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Background: After an increase of central line-associated bloodstream infections (CLABSIs) at our community hospital in 2021, a case-control study suggested that patients with CLABSIs were 3.0 times more likely to have missed daily chlorhexidine gluconate (CHG) bathing than patients without CLABSIs., Objective: To increase the rate of daily CHG bathing in hospitalized patients with central lines and subsequently reduce the number of CLABSIs., Methods: Our pre-post intervention was launched on September 2022 and consisted of enhancements to the electronic health record (EHR) to simplify the identification of overdue CHG bathing instances to increase compliance, and therefore decrease the CLABSI rate at our hospital. A workflow was implemented Monday-Friday utilizing these EHR enhancements for active surveillance to engage frontline nursing staff and address gaps in care in real time., Results: After the initiative was implemented, adherence to daily CHG bathing increased from 94.9% to 95.3%, with a considerable disparity between weekdays (97.6%) and weekends (89.3%). After weekend data were excluded, the post-intervention increase in the adherence rate was statistically significant ( p = .003)., Discussion: This initiative underscored the importance of involving health care informatics partners and showed how technology can bridge gaps in health care quality. Outreach and reminders effectively improved CHG bathing adherence by emphasizing the importance of consistent communication and follow-up., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: This project aimed to design and evaluate the potential to integrate an exercise oncology service into clinical care in a local healthcare system. The goal was to inform the design of an implementation strategy to promote its sustainable use in standard care., Methods: This two-phase, exploratory study used a mixed-methods approach. First, qualitative measures were used to understand the context for exercise integration into oncology care by clinicians and administrators in the healthcare system. Next, the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework guided a comprehensive evaluation of the exercise service. Reach and Adoption were measured via number of patients enrolled in the program relative to those treated. Adoption was measured via referrals from stakeholders. Implementation was described using the program structure and delivery. Maintenance was described using hospital funding decisions. Effectiveness was assessed using the Bellarmine Norton Assessment Tool (BNAT) and Functional Assessment of Cancer Therapy - Fatigue Scale., Results: Phase 1 context analysis suggested critical elements to guide program delivery, including limiting participants to post-primary treatment (surgery, chemotherapy and radiation) and streamlining referral process. The Phase 2 evaluation demonstrated suboptimal program reach (2%); significant program effectiveness (improved physical function (BNAT; p = 0.05 ) and decreased fatigue (p < 0.05)); receptiveness to program adoption (75%); and strong potential for program maintenance., Conclusions: Traditional approaches to exercise oncology research trials are not easily integrated into healthcare systems. Designing an exercise program for meaningful integration and sustainment requires understanding the context where the program will be delivered, followed by intentional and continuous engagement with key stakeholders to ensure the program continues to meet the needs of the system. Initial exploration of the settings is critical to inform a comprehensive implementation strategy., Trial Registration: clinicaltrials.gov: NCT06039488. Prospectively Registered Sept 15th, 2023., (© 2024. The Author(s).)

The recent interest in microscopic autonomous systems, including microrobots, colloidal state machines, and smart dust, has created a need for microscale energy storage and harvesting. However, macroscopic materials for energy storage have noted incompatibilities with microfabrication techniques, creating substantial challenges to realizing microscale energy systems. Here, we photolithographically patterned a microscale zinc/platinum/SU-8 system to generate the highest energy density microbattery at the picoliter (10 -12 liter) scale. The device scavenges ambient or solution-dissolved oxygen for a zinc oxidation reaction, achieving an energy density ranging from 760 to 1070 watt-hours per liter at scales below 100 micrometers lateral and 2 micrometers thickness in size. The parallel nature of photolithography processes allows 10,000 devices per wafer to be released into solution as colloids with energy stored on board. Within a volume of only 2 picoliters each, these primary microbatteries can deliver open circuit voltages of 1.05 ± 0.12 volts, with total energies ranging from 5.5 ± 0.3 to 7.7 ± 1.0 microjoules and a maximum power near 2.7 nanowatts. We demonstrated that such systems can reliably power a micrometer-sized memristor circuit, providing access to nonvolatile memory. We also cycled power to drive the reversible bending of microscale bimorph actuators at 0.05 hertz for mechanical functions of colloidal robots. Additional capabilities, such as powering two distinct nanosensor types and a clock circuit, were also demonstrated. The high energy density, low volume, and simple configuration promise the mass fabrication and adoption of such picoliter zinc-air batteries for micrometer-scale, colloidal robotics with autonomous functions.

The Long-read RNA-Seq Genome Annotation Assessment Project Consortium was formed to evaluate the effectiveness of long-read approaches for transcriptome analysis. Using different protocols and sequencing platforms, the consortium generated over 427 million long-read sequences from complementary DNA and direct RNA datasets, encompassing human, mouse and manatee species. Developers utilized these data to address challenges in transcript isoform detection, quantification and de novo transcript detection. The study revealed that libraries with longer, more accurate sequences produce more accurate transcripts than those with increased read depth, whereas greater read depth improved quantification accuracy. In well-annotated genomes, tools based on reference sequences demonstrated the best performance. Incorporating additional orthogonal data and replicate samples is advised when aiming to detect rare and novel transcripts or using reference-free approaches. This collaborative study offers a benchmark for current practices and provides direction for future method development in transcriptome analysis., (© 2024. The Author(s).)

Pseudomonas aeruginosa is a major cause of nosocomial infections and the leading cause of chronic lung infections in cystic fibrosis and chronic obstructive pulmonary disease patients. Antibiotic treatment remains challenging because P. aeruginosa is resistant to high concentrations of antibiotics and has a remarkable ability to acquire mutations conferring resistance to multiple groups of antimicrobial agents. Here we report that when P. aeruginosa is plated on ciprofloxacin (cipro) plates, the majority of cipro-resistant (ciproR) colonies observed at and after 48 h of incubation carry mutations in genes related to the Stringent Response (SR). Mutations in one of the major SR components, spoT, were present in approximately 40% of the ciproR isolates. Compared to the wild-type strain, most of these isolates had decreased growth rate, longer lag phase and altered intracellular ppGpp content. Also, 75% of all sequenced mutations were insertions and deletions, with short deletions being the most frequently occurring mutation type. We present evidence that most of the observed mutations are induced on the selective plates in a subpopulation of cells that are not instantly killed by cipro. Our results suggests that the SR may be an important contributor to antibiotic resistance acquisition in P. aeruginosa., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Breast cancer (BC) is one of the most common cancers in the United States. Advances in detection and treatment have resulted in an increased survival rate, meaning an increasing population experiencing declines in muscle mass and strength. Creatine supplementation has consistently demonstrated improvements in strength and muscle performance in older adults, though these findings have not been extended to cancer populations., Purpose: The purpose of this study was to investigate the effects of short-term creatine supplementation on muscular performance in BC survivors., Methods: Using a double-blind, placebo-controlled, randomized design, 19 female BC survivors (mean ± SD age = 57.63 ± 10.77 years) were assigned to creatine (SUPP) ( n = 9) or dextrose placebo (PLA) ( n = 10) groups. The participants completed two familiarization sessions, then two test sessions, each separated by 7 days, where the participants supplemented with 5 g of SUPP or PLA 4 times/day between sessions. The testing sessions included sit-to-stand power, isometric/isokinetic peak torque, and upper/lower body strength via 10 repetition maximum (10RM) tests. The interaction between supplement (SUPP vs. PLA) and time (Pre vs. Post) was examined using a group × time ANOVA and effect sizes., Results: No significant effects were observed for sit-to-stand power ( p = 0.471; η p 2 = 0.031), peak torque at 60°/second ( p = 0.533; η p 2 = 0.023), peak torque at 120°/second ( p = 0.944; η p 2 < 0.001), isometric peak torque ( p = 0.905; η p 2 < 0.001), 10RM chest press ( p = 0.407; η p 2 = 0.041), and 10RM leg extension ( p = 0.932; η p 2 < 0.001). However, a large effect size for time occurred for the 10RM chest press (η p 2 = 0.531) and leg extension (η p 2 = 0.422)., Conclusion: Seven days of creatine supplementation does not influence muscular performance among BC survivors.

The cancer hazard associated with lifetime exposure to radiofrequency radiation (RFR) was examined in Sprague Dawley (SD) rats at the Ramazzini Institute (RI), Italy. There were increased incidences of gliomas and cardiac schwannomas. The translational relevance of these rare rat tumors for human disease is poorly understood. We examined the genetic alterations in RFR-derived rat tumors through molecular characterization of important cancer genes relevant for human gliomagenesis. A targeted next-generation sequencing (NGS) panel was designed for rats based on the top 23 orthologous human glioma-related genes. Single-nucleotide variants (SNVs) and small insertion and deletions (indels) were characterized in the rat gliomas and cardiac schwannomas. Translational relevance of these genetic alterations in rat tumors to human disease was determined through comparison with the Catalogue of Somatic Mutations in Cancer (COSMIC) database. These data suggest that rat gliomas resulting from life-time exposure to RFR histologically resemble low grade human gliomas but surprisingly no mutations were detected in rat gliomas that had homology to the human IDH1 p.R132 or IDH2 p.R172 suggesting that rat gliomas are primarily wild-type for IDH hotspot mutations implicated in human gliomas. The rat gliomas appear to share some genetic alterations with IDH1 wildtype human gliomas and rat cardiac schwannomas also harbor mutations in some of the queried cancer genes. These data demonstrate that targeted NGS panels based on tumor specific orthologous human cancer driver genes are an important tool to examine the translational relevance of rodent tumors resulting from chronic/life-time rodent bioassays., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Robots have components that work together to accomplish a task. Colloids are particles, usually less than 100 µm, that are small enough that they do not settle out of solution. Colloidal robots are particles capable of functions such as sensing, computation, communication, locomotion and energy management that are all controlled by the particle itself. Their design and synthesis is an emerging area of interdisciplinary research drawing from materials science, colloid science, self-assembly, robophysics and control theory. Many colloidal robot systems approach synthetic versions of biological cells in autonomy and may find ultimate utility in bringing these specialized functions to previously inaccessible locations. This Perspective examines the emerging literature and highlights certain design principles and strategies towards the realization of colloidal robots., (© 2023. Springer Nature Limited.)

Renal proximal tubule epithelial cells (RPTECs) are a primary site for kidney injury. We created two RPTEC lines from CD-1 mice immortalized with hTERT (human telomerase reverse transcriptase) or SV40 LgT antigen (Simian Virus 40 Large T antigen). Our hypothesis was that low-level, repeated exposure to subcytotoxic levels of 0.25-2.5 μM cisplatin (CisPt) or 12.5-100 μM aflatoxin B1 (AFB1) would activate distinctive genes and pathways in these two differently immortalized cell lines. RNA-seq showed only LgT cells responded to AFB1 with 1139 differentially expressed genes (DEGs) at 72 h. The data suggested that AFB1 had direct nephrotoxic properties on the LgT cells. However, both the cell lines responded to 2.5 μM CisPt from 3 to 96 h expressing 2000-5000 total DEGs. For CisPt, the findings indicated a coordinated transcriptional program of injury signals and repair from the expression of immune receptors with cytokine and chemokine secretion for leukocyte recruitment; robust expression of synaptic and substrate adhesion molecules (SAMs) facilitating the expression of neural and hormonal receptors, ion channels/transporters, and trophic factors; and the expression of nephrogenesis transcription factors. Pathway analysis supported the concept of a renal repair transcriptome. In summary, these cell lines provide in vitro models for the improved understanding of repeated renal injury and repair mechanisms. High-throughput screening against toxicant libraries should provide a wider perspective of their capabilities in nephrotoxicity.

Recent progress in nanotechnology-enabled sensors that can be placed inside of living plants has shown that it is possible to relay and record real-time chemical signaling stimulated by various abiotic and biotic stresses. The mathematical form of the resulting local reactive oxygen species (ROS) wave released upon mechanical perturbation of plant leaves appears to be conserved across a large number of species, and produces a distinct waveform from other stresses including light, heat and pathogen-associated molecular pattern (PAMP)-induced stresses. Herein, we develop a quantitative theory of the local ROS signaling waveform resulting from mechanical stress in planta. We show that nonlinear, autocatalytic production and Fickian diffusion of H 2 O 2 followed by first order decay well describes the spatial and temporal properties of the waveform. The reaction-diffusion system is analyzed in terms of a new approximate solution that we introduce for such problems based on a single term logistic function ansatz. The theory is able to describe experimental ROS waveforms and degradation dynamics such that species-dependent dimensionless wave velocities are revealed, corresponding to subtle changes in higher moments of the waveform through an apparently conserved signaling mechanism overall. This theory has utility in potentially decoding other stress signaling waveforms for light, heat and PAMP-induced stresses that are similarly under investigation. The approximate solution may also find use in applied agricultural sensing, facilitating the connection between measured waveform and plant physiology., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Spontaneous oscillations on the order of several hertz are the drivers of many crucial processes in nature. From bacterial swimming to mammal gaits, converting static energy inputs into slowly oscillating power is key to the autonomy of organisms across scales. However, the fabrication of slow micrometre-scale oscillators remains a major roadblock towards fully-autonomous microrobots. Here, we study a low-frequency oscillator that emerges from a collective of active microparticles at the air-liquid interface of a hydrogen peroxide drop. Their interactions transduce ambient chemical energy into periodic mechanical motion and on-board electrical currents. Surprisingly, these oscillations persist at larger ensemble sizes only when a particle with modified reactivity is added to intentionally break permutation symmetry. We explain such emergent order through the discovery of a thermodynamic mechanism for asymmetry-induced order. The on-board power harvested from the stabilised oscillations enables the use of electronic components, which we demonstrate by cyclically and synchronously driving a microrobotic arm. This work highlights a new strategy for achieving low-frequency oscillations at the microscale, paving the way for future microrobotic autonomy., (© 2022. The Author(s).)

Living plants provide an opportunity to rethink the design and fabrication of devices ordinarily produced from plastic and circuit boards and ultimately disposed of as waste. The spongy mesophyll is a high -surface area composition of parenchyma cells that supports gas and liquid exchange through stomata pores within the surface of most leaves. Here, we investigate the mesophyll of living plants as biocompatible substrates for the photonic display of thin nanophosphorescent films for photonic applications. Size-sorted, silica-coated 650 ± 290 -nm strontium aluminate nanoparticles are infused into five diverse plant species with conformal display of 2-μm films on the mesophyll enabling photoemission of up to 4.8 × 10 13 photons/second. Chlorophyll measurements over 9 days and functional testing over 2 weeks at 2016 excitation/emission cycles confirm biocompatibility. This work establishes methods to transform living plants into photonic substrates for applications in plant-based reflectance devices, signaling, and the augmentation of plant-based lighting.

Aim: To determine whether macrovascular disease assessed by carotid ultrasonography and arterial stiffness by pulse wave velocity are independently associated with diabetic retinopathy in type 2 diabetes., Methods: A random subgroup of surviving participants with type 2 diabetes from the Fremantle Diabetes Study Phase II were invited to take part in this sub-study in 2018-2019. In addition to standardized questionnaires, a physical examination and fasting biochemical tests, each underwent dilated colour fundus photography, carotid arterial ultrasonography with measurement of the intima-media thickness (IMT) and quantification of the degree of stenosis, and pulse wave analysis calculation of the carotid-femoral pulse wave velocity (cfPWV). The cross-sectional association between arterial disease parameters and diabetic retinopathy was assessed using generalized estimating equation models which enabled both eyes to be included in the analysis., Results: Some 270 participants [mean ± sd age 72 ± 9 years, 153 (57%) men and median (IQR) diabetes duration 15 (11-22) years] were included in analysis. Of 524 assessable eyes, 82 (16%) had diabetic retinopathy. In multivariable analysis, significant independent associates of diabetic retinopathy were age at diabetes diagnosis (inversely), HbA 1c , insulin treatment and urinary albumin to creatinine ratio (all P ≤ 0.022), as well as cfPWV [odds ratio (OR) 1.13, 95% confidence interval (CI) 1.03, 1.23 per 1 m/s increase; P = 0.008] and common carotid artery (CCA) IMT ≥1 mm (OR 2.95, 95% CI 1.21, 7.23; P = 0.018)., Conclusions: The association between diabetic retinopathy and CCA IMT suggests that carotid disease may share cardiovascular risk factors with diabetic retinopathy. The association between diabetic retinopathy and cfPWV may reflect the consequences of altered intravascular haemodynamics., (© 2020 Diabetes UK.)

Islet transplantation is an effective therapy for life-threatening hypoglycemia, but graft function gradually declines over time in many recipients. We characterized islet-specific T cells in recipients within an islet transplant program favoring alemtuzumab (ATZ) lymphodepleting induction and examined associations with graft function. Fifty-eight recipients were studied: 23 pretransplant and 40 posttransplant (including 5 with pretransplant phenotyping). The proportion with islet-specific T cell responses was not significantly different over time (pre-Tx: 59%; 1-6 m posttransplant: 38%; 7-12 m: 44%; 13-24 m: 47%; and >24 m: 45%). However, phenotype shifted significantly, with IFN-γ-dominated response in the pretransplant group replaced by IL-10-dominated response in the 1-6 m posttransplant group, reverting to predominantly IFN-γ-oriented response in the >24 m group. Clustering analysis of posttransplant responses revealed two main agglomerations, characterized by IFN-γ and IL-10 phenotypes, respectively. IL-10-oriented posttransplant response was associated with relatively low graft function. Recipients within the IL-10 + cluster had a significant decline in C-peptide levels in the period preceding the IL-10 response, but stable graft function following the response. In contrast, an IFN-γ response was associated with subsequently decreased C-peptide. Islet transplantation favoring ATZ induction is associated with an initial altered islet-specific T cell phenotype but reversion toward pretransplant profiles over time. Posttransplant autoreactive T cell phenotype may be a predictor of subsequent graft function., (© 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To use optical coherence tomography angiography (OCTA) to determine whether retinal microvascular parameters are associated with carotid arterial disease in people with type 2 diabetes., Research Design and Methods: Participants (community-based) underwent detailed assessments including carotid ultrasonography and OCTA. Ultrasound images were assessed for mean intima-media thickness (IMT) and the presence of stenosis. OCTA image analysis provided measures of vessel density, foveal avascular zone (FAZ) area, blood flow areas, and retinal thickness. For each OCTA variable, the most parsimonious model was generated using generalized estimating equations, then ipsilateral and contralateral carotid disease-related variables were added to determine their significance., Results: A total of 474 eyes from 261 participants (mean ± SD age 72.0 ± 9.3 years, 57.1% males, median diabetes duration 15.4 years [interquartile range 11.1-22.4]) were analyzed. When carotid variables were added to the most parsimonious models, the ipsilateral natural logarithm of common carotid artery IMT (coefficient -2.56 [95% CI -4.76, -0.35], P = 0.023) and presence of any ipsilateral stenosis (-0.82 [-1.48, -0.17], P = 0.014) were statistically significantly associated with a lower parafoveal density in the deep capillary plexus. A mean bifurcation IMT ≥1 mm was associated with a decreased vessel density in the 300-μm ring surrounding the FAZ (coefficient -0.79 [-1.50, -0.08], P = 0.030)). Contralateral carotid disease-related variables were also significantly associated with retinal microvascular parameters., Conclusions: This is the first study to show that carotid disease is an independent associate of retinal microvascular disease assessed by OCTA in type 2 diabetes. Appropriately intensive management of carotid disease may improve the retinal microcirculation., (© 2020 by the American Diabetes Association.)

The selection and firing of DNA replication origins play key roles in ensuring that eukaryotes accurately replicate their genomes. This process is not well documented in plants due in large measure to difficulties in working with plant systems. We developed a new functional assay to label and map very early replicating loci that must, by definition, include at least a subset of replication origins. Arabidopsis ( Arabidopsis thaliana ) cells were briefly labeled with 5-ethynyl-2'-deoxy-uridine, and nuclei were subjected to two-parameter flow sorting. We identified more than 5500 loci as initiation regions (IRs), the first regions to replicate in very early S phase. These were classified as strong or weak IRs based on the strength of their replication signals. Strong initiation regions were evenly spaced along chromosomal arms and depleted in centromeres, while weak initiation regions were enriched in centromeric regions. IRs are AT-rich sequences flanked by more GC-rich regions and located predominantly in intergenic regions. Nuclease sensitivity assays indicated that IRs are associated with accessible chromatin. Based on these observations, initiation of plant DNA replication shows some similarity to, but is also distinct from, initiation in other well-studied eukaryotic systems., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

Formaldehyde (FA) is a simple biological aldehyde that is produced inside cells by several processes such as demethylation of DNA and proteins, amino acid metabolism, lipid peroxidation and one carbon metabolism (1-C). Although accumulation of excess FA in cells is known to be cytotoxic, it is unknown if an increase in FA level might be associated with mitochondrial dysfunction. We choose to use primary human fibroblasts cells in culture (foreskin, FSK) as a physiological model to gain insight into whether an increase in the level of FA might affect cellular physiology, especially with regard to the mitochondrial compartment. FSK cells were exposed to increasing concentrations of FA, and different cellular parameters were studied. Elevation in intracellular FA level was achieved and was found to be cytotoxic by virtue of both apoptosis and necrosis and was accompanied by both G2/M arrest and reduction in the time spent in S phase. A gene expression assessment by microarray analysis revealed FA affected FSK cells by altering expression of many genes including genes involved in mitochondrial function and electron transport. We were surprised to observe increased DNA double-strand breaks (DSBs) in mitochondria after exposure to FA, as revealed by accumulation of γH2A.X and 53BP1 at mitochondrial DNA foci. This was associated with mitochondrial structural rearrangements, loss of mitochondrial membrane potential and activation of mitophagy. Collectively, these results indicate that an increase in the cellular level of FA can trigger mitochondrial DNA double-strand breaks and dysfunction.

We present a novel method to image the vasculature of the anterior segment of the eye using a non-invasive optical coherence tomography angiography (OCTA) system with a modified lens system. This system utilises the Heidelberg Spectralis OCTA and a 3D printed lens mount holding a simple biconvex lens in place to allow capture of images in the anterior segment.

Background: Cluster-randomized trials (CRTs) are being increasingly used to test a range of interventions, including medical interventions commonly used in clinical practice. Policies created by the NIH and the Food and Drug Administration (FDA) require the reporting of demographics and the examination of demographic heterogeneity of treatment effect (HTE) for individually randomized trials. Little is known about how frequent demographics are reported and HTE analyses are conducted in CRTs., Objectives: We sought to understand the prevalence of HTE analyses and the statistical methods used to conduct them in CRTs focused on treating cardiovascular disease, cancer, and chronic lower respiratory diseases. Additionally, we also report on the proportion of CRTs that reported on baseline demographics of its populations and conducted demographic HTE analyses., Data Sources: We searched PubMed and Embase for CRTs published between 1/1/2010 and 3/29/2016 that focused on treating the top 3 Center for Disease Control causes of death (cardiovascular disease, chronic lower respiratory disease, and cancer). Evidence Screening And Review: Of 1,682 unique titles, 117 abstracts were screened. After excluding 53 articles, we included 64 CRT publications and abstracted information on study characteristics and demographic information, statistical analysis, HTE analysis, and study quality., Results: Age and sex were reported in greater than 95.3% of CRTs, while race and ethnicity were reported in only 20.3% of CRTs. HTE analyses were conducted in 28.1% (n = 18) of included CRTs and 77.8% (n = 12) were prespecified analyses. Four CRTs conducted a demographic subgroup analysis. Only 6/18 CRTs used interaction testing to determine whether HTE existed., Conclusions: Baseline demographic reporting was high for age and sex in CRTs, but was uncommon for race and ethnicity. HTE analyses were uncommon and was rare for demographic subgroups, which limits the ability to examine the extent of benefits or risks for treatments tested with CRT designs., Competing Interests: MA Starks - none; GD Sanders - none; RR Coeytaux - none; IL Riley - none; LR Jackson - education support from Medtronic and Biotronik; honoraria from Biotronik; AM Brooks - none; KL Thomas - Consultant: Pfizer, BMS, Janssen; KR Choudhury - none; RM Califf - sits on the corporate board for Cytokinetics and is board chair for the People-Centered Research Foundation. He receives personal fees for consulting from Merck, Amgen, Biogen, Genentech, Eli Lilly, and Boehringer Ingelheim. He is also employed as an advisor by Verily Life Sciences (Alphabet); AF Hernandez - consulting fees from Sanofi, Johnson & Johnson, AstraZeneca, and Cortera; research support from Amylin and Scios/Johnson & Johnson. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Active colloids are a class of microparticles that 'swim' through fluids by breaking the symmetry of the force distribution on their surfaces. Our ability to direct these particles along complex trajectories in three-dimensional (3D) space requires strategies to encode the desired forces and torques at the single particle level. Here, we show that spherical colloids with metal patches of low symmetry self-propel along non-linear 3D trajectories when powered remotely by an alternating current (AC) electric field. In particular, particles with triangular patches of approximate mirror symmetry trace helical paths along the axis of the field. We demonstrate that the speed and shape of the particle's trajectory can be tuned by the applied field strength and the patch geometry. We show that helical motion can enhance particle transport through porous materials with implications for the design of microrobots that can navigate complex environments.

The pursuit of chemically-powered colloidal machines requires individual components that perform different motions within a common environment. Such motions can be tailored by controlling the shape and/or composition of catalytic microparticles; however, the ability to design particle motions remains limited by incomplete understanding of the relevant propulsion mechanism(s). Here, we demonstrate that platinum microparticles move spontaneously in solutions of hydrogen peroxide and that their motions can be rationally designed by controlling particle shape. Nanofabricated particles with n-fold rotational symmetry rotate steadily with speed and direction specified by the type and extent of shape asymmetry. The observed relationships between particle shape and motion provide evidence for a self-electrophoretic propulsion mechanism, whereby anodic oxidation and cathodic reduction occur at different rates at different locations on the particle surface. We develop a mathematical model that explains how particle shape impacts the relevant electrocatalytic reactions and the resulting electrokinetic flows that drive particle motion.

The propulsion of micro- and nanoparticles using ultrasound is an attractive strategy for the remote manipulation of colloidal matter using biocompatible energy inputs. However, the physical mechanisms underlying acoustic propulsion are poorly understood, and our ability to transduce acoustic energy into different types of particle motions remains limited. Here, we show that the three-dimensional shape of a colloidal particle can be rationally engineered to direct desired particle motions powered by ultrasound. We investigate the dynamics of gold microplates with twisted star shape ( C nh symmetry) moving within the nodal plane of a uniform acoustic field at megahertz frequencies. By systematically perturbing the parametric shape of these "spinners", we quantify the relationship between the particle shape and its rotational motion. The experimental observations are reproduced and explained by hydrodynamic simulations that describe the steady streaming flows and particle motions induced by ultrasonic actuation. Our results suggest how particle shape can be used to design colloids capable of increasingly complex motions powered by ultrasound.

Eukaryotes use a temporally regulated process, known as the replication timing program, to ensure that their genomes are fully and accurately duplicated during S phase. Replication timing programs are predictive of genomic features and activity and are considered to be functional readouts of chromatin organization. Although replication timing programs have been described for yeast and animal systems, much less is known about the temporal regulation of plant DNA replication or its relationship to genome sequence and chromatin structure. We used the thymidine analog, 5-ethynyl-2'-deoxyuridine, in combination with flow sorting and Repli-Seq to describe, at high-resolution, the genome-wide replication timing program for Arabidopsis ( Arabidopsis thaliana ) Col-0 suspension cells. We identified genomic regions that replicate predominantly during early, mid, and late S phase, and correlated these regions with genomic features and with data for chromatin state, accessibility, and long-distance interaction. Arabidopsis chromosome arms tend to replicate early while pericentromeric regions replicate late. Early and mid-replicating regions are gene-rich and predominantly euchromatic, while late regions are rich in transposable elements and primarily heterochromatic. However, the distribution of chromatin states across the different times is complex, with each replication time corresponding to a mixture of states. Early and mid-replicating sequences interact with each other and not with late sequences, but early regions are more accessible than mid regions. The replication timing program in Arabidopsis reflects a bipartite genomic organization with early/mid-replicating regions and late regions forming separate, noninteracting compartments. The temporal order of DNA replication within the early/mid compartment may be modulated largely by chromatin accessibility., (© 2018 American Society of Plant Biologists. All Rights Reserved.)

The symmetry and shape of colloidal particles can direct complex particle motions through fluid environments powered by simple energy inputs. The ability to rationally design or "program" the dynamics of such active colloids is an important step toward the realization of colloidal machines, in which components assemble spontaneously in space and time to perform dynamic (dissipative) functions such as actuation and transport. Here, we systematically investigate the dynamics of polarizable particles of different shapes moving in an oscillating electric field via induced-charge electrophoresis (ICEP). We consider particles from each point group in three dimensions (3D) and identify the different rotational and translational motions allowed by symmetry. We describe how the 3D shape of rigid particles can be tailored to achieve desired dynamics including oscillatory motions, helical trajectories, and complex periodic orbits. The methodology we develop is generally applicable to the design of shape-directed particle motions powered by other energy inputs., Competing Interests: The authors declare no conflict of interest.

The overall goal of this work was to measure the efficacy of fMRI for predicting whether a dog would be a successful service dog. The training and imaging were performed in 49 dogs entering service training at 17-21 months of age. 33 dogs completed service training and were matched with a person, while 10 were released for behavioral reasons (4 were selected as breeders and 2 were released for medical reasons.) After 2 months of training, fMRI responses were measured while each dog observed hand signals indicating either reward or no reward and given by both a familiar handler and a stranger. Using anatomically defined ROIs in the caudate, amygdala, and visual cortex, we developed a classifier based on the dogs' subsequent training outcomes. The classifier had a positive predictive value of 94% and a negative predictive value of 67%. The area under the ROC curve was 0.91 (0.80 with 4-fold cross-validation, P = 0.01), indicating a significant predictive capability. The magnitude of response in the caudate was positively correlated with a successful outcome, while the response in the amygdala depended on the interaction with the visual cortex during the stranger condition and was negatively correlated with outcome (higher being associated with failure). These results suggest that, as indexed by caudate activity, successful service dogs generalize associations to hand signals regardless who gives them but without excessive arousal as measured in the amygdala.

Controlled or paced breathing is often used as a stress reduction technique but the impact on blood pressure (BP) and sympathetic outflow have not been consistently reported. The purpose of this study was to determine whether a controlled breathing (12 breaths/min, CB) rate would be similar to an individual's spontaneous breathing (SB) rate. Secondly, would a CB rate of 12 breaths/min alter heart rate (HR), BP, and indices of muscle sympathetic nerve activity (MSNA). Twenty-one subjects (10 women, 11 men) performed two trials: SB, where the subject chose a comfortable breathing rate; and CB, where the subject breathed at a pace of 12 breaths/min. Each trial was 6 min during which respiratory waveforms, HR, BP (systolic, SBP; diastolic, DBP), and MSNA were recorded. During CB, the 6 min average breathing frequency (14±4 vs 12±1 breaths/min, P <0.05 for SB and CB, respectively), MSNA burst frequency (18±12 vs 14±10 bursts/min, P <0.01) and MSNA burst incidence (28±19 vs 21± 6 bursts/100 heart beats, P <0.01) were significantly lower than during SB. HR (66±9 vs 67±9 beats/min, P <0.05) was higher during CB. SBP (120±13 vs 121±15 mmHg, P =0.741), DBP (56±8 vs 57±9 mmHg, P =0.768), and MSNA total activity (166±94 vs 145±102 a.u./min, P =0.145) were not different between the breathing conditions. In conclusion, an acute reduction in breathing frequency such as that observed during CB elicited a decrease in indices of MSNA (burst frequency and incidence) with no change in BP.

5-Ethynyl-2'-deoxyuridine (EdU) is a nucleoside analog of thymidine that can be rapidly incorporated into replicating DNA in vivo and, subsequently, detected by using "click" chemistry to couple its terminal alkyne group to fluorescent azides such as Alexa Fluor 488. Recently, EdU incorporation followed by coupling with a fluorophore has been used to visualize newly synthesized DNA in a wide range of plant species. One particularly useful application is in flow cytometry, where two-parameter sorting can be employed to analyze different phases of the cell cycle, as defined both by total DNA content and the amount of EdU pulse-labeled DNA. This approach allows analysis of the cell cycle without the need for synchronous cell populations, which can be difficult to obtain in many plant systems. The approach presented here, which was developed for fixed, EdU-labeled nuclei, can be used to prepare analytical profiles as well as to make highly purified preparations of G1, S, or G2/M phase nuclei for molecular or biochemical analysis. We present protocols for EdU pulse labeling, tissue fixation and harvesting, nuclei preparation, and flow sorting. Although developed for Arabidopsis suspension cells and maize root tips, these protocols should be modifiable to many other plant systems.

Increased incidence of infections due to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) was noted among patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) at a single hospital. An epidemiologic investigation identified KPC-Kp and non-KPC-producing, extended-spectrum β-lactamase (ESBL)-producing Kp in cultures from 2 endoscopes. Genotyping was performed on patient and endoscope isolates to characterize the microbial genomics of the outbreak. Genetic similarity of 51 Kp isolates from 37 patients and 3 endoscopes was assessed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Five patient and 2 endoscope isolates underwent whole genome sequencing (WGS). Two KPC-encoding plasmids were characterized by single molecule, real-time sequencing. Plasmid diversity was assessed by endonuclease digestion. Genomic and epidemiologic data were used in conjunction to investigate the outbreak source. Two clusters of Kp patient isolates were genetically related to endoscope isolates by PFGE. A subset of patient isolates were collected post-ERCP, suggesting ERCP endoscopes as a possible source. A phylogeny of 7 Kp genomes from patient and endoscope isolates supported ERCP as a potential source of transmission. Differences in gene content defined 5 ST258 subclades and identified 2 of the subclades as outbreak-associated. A novel KPC-encoding plasmid, pKp28 helped define and track one endoscope-associated ST258 subclade. WGS demonstrated high genetic relatedness of patient and ERCP endoscope isolates suggesting ERCP-associated transmission of ST258 KPC-Kp. Gene and plasmid content discriminated the outbreak from endemic ST258 populations and assisted with the molecular epidemiologic investigation of an extended KPC-Kp outbreak.

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post-second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03)., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: Maintenance of endogenous pancreatic β-cell function could be an important goal in the management of type 1 diabetes. However, the impact of stimulated C-peptide level on overall glycemic control is unknown. The relationship between C-peptide and parameters of glucose control was therefore characterized in a cohort with rapidly changing β-cell function following islet transplantation., Research Design and Methods: Standardized mixed-meal tolerance test was undertaken in 12 consecutive islet recipients at 1-6-month intervals, with graft function determined by 90-min stimulated C-peptide. Continuous glucose monitoring was undertaken in the week preceding each assessment and the relationship between C-peptide and glucose control evaluated by mixed Poisson regression., Results: Recipients completed 5 (1-14) [median (range)] clinical assessments over 18 (1-51) months posttransplant encompassing a wide range of stimulated C-peptide levels (7-2,622 pmol/L). Increasing β-cell function across predefined C-peptide groups was associated with reduced insulin dose, HbA1c, mean glucose (low [<200 pmol/L] 10.7 vs. excellent [>1,000 pmol/L] 7.5 mmol/L), and glucose SD (low, 4.4 vs. excellent, 1.4 mmol/L). Highly statistically significant continuous associations between stimulated C-peptide and mean interstitial glucose (lower by 2.5% [95% CI 1.5-3.5%] per 100 pmol/L higher C-peptide), glucose SD, time outside glucose target range, and measures of hyper-/hypoglycemia risk were confirmed., Conclusions: Repeated assessment of islet transplant recipients has enabled modeling of the relationship between endogenous β-cell function and measures of glycemic control providing quantitative estimates of likely impact of an acute change in β-cell function in individuals with type 1 diabetes., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)