. This 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.)

Lyme disease is caused by the bacterial pathogen Borrelia burgdorferi , which can be readily modeled in laboratory mice. In order to understand the cellular and transcriptional changes that occur during B. burgdorferi infection, we conducted single-cell RNA sequencing (scRNA-seq) of ankle joints of infected C57BL/6 mice over time. We found that macrophages/monocytes, T cells, synoviocytes and fibroblasts all showed significant differences in gene expression of both inflammatory and non-inflammatory genes that peaked early and returned to baseline before the typical resolution of arthritis. Predictions of cellular interactions showed that macrophages appear to communicate extensively between different clusters of macrophages as well as with fibroblasts and synoviocytes. Our data give unique insights into the interactions between B. burgdorferi and the murine immune system over time and allow for a better understanding of mechanisms by which the dysregulation of the immune response may lead to prolonged symptoms in some patients., Competing Interests: L.T.H. receives support for contract research services through Tufts University from companies including Moderna, Sanofi, Tarsus, and Massbiologics for vaccine and drug development unrelated to the content of this article., (© 2023 The Author(s).)

Objective: Neurodegenerative conditions often manifest radiologically with the appearance of premature aging. Multiple sclerosis (MS) biomarkers related to lesion burden are well developed, but measures of neurodegeneration are less well-developed. The appearance of premature aging quantified by machine learning applied to structural MRI assesses neurodegenerative pathology. We assess the explanatory and predictive power of "brain age" analysis on disability in MS using a large, real-world dataset., Methods: Brain age analysis is predicated on the over-estimation of predicted brain age in patients with more advanced pathology. We compared the performance of three brain age algorithms in a large, longitudinal dataset (>13,000 imaging sessions from >6,000 individual MS patients). Effects of MS, MS disease course, disability, lesion burden, and DMT efficacy were assessed using linear mixed effects models., Results: MS was associated with advanced predicted brain age cross-sectionally and accelerated brain aging longitudinally in all techniques. While MS disease course (relapsing vs. progressive) did contribute to advanced brain age, disability was the primary correlate of advanced brain age. We found that advanced brain age at study enrollment predicted more disability accumulation longitudinally. Lastly, a more youthful appearing brain (predicted brain age less than actual age) was associated with decreased disability., Interpretation: Brain age is a technically tractable and clinically relevant biomarker of disease pathology that correlates with and predicts increasing disability in MS. Advanced brain age predicts future disability accumulation., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Borrelia burgdorferi is a pathogenic bacterium and the causative agent of Lyme disease. It is exposed to reactive oxygen species (ROS) in both the vertebrate and tick hosts. While some mechanisms by which B. burgdorferi ameliorates the effects of ROS exposure have been studied, there are likely other unknown mechanisms of ROS neutralization that contribute to virulence. Here, we follow up on a three gene cluster of unknown function, bb_0554, bb_0555, and bb_0556, that our prior unbiased transposon insertional sequencing studies implicated in both ROS survival and survival in Ixodes scapularis . We confirmed these findings through genetic knockout and provide evidence that these genes are co-transcribed as an operon to produce a xanthine dehydrogenase. In agreement with these results, we found that B. burgdorferi exposure to either uric acid (a product of xanthine dehydrogenase) or allopurinol (an inhibitor of xanthine dehydrogenase) could modulate sensitivity to ROS in a bb_0554-bb_0556 dependent manner. Together, this study identifies a previously uncharacterized three gene operon in B. burgdorferi as encoding a putative xanthine dehydrogenase critical for virulence. We propose renaming this locus xdhACB .

Prior studies of aging and Alzheimer disease have evaluated resting state functional connectivity (FC) using either seed-based correlation (SBC) or independent component analysis (ICA), with a focus on particular functional systems. SBC and ICA both are insensitive to differences in signal amplitude. At the same time, accumulating evidence indicates that the amplitude of spontaneous BOLD signal fluctuations is physiologically meaningful. We systematically compared covariance-based FC, which is sensitive to amplitude, vs. correlation-based FC, which is not, in affected individuals and controls drawn from two cohorts of participants including autosomal dominant Alzheimer disease (ADAD), late onset Alzheimer disease (LOAD), and age-matched controls. Functional connectivity was computed over 222 regions of interest and group differences were evaluated in terms of components projected onto a space of lower dimension. Our principal observations are: (1) Aging is associated with global loss of resting state fMRI signal amplitude that is approximately uniform across resting state networks. (2) Thus, covariance FC measures decrease with age whereas correlation FC is relatively preserved in healthy aging. (3) In contrast, symptomatic ADAD and LOAD both lead to loss of spontaneous activity amplitude as well as severely degraded correlation structure. These results demonstrate a double dissociation between age vs. Alzheimer disease and the amplitude vs. correlation structure of resting state BOLD signals. Modeling results suggest that the AD-associated loss of correlation structure is attributable to a relative increase in the fraction of locally restricted as opposed to widely shared variance., Competing Interests: Declaration of Competing Interest Randall J. Bateman Randall Bateman (RJB), Professor of Neurology at Washington University's School of Medicine (WUSM) receives lab research funding from the National Institutes of Health, Alzheimer's Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, the Cure Alzheimer's Fund, Centene Corporation, Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Company), and an anonymous organization. RJB has received honoraria as a speaker/consultant/advisory board member from Amgen, AC Immune, Eisai, F. Hoffman-LaRoche, and Janssen; and reimbursement of travel expenses from AC Immune, F. Hoffman-La Roche and Janssen. Unrelated to this article, RJB serves as principal investigator of the DIAN-TU, which is supported by the Alzheimer's Association, GHR Foundation, an anonymous organization and the DIAN-TU Pharma Consortium (Active: Eli Lilly and Company/Avid Radiopharmaceuticals, F. Hoffman-La Roche/Genentech, Biogen, Eisai, Janssen, and United Neuroscience. Previous: Abbvie, Amgen, AstraZeneca, Forum, Mithridion, Novartis, Pfizer, Sanofi). The DIAN-TU-001 Clinical Trial is supported by Pharmaceutical Partners Eli Lilly and Company, F. Hoffman-La Roche and Janssen, the Alzheimer's Association, NIH U01AG042791, NIH U01AG42791-S1 (FNIH and Accelerating Medicines Partnership), NIH R01AG046179, NIH R56AG053267, NIH R01AG053267, NIH U01AG059798, NIH R01AG068319, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous organization. In-kind support has been received from CogState and Bracket. Washington University, Randall Bateman, and David Holtzman have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition”. Tammie L.S. Benzinger Dr. Benzinger reports grants and non-financial support from Avid Radiopharmaceuticals/ Eli Lilly, during the conduct of the study; grants and non-financial support from Avid Radiopharmaceuticals/ Eli Lilly, other from Eli Lilly, Biogen, Eisai, Jaansen, personal fees from Biogen, non-financial support from Eisai, non-financial support from Siemens, outside the submitted work. Matthew R. Brier Dr. Brier reports grants from NIH, during the conduct of the study. Gregory S. Day Dr. Day reports grants from NIH, during the conduct of the study; personal fees from Parabon Nanolabs, Inc, personal fees from DynaMed (EBSCO Health), outside the submitted work. Brian A. Gordon Dr. Gordon reports participation in clinical trials of therapies to alter the course of Alzheimer Disease. Neill Graff-Radford Dr. Graff-Radford reports grants from NIH, during the conduct of the study; grants from Biogen, grants from AbbVie, grants from Lilly, outside the submitted work. Taleshi Ikeuchi Dr. Ikeuchi reports grants from AMED (Japan Agency for Medical Research and Development), during the conduct of the study. Daniel S. Marcus Dr. Marcus reports other from Radiologics, Inc, outside the submitted work. John C. Morris Dr. Morris reports grants from NIH grant P30 AG066444, grants from NIH grant P01AG003991, grants from NIH grant P01AG026276, grants from NIH grant UF1AG032438, during the conduct of the study. Richard J. Perrin Dr. Perrin reports grants from NIH during the conduct of the study. Stephen Salloway Dr. Salloway reports grants and personal fees from Biogen, grants and personal fees from Eisai, grants and personal fees from Avid, grants and personal fees from Lilly, personal fees from Genentech, personal fees from Novartis, grants and personal fees from Roche, outside the submitted work. Peter Schofield Dr. Schofield reports grants from NIH, grants from Anonymous Foundation, grants from Roth Charitable Foundation, during the conduct of the study. Abraham Z. Snyder Dr. Snyder is a consultant for Sora Neuroimaging, LLC., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Lyme disease bacterial pathogen, Borrelia burgdorferi, establishes a long-term infection inside its mammalian hosts. Despite the continued presence of the bacteria in animal models of disease, inflammation is transitory and resolves spontaneously. T cells with limited effector functions and the inability to become activated by antigen, termed exhausted T cells, are present in many long-term infections. These exhausted T cells mediate a balance between pathogen clearance and preventing tissue damage resulting from excess inflammation. Exhausted T cells express a variety of immunoinhibitory molecules, including the molecule PD-1. Following B. burgdorferi infection, we found that PD-1 and its ligand PD-L1 are significantly upregulated on CD4+ T cells and antigen presenting cell subsets, respectively. Using mice deficient in PD-1, we found that the PD-1/PD-L1 pathway did not impact bacterial clearance but did impact T cell expansion and accumulation in the ankle joint and popliteal lymph nodes without affecting B cell populations or antibody production, suggesting that the PD-1/PD-L1 pathway may play a role in shaping the T cell populations present in affected tissues., Competing Interests: I have read the journal’s policy and the authors of the manuscript have the following competing interests: LTH receives support for contract research services through Tufts University from companies including Moderna, Sanofi, Tarsus, and Massbiologics for vaccine and drug development unrelated to the content of this manuscript. All other authors report no competing interests.

During the COVID-19 pandemic, significantly fewer of New York City's (NYC's) 1.1 million public school children participated in emergency grab-and-go meals-heightening the risk of inadequate nutrition security for many of NYC's most vulnerable residents. This study sought to examine student families' facilitators and barriers to participation in the grab-and-go meal service and their experiences with pandemic-electronic benefit transfer (P-EBT) funds, a cash benefit distributed when schools were closed. We recruited 126 parents of children in NYC public schools who had participated in the grab-and-go service. Using opened-ended questions, we interviewed 101 parents in 25 1-h online focus groups. We identified four main themes which broadly impacted school meal participation: communication, logistics, meal appeal, and personal circumstances. Key facilitating subthemes included clear communication, ease of accessing sites, and high variety. Key sub-themes negatively impacting participation included limited communication and low meal variety. Accurate, timely communication; easily accessible distribution locations; and convenient distribution times could have increased participation and satisfaction. For P-EBT, parents welcomed the funds and used them readily, but some experienced difficulties obtaining payments. The simultaneous inclusion of community-based research in the evaluation of emergency feeding programs could improve future outcomes for school meal participation and electronic benefits., Competing Interests: J.W.C., T.T.T.N., M.R. and P.A.K. have no known conflict of interest. J.A.M., initially had no relationship with the funder when the study was first conceptualized, designed, and funding obtained. After the study commenced, J.A.M. was employed by the funder and assisted with the review and editing of the manuscript. However, given the nature of the study, the authors do not believe this constitutes a conflict of interest.

Background: The COVID-19 pandemic created barriers to participation in school meals. As a result, many students may have missed out on school meals. The objectives of this study are (1) to compare the number of school meals served by New York State public schools during the first spring and summer of the COVID-19 pandemic to the number served before the COVID-19 pandemic, and (2) to determine relationships between the number of meals served and the levels of school district need and urbanicity., Methods: This study is a secondary analysis of administrative data. The percentage change in the number of school breakfasts and lunches served was calculated for each month and by school district need level and urbanicity level., Results: The number of school meals served decreased during the first spring of the pandemic compared to the spring of the previous school year (-43% in April, -51% in May), while the number of school meals served increased during the first summer of the pandemic compared to the summer of the previous school year (+92% in July, +288% in August)., Conclusions: Waivers may provide flexibility to increase participation in school meals, especially during the summer.

Lyme disease is on the rise. Caused by a spirochete Borreliella burgdorferi, it affects an estimated 500,000 people in the United States alone. The antibiotics currently used to treat Lyme disease are broad spectrum, damage the microbiome, and select for resistance in non-target bacteria. We therefore sought to identify a compound acting selectively against B. burgdorferi. A screen of soil micro-organisms revealed a compound highly selective against spirochetes, including B. burgdorferi. Unexpectedly, this compound was determined to be hygromycin A, a known antimicrobial produced by Streptomyces hygroscopicus. Hygromycin A targets the ribosomes and is taken up by B. burgdorferi, explaining its selectivity. Hygromycin A cleared the B. burgdorferi infection in mice, including animals that ingested the compound in a bait, and was less disruptive to the fecal microbiome than clinically relevant antibiotics. This selective antibiotic holds the promise of providing a better therapeutic for Lyme disease and eradicating it in the environment., Competing Interests: Declaration of interests K.L. serves on the scientific advisory board of Flightpath., (Copyright © 2021 Elsevier Inc. All rights reserved.)

RMD-1,2,3,6 (regulator of microtubule dynamics) is a family of homologous proteins conserved between humans and C. elegans . Human RMD-3/PTPIP51 is a mitochondrial protein that tethers mitochondria to the endoplasmic reticulum. C. elegans RMD-2, 3, and 6 are expressed in sperm. To test whether paternal RMD-2, 3, 6 might redundantly tether paternal mitochondria to maternal ER at fertilization, we generated an rmd-2, rmd-3, rmd-6 triple mutant. Paternal mitochondria derived from control or triple mutant worms were concentrated in a cloud around the paternal DNA at the future posterior end of zygotes during meiosis. No significant difference was detected in the position of paternal mitochondria within the zygote nor in the position of paternal mitochondria relative to paternal DNA within the zygote. There was also no reduction in progeny viability between control and triple mutant worms., (Copyright: © 2021 by the authors.)

Unrecognized immunodeficiency has been proposed as a possible cause of failure of antibiotics to resolve symptoms of Lyme disease. Here, we examined the efficacy of doxycycline in different immunodeficient mice to identify defects that impair antibiotic treatment outcomes. We found that doxycycline had significantly lower efficacy in the absence of adaptive immunity, specifically B cells. This effect was most pronounced in immunodeficient C3H mice compared with C57BL/6 mice, suggesting a role for genetic background beyond immunodeficiency. Addition of a single dose of ceftriaxone to doxycycline treatment effectively cleared infection in C3H mice with severe combined immunodeficiency., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The bacterial pathogen Borrelia burgdorferi is the causative agent of Lyme disease and is transmitted to humans through an Ixodes tick vector. B. burgdorferi is able to survive in both mammalian and tick hosts through careful modulation of its gene expression. This allows B. burgdorferi to adapt to the environmental and nutritional changes that occur when it is transmitted between the two hosts. Distinct interactions between the spirochete and its host occur at every step of the enzootic cycle and dictate the ability of the spirochete to survive until the next stage of the cycle. Studying the interface between B. burgdorferi, the Ixodes tick vector and the natural mammalian reservoirs has been made significantly more feasible through the complete genome sequences of the organisms and the advent of high throughput screening technologies. Ultimately, a thorough investigation of the interplay between the two domains (and two phyla within one domain) is necessary in order to completely understand how the pathogen is transmitted., (© 2020 John Wiley & Sons Ltd.)

Risk-cost-benefit analysis requires the enumeration of decision alternatives, their associated outcomes, and the quantification of uncertainty. Public and private decision-making surrounding the COVID-19 pandemic must contend with uncertainty about the probability of infection during activities involving groups of people, in order to decide whether that activity is worth undertaking. We propose a model of SARS-CoV-2 infection probability that can produce estimates of relative risk of infection for diverse activities, so long as those activities meet a list of assumptions, including that they do not last longer than one day (e.g., sporting events, flights, concerts), and that the probability of infection among possible routes of infection (i.e., droplet, aerosol, fomite, and direct contact) are independent. We show how the model can be used to inform decisions facing governments and industry, such as opening stadiums or flying on airplanes; in particular, it allows for estimating the ranking of the constituent components of activities (e.g., going through a turnstile, sitting in one's seat) by their relative risk of infection, even when the probability of infection is unknown or uncertain. We prove that the model is a good approximation of a more refined model in which we assume infections come from a series of independent risks. A linearity assumption governing several potentially modifiable risks factors-such as duration of the activity, density of participants, and infectiousness of the attendees-makes interpreting and using the model straightforward, and we argue that it does so without significantly diminishing the reliability of the model., Competing Interests: BAD is the owner of W. Etienne Dumas Co., an S Corporation in the state of Washington that is a vendor to Omnium LLC. JEM is the owner of E M C Squared and MTM is a vendor to E M C Squared, which is a vendor to Omnium LLC. JEM, BAD, and MTM received funding through Omnium LLC in Omnium’s capacity as a consultant for Delaware North, a company that may be affected by the research reported in the paper. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Gambling-related cognitive distortions are associated with gambling disorder severity, but few studies have provided an in-depth examination of the interrelationship between cognitive distortions, gambling severity, psychiatric comorbidity and treatment outcomes. The present study sought to identify factors associated with elevated cognitive distortions among problem gamblers entering residential treatment, examine changes in cognitive distortions through treatment, and explore the association between cognitive distortions and treatment outcomes. Pre- and post-treatment data were extracted from the charts of 125 individuals who participated in a 21-day residential treatment program for gambling disorder. Assessments included measures of demographics, gambling disorder severity, psychiatric symptoms and gambling-related cognitive distortions. Several significant associations were found between baseline cognitive distortions and psychiatric symptoms. Cognitive distortions decreased significantly from pre- to post-treatment. Pre- to post-treatment changes on several cognitive distortion scales were positively associated with greater baseline psychiatric symptomology. Treatment drop-out was associated with higher scores on measures reflecting greater impulsivity/addiction and greater perceived predictive control. Gambling-related cognitive distortions represent an important mechanism of gambling disorder and its treatment and provide a target for the development and refinement of treatment for gambling disorder.

It is often seen as axiomatic in the social capital literature that relationships require ongoing maintenance to remain valuable. As a result, nearly all social network research has only considered relationships that are active (or recently restored to activity after a period of dormancy). Seldom considered is the impact of still-dormant, unmaintained ties that remain dormant. Using two bounded-network studies (one in a school district, one in a private company), we find consistently that still-dormant ties increase employees' organizational commitment. However, we also find that active ties can "dilute" this effect, rendering dormant ties less relevant and meaningful to individuals, or act as "preservatives" keeping dormant ties relevant and valued. In a third, vignette-based study, we find two mechanisms for the effect of dormant ties on organizational commitment: perceptions of the past (fond recollections) and future (information access). Thus, we offer a more time-oriented, layered theory of social network ties that can be activated in people's minds even when not active in practice. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Image-based classification of liver disease generally lacks specificity for distinguishing between acute, resolvable injury and chronic irreversible injury. We propose that ultrasound radiofrequency data acquired in vivo from livers subjected to toxic drug injury can be analyzed with information theoretic detectors to derive entropy metrics, which classify a statistical distribution of pathologic scatterers that dissipate over time as livers heal. Here we exposed 38 C57BL/6 mice to carbon tetrachloride to cause liver damage, and imaged livers in vivo 1, 4, 8, 12 and 18 d after exposure with a broadband 15-MHz probe. Selected entropy metrics manifested monotonic recovery to normal values over time as livers healed, and were correlated directly with progressive restoration of liver architecture by histologic assessment (r 2 ≥ 0.95, p < 0.004). Thus, recovery of normal liver microarchitecture after toxic exposure can be delineated sensitively with entropy metrics., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

We prove a Julia inequality for bounded non-commutative functions on polynomial polyhedra. We use this to deduce a Julia inequality for holomorphic functions on classical domains in ℂ d . We look at differentiability at a boundary point for functions that have a certain regularity there.

Background: Across the world, many species of nondomesticated animals dwell among humans in metropolitan areas. Rare animal bites pose a dilemma for hand surgeons, as they often result in operative injuries and recalcitrant infections. The authors treated an 85-year-old man who experienced severe cellulitis of the index finger following an opossum bite. This case prompted a systematic review of upper extremity injuries caused by species other than dogs, cats, snakes, and insects., Methods: The authors conducted a systematic review of PubMed and Scopus databases to identify relevant articles published between 1980 and 2016. Two reviewers critically appraised the studies that met inclusion and exclusion criteria., Results: The hand infection in the man who sustained an opossum bite at the authors' institution was successfully treated with targeted antibiotic therapy, hand elevation, and splinting. Seventy-one articles met inclusion criteria for and were included in this systematic review. The vast majority of existing articles represent level IV and level V evidence. The relevant literature suggests that the majority of hand infections attributable to animal bites and stings are polymicrobial., Conclusions: Injuries secondary to aquatic animals appear to be the most frequently described in the literature, and hot water immersion should be used for the majority of envenomation attributable to aquatic species. Infections can often be treated with an aminopenicillin antibiotic combined with a beta-lactamase inhibitor. Given the variability in presentation and potential for sequelae such as soft-tissue necrosis and systemic reactions, hand surgeons should approach such upper extremity injuries with a high degree of caution.

Measurement of correlations between brain regions (functional connectivity) using blood oxygen level dependent (BOLD) fMRI has proven to be a powerful tool for studying the functional organization of the brain. Recently, dynamic functional connectivity has emerged as a major topic in the resting-state BOLD fMRI literature. Here, using simulations and multiple sets of empirical observations, we confirm that imposed task states can alter the correlation structure of BOLD activity. However, we find that observations of "dynamic" BOLD correlations during the resting state are largely explained by sampling variability. Beyond sampling variability, the largest part of observed "dynamics" during rest is attributable to head motion. An additional component of dynamic variability during rest is attributable to fluctuating sleep state. Thus, aside from the preceding explanatory factors, a single correlation structure-as opposed to a sequence of distinct correlation structures-may adequately describe the resting state as measured by BOLD fMRI. These results suggest that resting-state BOLD correlations do not primarily reflect moment-to-moment changes in cognitive content. Rather, resting-state BOLD correlations may predominantly reflect processes concerned with the maintenance of the long-term stability of the brain's functional organization., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Gene expression noise influences organism evolution and fitness. The mechanisms determining the relationship between stochasticity and the functional role of translation machinery components are critical to viability. eIF4G is an essential translation factor that exerts strong control over protein synthesis. We observe an asymmetric, approximately bell-shaped, relationship between the average intracellular abundance of eIF4G and rates of cell population growth and global mRNA translation, with peak rates occurring at normal physiological abundance. This relationship fits a computational model in which eIF4G is at the core of a multi-component-complex assembly pathway. This model also correctly predicts a plateau-like response of translation to super-physiological increases in abundance of the other cap-complex factors, eIF4E and eIF4A. Engineered changes in eIF4G abundance amplify noise, demonstrating that minimum stochasticity coincides with physiological abundance of this factor. Noise is not increased when eIF4E is overproduced. Plasmid-mediated synthesis of eIF4G imposes increased global gene expression stochasticity and reduced viability because the intrinsic noise for this factor influences total cellular gene noise. The naturally evolved eIF4G gene expression noise minimum maps within the optimal activity zone dictated by eIF4G's mechanistic role. Rate control and noise are therefore interdependent and have co-evolved to share an optimal physiological abundance point., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The purpose of this article is to describe the indications, operative technique, outcomes, and systematic review of the literature on the reconstruction of patients with end-stage pressure ulcers using a fillet flap technique. In this technique, the femur, tibia, and fibula are removed from the thigh and leg, and the soft tissue is used as a pedicled, or free, myocutaneous flap for reconstruction. Long-term outcomes, salient surgical technique of flap elevation, and design are detailed for patients who had a fillet of leg flap for reconstruction of extensive pressure ulcers., Methods: The indications, surgical technique, and postoperative outcomes of 5 patients who had pedicled fillet flaps are reviewed including patient age, sex, underlying comorbidities, duration of paraplegia, operative technique, and complications. A systematic review of the literature was performed searching PubMed, Cochrane Database, and Medline with the following MeSH terms: pressure ulcer, pressure sore, decubitus ulcer, fillet flap, and fillet flap. Inclusion criteria were use of a fillet technique, article data on the number of reconstructions before fillet flap, complications, and English language., Results: Most of our patients were male 75% (n = 3) with an average age of 47.5 years, had been paralyzed for an average of 16 years, and had few medical comorbidities. Two patients (3 flaps) required hip disarticulation, 1 patient had a bilateral fillet flaps, and 3 patients had resection of tibia/fibula. After following patients for an average of 1.4 years (4 mo to 2 yr), complications were limited to 1 patient who had partial-thickness flap loss at the distal skin flap that healed by secondary intention and 1 patient who had ulcer recurrence because of noncompliance. Four articles met inclusion criteria for systematic review and 3 were excluded., Conclusions: The fillet of leg flap remains a useful and reliable method of reconstructing end-stage pressure ulcers., Competing Interests: The authors have no financial interest to declare in relation to the content of this article. The Article Processing Charge was paid for by the authors.

This works aim is to evaluate the efficacy of skin grafts and flaps in reconstruction of post-burn hand and wrist deformities. A prospective study of 57 burn contractures of the wrist and dorsum of the hand was performed. Flaps were used only if there was a non-vascularized structure after contracture release, otherwise a skin graft was used. Active range of motion (ROM) was used to assess hand function. The extension deformity cohort uniformly underwent skin graft following contracture release with a mean improvement of 71 degrees (p<0.0001). The flexion deformity cohort was treated with either skin grafts (8 patients) or flaps (9 patients) with a mean improvement of 44 degrees (p<0.0001). Skin grafts suffice for dorsal hand contractures to restore functional wrist ROM. For flexion contractures, flaps were more likely for contractures >6 months. Early release of burn contracture is advisable to avoid deep structure contracture., (Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.)

Two different signal processing algorithms are described for detection and classification of acoustic signals generated by firearm discharges in small enclosed spaces. The first is based on the logarithm of the signal energy. The second is a joint entropy. The current study indicates that a system using both signal energy and joint entropy would be able to both detect weapon discharges and classify weapon type, in small spaces, with high statistical certainty.

Amyloid-beta plaques are a hallmark of Alzheimer's disease (AD) that can be assessed by amyloid imaging (e.g., Pittsburgh B compound [PiB]) and summarized as a scalar value. Summary values may have clinical utility but are an average over many regions of interest, potentially obscuring important topography. This study investigates the longitudinal evolution of amyloid topographies in cognitively normal older adults who had normal (N = 131) or abnormal (N = 26) PiB scans at baseline. At 3 years follow-up, 16 participants with a previously normal PiB scan had conversion to PiB scans consistent with preclinical AD. We investigated the multivariate relationship (canonical correlation) between baseline and follow-up PiB topographies. Furthermore, we used penalized regression to investigate the added information derived from PiB topography compared to summary measures. PiB accumulation can be local, that is, a topography predicting the same topography in the future, and/or distributed, that is, one topography predicting another. Both local and distributed PiB accumulation was associated with conversion of PiB status. Additionally, elements of the multivariate topography, and not the commonly used summary scalar, correlated with future PiB changes. Consideration of the entire multivariate PiB topography provides additional information regarding the development of amyloid-beta pathology in very early preclinical AD., Competing Interests: statement The authors report no conflict of interest. This study was funded by the NIH as specified in the acknowledgements., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We characterize functions of d -tuples of bounded operators on a Hilbert space that are uniformly approximable by free polynomials on balanced open sets.

Yeast commits approximately 76% of its energy budget to protein synthesis and the efficiency and control of this process are accordingly critical to organism growth and fitness. We now have detailed genetic, biochemical and biophysical knowledge of the components of the eukaryotic translation machinery. However, these kinds of information do not, in themselves, give us a satisfactory picture of how the overall system is controlled. This is where quantitative system analysis can enable a step-change in our understanding of biological resource management and how this relates to cell physiology and evolution. An important aspect of this more system-oriented approach to translational control is the inherent heterogeneity of cell populations that is generated by gene expression noise. In this short review, we address the fact that, although the vast majority of our knowledge of the translation machinery is based on experimental analysis of samples that each contain hundreds of millions of cells, in reality every cell is unique in terms of its composition and control properties. We have entered a new era in which research into the heterogeneity of cell systems promises to provide answers to many (previously unanswerable) questions about cell physiology and evolution., (© 2015 Authors; published by Portland Press Limited.)

Functional connectivity refers to shared signals among brain regions and is typically assessed in a task free state. Functional connectivity commonly is quantified between signal pairs using Pearson correlation. However, resting-state fMRI is a multivariate process exhibiting a complicated covariance structure. Partial covariance assesses the unique variance shared between two brain regions excluding any widely shared variance, hence is appropriate for the analysis of multivariate fMRI datasets. However, calculation of partial covariance requires inversion of the covariance matrix, which, in most functional connectivity studies, is not invertible owing to rank deficiency. Here we apply Ledoit-Wolf shrinkage (L2 regularization) to invert the high dimensional BOLD covariance matrix. We investigate the network organization and brain-state dependence of partial covariance-based functional connectivity. Although RSNs are conventionally defined in terms of shared variance, removal of widely shared variance, surprisingly, improved the separation of RSNs in a spring embedded graphical model. This result suggests that pair-wise unique shared variance plays a heretofore unrecognized role in RSN covariance organization. In addition, application of partial correlation to fMRI data acquired in the eyes open vs. eyes closed states revealed focal changes in uniquely shared variance between the thalamus and visual cortices. This result suggests that partial correlation of resting state BOLD time series reflect functional processes in addition to structural connectivity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Graphene has been envisaged as a highly promising material for various field emission devices, supercapacitors, photocatalysts, sensors, electroanalytical systems, fuel cells and photovoltaics. The main goal of our work is to develop new Pt and transparent conductive oxide (TCO) free graphene based counter electrodes (CEs) for dye sensitized solar cells (DSSCs). We have prepared new composites which are based on graphene nano-platelets (GNPs) and conductive polymers such as poly (3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS). Films of these composites were deposited on non-conductive pristine glass substrates and used as CEs for DSSCs which were fabricated by the "open cell" approach. The electrical conductivity studies have clearly demonstrated that the addition of GNPs into PEDOT:PSS films resulted in a significant increase of the electrical conductivity of the composites. The highest solar energy conversion efficiency was achieved for CEs comprising of GNPs with the highest conductivity (190 S/cm) and n-Methyl-2-pyrrolidone (NMP) treated PEDOT:PSS in a composite film. The performance of this cell (4.29% efficiency) compares very favorably to a DSSC with a standard commercially available Pt and TCO based CE (4.72% efficiency in the same type of open DSSC) and is a promising replacement material for the conventional Pt and TCO based CE in DSSCs.

Virtually all modern imaging devices collect electromagnetic or acoustic waves and use the energy carried by these waves to determine pixel values to create what is basically an "energy" picture. However, waves also carry "information", as quantified by some form of entropy, and this may also be used to produce an "information" image. Numerous published studies have demonstrated the advantages of entropy, or "information imaging", over conventional methods. The most sensitive information measure appears to be the joint entropy of the collected wave and a reference signal. The sensitivity of repeated experimental observations of a slowly-changing quantity may be defined as the mean variation ( i.e. , observed change) divided by mean variance ( i.e. , noise). Wiener integration permits computation of the required mean values and variances as solutions to the heat equation, permitting estimation of their relative magnitudes. There always exists a reference, such that joint entropy has larger variation and smaller variance than the corresponding quantities for signal energy, matching observations of several studies. Moreover, a general prescription for finding an "optimal" reference for the joint entropy emerges, which also has been validated in several studies.

A series of xAs40Se60·(100 - x)As40S60 glasses, where x = 0, 25, 33, 50, 67, 75 and 100 mol% As40Se60, has been studied using neutron and X-ray total scattering, Raman spectroscopy and (77)Se MAS-NMR. The results are presented with measurements of non-linear refractive indices, n2, and densities. There is no evidence for the formation of homopolar bonds in these glasses, but neutron correlation functions suggest that there is a non-random distribution of sulfur and selenium atoms in sulfur-rich glasses. The average number of sulfur atoms at a distance of 3-4 Å from a selenium atom, nSeS, deviates from a linear variation with x in glasses containing <50 mol% As40Se60; n2 for these glasses also varies non-linearly with x. Importantly, a direct comparison of n2 and nSeS gives a linear correlation, suggesting that n2 may be related to the distribution of chalcogen atoms in the glasses.

Previous results on the use of joint entropy for detection of targeted nanoparticles accumulating in the neovasculature of MDA435 tumors [Fig. 7 of M. S. Hughes et al., J. Acoust. Soc. Am. 133, 283-300 (2013)] are extended, with sensitivity improving by nearly another factor of 2. This result is obtained using a "quasi-optimal" reference waveform in the computation of the joint entropy imaging technique used to image the accumulating nanoparticles.

In this paper we report a two octave spanning supercontinuum generation in a bandwidth of 700-3000 nm in a single-mode photonic crystal fiber made of lead-bismuth-gallate glass. To our knowledge this is the broadest supercontinuum reported in heavy metal oxide glass based fibers. The fiber was fabricated using an in-house synthesized glass with optimized nonlinear, rheological and transmission properties in the range of 500-4800 nm. The photonic cladding consists of 8 rings of air holes. The fiber has a zero dispersion wavelength (ZDW) at 1460 nm. Its dispersion is determined mainly by the first ring of holes in the cladding with a relative hole size of 0.73. Relative hole size of the remaining seven rings is 0.54, which allows single mode performance of the fiber in the infrared range and reduces attenuation of the fundamental mode. The fiber is pumped into anomalous dispersion with 150 fs pulses at 1540 nm. Observed spectrum of 700-3000 nm was generated in 2 cm of fiber with pulse energy below 4 nJ. A flatness of 5 dB was observed in 950-2500 nm range.

Background: This work analyzes the utility of distraction osteogenesis as a surgical option for the management of acquired and traumatic hand deformities through a systematic review of the published literature., Methods: A PubMed search for articles reporting results of distraction osteogenesis in the hand was performed. Data collected included age, sex, cause, bone distracted, latency period, distraction rate, consolidation period, treatment time, length gained, and complications. Proportion data variables were compared using the chi-square test. A meta-analysis was also performed to assess the size effect of variables on complication development., Results: Thirty articles (424 distractions) met inclusion criteria. The average length gained from distraction was 2.2 cm; the average total treatment time was 116 days; the average complication rate was 26.4 percent. Proportion analysis, including all articles, showed that congenital cause had significantly fewer complications compared with traumatic cause (p = 0.0129). A lower complication rate in pediatric patients compared with adults approached but did not reach significance (p = 0.0507). Studies that underwent meta-analysis, including only articles comparing both variables of interest, were homogeneous (I < 25) and without publication bias (Kendall's tau p > 0.05 and symmetric funnel plot). None of the variables analyzed by meta-analysis had a significant odds ratio for complication development (p > 0.05)., Conclusion: Despite distinct advantages, distraction osteogenesis is associated with a long duration of treatment and high complication rates, particularly in adults and in posttraumatic reconstruction., Clinical Question/level of Evidence: Therapeutic, IV.

We present an experimental and computational pipeline for the generation of kinetic models of metabolism, and demonstrate its application to glycolysis in Saccharomyces cerevisiae. Starting from an approximate mathematical model, we employ a "cycle of knowledge" strategy, identifying the steps with most control over flux. Kinetic parameters of the individual isoenzymes within these steps are measured experimentally under a standardised set of conditions. Experimental strategies are applied to establish a set of in vivo concentrations for isoenzymes and metabolites. The data are integrated into a mathematical model that is used to predict a new set of metabolite concentrations and reevaluate the control properties of the system. This bottom-up modelling study reveals that control over the metabolic network most directly involved in yeast glycolysis is more widely distributed than previously thought., (Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

This study is based on an extension of the concept of joint entropy of two random variables to continuous functions, such as backscattered ultrasound. For two continuous random variables, X and Y, the joint probability density p(x,y) is ordinarily a continuous function of x and y that takes on values in a two dimensional region of the real plane. However, in the case where X=f(t) and Y=g(t) are both continuously differentiable functions, X and Y are concentrated exclusively on a curve, γ(t)=(f(t),g(t)), in the x,y plane. This concentration can only be represented using a mathematically "singular" object such as a (Schwartz) distribution. Its use for imaging requires a coarse-graining operation, which is described in this study. Subsequently, removal of the coarse-graining parameter is accomplished using the ergodic theorem. The resulting expression for joint entropy is applied to several data sets, showing the utility of the concept for both materials characterization and detection of targeted liquid nanoparticle ultrasonic contrast agents. In all cases, the sensitivity of these techniques matches or exceeds, sometimes by a factor of two, that demonstrated in previous studies that employed signal energy or alternate entropic quantities.

Rate control analysis defines the in vivo control map governing yeast protein synthesis and generates an extensively parameterized digital model of the translation pathway. Among other non-intuitive outcomes, translation demonstrates a high degree of functional modularity and comprises a non-stoichiometric combination of proteins manifesting functional convergence on a shared maximal translation rate. In exponentially growing cells, polypeptide elongation (eEF1A, eEF2, and eEF3) exerts the strongest control. The two other strong control points are recruitment of mRNA and tRNA(i) to the 40S ribosomal subunit (eIF4F and eIF2) and termination (eRF1; Dbp5). In contrast, factors that are found to promote mRNA scanning efficiency on a longer than-average 5'untranslated region (eIF1, eIF1A, Ded1, eIF2B, eIF3, and eIF5) exceed the levels required for maximal control. This is expected to allow the cell to minimize scanning transition times, particularly for longer 5'UTRs. The analysis reveals these and other collective adaptations of control shared across the factors, as well as features that reflect functional modularity and system robustness. Remarkably, gene duplication is implicated in the fine control of cellular protein synthesis.

We report the successful fabrication of mid-infrared waveguides written in a gallium lanthanum sulphide (GLS) substrate via the ultrafast laser inscription technique. Single mode guiding at 2485 nm and 3850 nm is observed. Spectral broadening spanning 1500 nm (-15dB points) is demonstrated under 3850 nm excitation.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by progressive weakness and wasting of skeletal and cardiac muscle; boys present with weakness by the age of 5 years and, if left untreated, are unable to walk without assistance by the age of 10 years. Therapy for DMD has been primarily palliative, with oral steroids emerging as a first-line approach even though this treatment has serious side-effects. Consequently, low-cost imaging technology suitable for improved diagnosis and treatment monitoring of DMD would be of great value, especially in remote and underserved areas. Previously, we reported use of the logarithm of the signal energy, log [E(f)], and a new method for ultrasound signal characterization using entropy, H(f), to monitor prednisolone treatment of skeletal muscle in a dystrophin-deficient mouse model. Three groups were studied: mdx mice treated with prednisolone, a control group of mdx mice treated with saline, and a control group of wild-type mice treated with saline. It was found that both log [E(f)] and H(f) were required to statistically differentiate the three groups. In the current study, we show that preprocessing of the raw ultrasound using optimal smoothing splines before computation of either log [E(f)] or a rapidly computable variant of Hf, denoted I(f,∞), permits delineation of all three groups by either metric alone. This opens the way to the ultimate goal of this study, which is identification and implementation of new diagnostically sensitive algorithms on the new generation of low-cost hand-held clinical ultrasonic imaging systems.

Dhh1 and Pat1 in yeast are mRNA decapping activators/translational repressors thought to play key roles in the transition of mRNAs from translation to degradation. However, little is known about the physical and functional relationships between these proteins and the translation machinery. We describe a previously unknown type of diauxic shift-dependent modulation of the intracellular locations of Dhh1 and Pat1. Like the formation of P bodies, this phenomenon changes the spatial relationship between components involved in translation and mRNA degradation. We report significant spatial separation of Dhh1 and Pat1 from ribosomes in exponentially growing cells. Moreover, biochemical analyses reveal that these proteins are excluded from polysomal complexes in exponentially growing cells, indicating that they may not be associated with active states of the translation machinery. In contrast, under diauxic growth shift conditions, Dhh1 and Pat1 are found to co-localize with polysomal complexes. This work suggests that Dhh1 and Pat1 functions are modulated by a re-localization mechanism that involves eIF4A. Pull-down experiments reveal that the intracellular binding partners of Dhh1 and Pat1 change as cells undergo the diauxic growth shift. This reveals a new dimension to the relationship between translation activity and interactions between mRNA, the translation machinery and decapping activator proteins.