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Lighting makes up 17% of electrical loads and the largest energy end use in commercial buildings. Linear fixtures are among the largest opportunities for energy efficiency improvement, given their long operating hours. With continued, rapid light-emitting diode (LED) development and more LED replacement products on the market, lighting replacement decisions become more complex and warrant re-examination. With a goal to inform building managers and other decision-makers with practical guidance on lighting replacement, this study is a life cycle cost (LCC) analysis that compares the cost–benefit of six replacement options (one fluorescent and five LED) for a 0.61 m by 1.22 m (2 ft by 4 ft) T8 recessed troffer based on data for 168 lighting products from an online vendor. Results show that direct wire (i.e. unballasted) LED retrofits are the least-cost option to replacing fluorescent lamps in terms of normalized LCC. Plug-and-play lamps suffer from a lock-in with ballasts, but their ease of installation can help spur LED adoption. In cases where an existing ballast is still usable, hybrid LED retrofits provide the least upfront cost option by deferring the cost of rewiring. LED luminaires can offer improved aesthetics and reliability; however, they have high upfront cost. Among them, luminaires with replaceable lamps offer lower cost than those without. [ABSTRACT FROM AUTHOR]

Seventeen commercial and research laboratories participated in two comparison tests under the auspices of the International Society for Animal Genetics to develop an internationally tested, microsatellite-based parentage and identification panel for the domestic cat (Felis catus). Genetic marker selection was based on the polymorphism information content and allele ranges from seven random-bred populations (n = 261) from the USA, Europe and Brazil and eight breeds (n = 200) from the USA. Nineteen microsatellite markers were included in the comparison test and genotyped across the samples. Based on robustness and efficiency, nine autosomal microsatellite markers were ultimately selected as a single multiplex 'core' panel for cat identification and parentage testing. Most markers contained dinucleotide repeats. In addition to the autosomal markers, the panel included two gender-specific markers, amelogenin and zinc-finger XY, which produced genotypes for both the X and Y chromosomes. This international cat parentage and identification panel has a power of exclusion comparable to panels used in other species, ranging from 90.08% to 99.79% across breeds and 99.47% to 99.87% in random-bred cat populations.

The authors report on a comparative questionnaire study of semen donors at two London clinics offering donor insemination (DI). Results presented here include donors' attitudes towards the storage of identifying information on the UK Human Fertilisation and Embryology Authority's central register, the importance of anonymity when donating, feelings about being traced by DI offspring, and views on the release of identifying donor information to mature offspring. Donors from the two clinics were found to differ on some, although not all, of the above points; in particular, donors from one clinic offered more support for the eventual release of identifying information to DI offspring. The discussion brings in the results of other studies and highlights the complexity of the anonymity question. The authors conclude that some donors may be willing to move towards greater openness of information under controlled conditions using the existing central register and a 'veto' system. [ABSTRACT FROM AUTHOR]

Burn survivors are involved in burn research, but typically in the role of research subject. We believe that the outcomes and impact of burn research can be improved by engaging survivors as collaborators in the planning, implementation, and dissemination of burn research. The goal of this work was to produce the first burn research agenda generated and prioritized by burn survivors and other stakeholders from the burn community. A series of structured focus groups covering five topics (Patient and Family Education, Aftercare, Navigating the Healthcare System, Recovery: Physical and Psychosocial, and Barriers to Research) were held with burn survivors and their family members. Specific research questions/topics were identified from the transcripts and prioritized via an anonymous survey of burn survivors, their caregivers, and other stakeholders from the burn community. From these sessions, 37 specific research questions/topics were identified and ranked. In addition, 19 research barriers were identified and ranked. This work presents an innovative approach to burn research through co-production with survivors and other stakeholders. Burn survivors and their caregivers are experts in their lived experiences. By involving them in burn research as collaborators and contributors from the very first steps of research and throughout the continuum of the research planning, conducting projects, and distributing findings, we believe that the research will be both more successful and more impactful. We have taken the first steps in burn research co-production with this novel stakeholder-generated research agenda for the burn community., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association.)

The production of maple syrup from sap requires extensive processing, which has traditionally led to significant energy inputs and greenhouse gas (GHG) emissions per gallon produced. Technology advancements, e.g., vacuum tubing sap collection systems, reverse osmosis (RO), and electric evaporators have changed the way syrup is produced, resulting in widespread variability in processing equipment and sugar-making operational decisions. This paper evaluates these complex operations through a cradle-to-retail gate carbon footprinting model and by capturing variability in a series of producer archetypes. By isolating energy and emissions impacts, we find that implementing RO has the largest reduction effect on energy (54-77%) and emissions (57-82%), depending on both production size and evaporator fuel (wood, fuel-oil, or electricity). Results also demonstrate the effect of production scale on cumulative energy demand (CED) and emissions per gallon of syrup, with small producers ranging from 333-1,425 MJ/gal and 27-118 kg CO 2 e/gal (61-90% biogenic on-site) for wood-fired operations and 18-65 kg CO 2 e/gal for oil-fired operations. Large producers ranged from 90-131 MJ and 3.5-7 kg CO 2 e/gal (electricity to oil-fired operations). Producers of all scales with the highest rates of electrification in their operations have the lowest GHG emissions and energy use per gallon of syrup produced.

Purpose: This study characterizes the current landscape of genetics advanced practice providers (APPs) in the United States., Methods: A 35-question survey was emailed to the Genetics APP Listserv in the fall of 2023. Questions represented 5 domains: demographics, practice, onboarding, compensation, and perceptions., Results: A total of 105 genetics APPs (93%) completed the survey. Genetics APPs evaluate various patient types and populations in multiple settings, working an average of 41.3 hours and seeing 15 patients weekly. Nearly all see new (96%) and follow-up (98%) patients and utilize telemedicine (93%). Half (51%) have only worked in the genetics specialty during their career. Overall, APPs are generally satisfied with their career as a genetics APP (98%) and work-life balance (86%), and most (86%) feel that they function at the top of their scope., Conclusion: Study findings elucidate the current state of genetics APPs. Results define the characteristics and role of an APP in the genetics specialty and will guide employers and genetics organizations to utilize APPs at the top of their scope and recruit new APPs to this exciting field. A collaborative effort is needed to increase the overall genetics workforce, decrease patient wait times, and increase access to genetics care., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

We sought to enrich our neuroscience curriculum by developing a study abroad program that would address curricular goals and requirements at several levels. "Neuroscience and Technology in Germany" was designed to include a diversity of participants, integrate intercultural competence in participants, fulfill university core curriculum requirements, build on the Science, Technology, Engineering, and Math (STEM) foundation of our major, and fulfill major electives. We also hoped that it would serve as a synthetic experience allowing students to integrate foundational coursework with novel ideas and real-world research applications. We developed an itinerary that balanced multiple activities to meet those goals. We included scientific visits, STEM-focused museums, and significant cultural and historical sites. Scientific visits covered a range of topics in the field of neuroscience including cellular and pharmacological neuroscience, development, cognition, mental illness, artificial intelligence, and the mind-body problem. Pre-visit academic activities included review lectures on general topics (e.g., visual system), scaffolded literature reading, and discussion of previous literature from our hosts. Post-visit academic activities integrated previous foundational curriculum with new research. Cultural historical activities encouraged comparison between a student's home culture, predominant North American culture, and German culture. The first iteration was successful academically and logistically. In post-program surveys, 87.5% of students felt the program had met the learning objectives (n= 16). Students agreed that scientific visits and preparatory lectures were relevant to the learning objectives, together with several cultural and historical visits. Students responded positively to an outing to the mountains and found a concentration camp memorial visit moving. They nearly universally reported that the program led to their personal growth. Students did not find several guided tours of STEM-related sites were relevant to our learning objectives, and opinions were mixed as to the balance of structured vs. unstructured time, balance of scientific vs. historical/cultural activities, and how to schedule free time. Students asked for more scientific background preparation, so we modified the upcoming iteration to include a "Neuroscience Boot Camp" prior to departure. We also selected guided tours more carefully and modified scheduling according to student feedback., (Copyright © 2024 Faculty for Undergraduate Neuroscience.)

We present an approach for studying the primary, secondary, and tertiary flow transitions in sheared annular electroconvection. In particular, we describe a Newton-Krylov method based on time integration for the computation of rotating waves and amplitude-modulated rotating waves, and for the continuation of these flows as a parameter of the system is varied. The method exploits the rotational nature of the flows and requires only a time-stepping code of the model differential equations, i.e., it does not require an explicit code for the discretization of the linearized equations. The linear stability of the solutions is computed to identify the parameter values at which the transitions occur. We apply the method to a model of electroconvection that simulates the flow of a liquid crystal film in the smectic A phase suspended between two annular electrodes and subjected to an electric potential difference and a radial shear. Due to the layered structure of the smectic A phase, the fluid can be treated as two-dimensional (2D) and is modeled using the 2D incompressible Navier-Stokes equations coupled with an equation for charge continuity. The system is a close analog to laboratory-scale geophysical fluid experiments and thus represents an ideal system in which to apply the method before its application to these other systems that exhibit similar flow transitions. In the model for electroconvection, we identify the parameter values at which the primary transition from steady axisymmetric flow to rotating waves occurs, as well as at which the secondary transition from the rotating waves to amplitude-modulated rotating waves occurs. In addition, we locate the tertiary transition, which corresponds to a transition from the amplitude-modulated waves to a three-frequency flow. Of particular interest is that the method also finds a period-doubling bifurcation from the amplitude-modulated rotating waves and a subsequent transition from the flow resulting from this bifurcation.

Objectives: ABRUPT was a prospective, noninterventional, observational study of resuscitation practices at 21 burn centers. The primary goal was to examine burn resuscitation with albumin or crystalloids alone, to design a future prospective randomized trial., Summary Background Data: No modern prospective study has determined whether to use colloids or crystalloids for acute burn resuscitation., Methods: Patients ≥18 years with burns ≥ 20% total body surface area (TBSA) had hourly documentation of resuscitation parameters for 48 hours. Patients received either crystalloids alone or had albumin supplemented to crystalloid based on center protocols., Results: Of 379 enrollees, two-thirds (253) were resuscitated with albumin and one-third (126) were resuscitated with crystalloid alone. Albumin patients received more total fluid than Crystalloid patients (5.2 ± 2.3 vs 3.7 ± 1.7 mL/kg/% TBSA burn/24 hours), but patients in the Albumin Group were older, had larger burns, higher admission Sequential Organ Failure Assessment (SOFA) scores, and more inhalation injury. Albumin lowered the in-to-out (I/O) ratio and was started ≤12 hours in patients with the highest initial fluid requirements, given >12 hours with intermediate requirements, and avoided in patients who responded to crystalloid alone., Conclusions: Albumin use is associated with older age, larger and deeper burns, and more severe organ dysfunction at presentation. Albumin supplementation is started when initial crystalloid rates are above expected targets and improves the I/O ratio. The fluid received in the first 24 hours was at or above the Parkland Formula estimate., Competing Interests: ABRUPT Financial Disclosures: Conflict of Interest: A.G.: Consultant for Mallinckrodt, Inc.; L.A.W.: Research support from Avita, Inc., MEDIWound, Inc., Mallincrodt, Inc.; J.H.H.: Equity in Abbott Labs, AbbVie, Change Healthcare, Imbed Biosciences, and consultant for Avita, Inc. and Mallinckrodt, Inc.; K.N.F.: Consultant for Baxter, Integra, Inc., Skingenix; A.K.: Consultant for Avita, Inc. The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Nocardioform placentitis (NP) has been associated with mid to late pregnancy loss in mares. To date, disease outbreaks have been described only in central Kentucky, although sporadic, isolated cases have been reported globally. This study describes a series of cases of NP that occurred in a sample population of 299 mares foaling in southeastern Pennsylvania and northeastern Maryland in 2020. These cases coincided with an outbreak of NP that occurred in Kentucky that same year. On farms that reported information on both normal and abnormal foalings, nocardioform organisms/DNA were isolated from 6.3% of placental samples based on aerobic culture and/or PCR. In cases with characteristic gross lesions of the chorion, 41% of cases were positive on aerobic culture and/or PCR. NP was confirmed in 16 mares that had not resided in Kentucky for breeding or any part of gestation. Characteristics of mares confirmed positive for NP, including age, gestation length, and problems during gestation are described. Standardbred mares bred by artificial insemination were less likely to be affected than Thoroughbred mares bred by natural cover. Affected mares had prolonged Stage III labor compared with normal mares. These findings suggest that regional increases in NP may occur outside of Kentucky, potentially in parallel with Kentucky outbreaks., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022. Published by Elsevier Inc.)

Weakly electric fish encode perturbations in a self-generated electric field to sense their environment. Localizing objects using this electric sense requires that distance be decoded from a two-dimensional electric image of the field perturbations on their skin. Many studies of object localization by weakly electric fish, and by electric sensing in a generic context, have focused on extracting location information from different features of the electric image. Some of these studies have also considered the additional information gained from sampling the electric image at different times, and from different viewpoints. Here, we take a different perspective and instead consider the information available at a single point in space (i.e. a single sensor or receptor) at a single point in time (i.e. constant field). By combining the information from multiple receptors, we show that an object's distance can be unambiguously encoded by as few as four receptors at specific locations on a sensing surface in a manner that is relatively robust to environmental noise. This provides a lower bound on the information (i.e. receptor array size) required to decode the three-dimensional location of an object using an electric sense., (© 2022 IOP Publishing Ltd.)

Electrification of delivery fleets has emerged as an important opportunity to reduce the transportation sector's environmental impact, including reducing greenhouse gas (GHG) emissions. When, where, and how vehicles are charged, however, impact the reduction potential. Not only does the carbon intensity of the grid vary across time and space, but charging decisions also influence battery degradation rates, resulting in more or less frequent battery replacement. Here, we propose a model that accounts for the spatial and temporal differences in charging emissions using marginal emission factors and degradation-induced differences in production emissions using a semi-empirical degradation model. We analyze four different charging strategies and demonstrate that a baseline charging scenario, in which a vehicle is fully charged immediately upon returning to a central depot, results in the highest emissions and employing alternative charging methods can reduce emissions by 8-37%. We show that when, where, and how batteries are charged also impact the total cost of ownership. Although the lowest cost and the lowest emitting charging strategies often align, the lowest cost deployment location for electric delivery vehicles may not be in the same location that maximizes environmental benefits.

Trait dysphoric rumination is a transdiagnostic factor associated with depression and anxiety that has also been linked with blunted respiratory sinus arrhythmia (RSA), an index of reduced emotion regulation capacity. However, the autonomic correlates of state dysphoric rumination remain unclear. We examined the physiological correlates of state dysphoric rumination and the potential repairing effects of savoring on autonomic functioning. To provide a comprehensive assessment of autonomic correlates, we examined changes in parasympathetic (RSA) and sympathetic (cardiac pre-ejection period, PEP; and electrodermal activity, EDA) arousal independently, as well as autonomic coordination among indices. Eighty-two women (ages 18-25) completed laboratory physiological assessments, including rumination and savoring tasks, and self-report measures of trait rumination. Dysphoric rumination was associated with sympathetic activation (i.e., decreases in PEP, increases in EDA), and subsequent savoring following a recovery period also corresponded with decreases in PEP. Trait rumination did not predict autonomic changes during state rumination. However, higher trait rumination was associated with greater sympathetic coordination (PEP-EDA correspondence) during savoring. In summary, dysphoric rumination co-occurred with sympathetic activation, and subsequent savoring successfully recruited sympathetic activity (PEP) redirected on positive moods and events. Results also emphasize the utility of examining sympathetic and parasympathetic indices, and coordination among autonomic indices to delineate autonomic activity associated with emotion regulation strategies., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

During neural tube closure and spinal cord development, many cells die in both the central and peripheral nervous systems (CNS and PNS, respectively). However, myeloid-derived professional phagocytes have not yet colonized the trunk region during early neurogenesis. How apoptotic cells are removed from this region during these stages remains largely unknown. Using live imaging in zebrafish, we demonstrate that neural crest cells (NCCs) respond rapidly to dying cells and phagocytose cellular debris around the neural tube. Additionally, NCCs have the ability to enter the CNS through motor exit point transition zones and clear debris in the spinal cord. Surprisingly, NCCs phagocytosis mechanistically resembles macrophage phagocytosis and their recruitment toward cellular debris is mediated by interleukin-1β. Taken together, our results reveal a role for NCCs in phagocytosis of debris in the developing nervous system before the presence of professional phagocytes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A large portion of life cycle transportation impacts occur during vehicle operation, and key improvement strategies include increasing powertrain efficiency, vehicle electrification, and lightweighting vehicles by reducing their mass. The potential energy benefits of vehicle lightweighting are large, given that 29.5 EJ was used in all modes of U.S. transportation in 2016, and roughly half of the energy spent in wheeled transportation and the majority of energy spent in aircraft is used to move vehicle mass. We collect and review previous work on lightweighting, identify key parameters affecting vehicle environmental performance (e.g., vehicle mode, fuel type, material type, and recyclability), and propose a set of 10 principles, with examples, to guide environmental improvement of vehicle systems through lightweighting. These principles, based on a life cycle perspective and taken as a set, allow a wide range of stakeholders (designers, policy-makers, and vehicle manufacturers and their material and component suppliers) to evaluate the trade-offs inherent in these complex systems. This set of principles can be used to evaluate trade-offs between impact categories and to help avoid shifting of burdens to other life cycle phases in the process of improving use-phase environmental performance.

Electric sensing involves measuring the voltage changes in an actively generated electric field, enabling an environment to be characterized by its electrical properties. It has been applied in a variety of contexts, from geophysics to biomedical imaging. Some species of fish also use an active electric sense to explore their environment in the dark. One of the primary challenges in such electric sensing involves mapping an environment in three-dimensions using voltage measurements that are limited to a two-dimensional sensor array (i.e. a two-dimensional electric image). In some special cases, the distance of simple objects from the sensor array can be estimated by combining properties of the electric image. Here, we describe a novel algorithm for distance estimation based on a single property of the electric image. Our algorithm can be implemented in two simple ways, involving either different electric field strengths or different sensor thresholds, and is robust to changes in object properties and noise., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Clinical decision making regarding the use of imaging is appropriately centered on diagnostic efficacy and individual patient factors. However, health policy and imaging guidelines may incorporate other inputs, such as cost-effectiveness and patient preference. In the context of climate change and resource scarcity, the environmental impacts of imaging modalities including ultrasound, CT, and MRI will also become relevant. The purpose of this study was to estimate the environmental impacts of various abdominal imaging examinations., Methods: Using commercially available software (SimaPro) and data from user manuals and field experts, a streamlined life cycle assessment was performed to estimate multifactorial environmental impacts of the production and use of ultrasound, CT, and MRI per abdominal imaging examination., Results: Ultrasound consumed less energy in both production and use phases (7.8 and 10.3 MJ/examination, respectively) than CT (58.9 and 41.1 MJ/examination) or MRI (93.2 and 216 MJ/examination). Ultrasound emitted fewer CO 2 equivalents in production and use phases (0.5 and 0.65 kg/examination) than CT (4.0 and 2.61 kg/examination) or MRI (6.0 and 13.72 kg/examination). Potential human health effects from pollutant emissions were found to be smallest with ultrasound in both production and use phases., Conclusions: Among the three imaging modalities, ultrasound was found to have the least environmental impact, by one or more orders of magnitude in various domains. This analysis provides an initial framework for comparing environmental impacts across imaging modalities, which may provide useful inputs for cost-effectiveness analyses and policymaking., (Copyright © 2018 American College of Radiology. All rights reserved.)

Digital ulcers (DU) are a common clinical problem in systemic sclerosis (SSc); however, there is no standardization of local wound care protocols for management of these lesions. There is a well-recognized need to develop and standardize non-pharmacological management of DU in patients with SSc, and to adopt these protocols in future clinical trials that focus on DU healing. The purpose of this review is to outline the types of DU that occur in SSc, and provide an update on the principles of wound management for these lesions based on the current literature and expert opinion., Competing Interests: Conflict of interest: None of the authors has financial interest related to this study to disclose.

To summarize the most salient literature regarding the pathogenesis, diagnosis, and prevention of ischemic enterocolitis (IE) in thermal injury. IE is a poorly characterized gastrointestinal complication associated with large burns. This entity occurs irrespective of abdominal trauma. The diagnostic challenges, paucity of treatment options and related complications make IE particularly lethal. Herein we present a case of profound IE in a 40-year-old male who sustained 80% total body surface area (TBSA) burns. We provide an overview of our current understanding of IE, discuss early diagnostic strategies, and review possible treatment options. Although there are several promising biomarkers of early IE and potential treatment strategies, prospective studies are lacking. IE secondary to massive thermal injury is a lethal complication of severely burned patients. Early recognition and evidenced-based treatment strategies are paramount to successful management of patients with IE. Additional research and prospective trials are warranted given this devastating complication of massive burns.

Objective: To investigate the current state of knowledge about emotional intelligence and affective events that arise during nursing students' clinical placement experiences., Design: Narrative literature review., Data Sources: CINAHL, MEDLINE, PsycINFO, Scopus, Web of Science, ERIC and APAIS-Health databases published in English between 1990 and 2016., Review Methods: Data extraction from and constant comparative analysis of ten (10) research articles., Results: We found four main themes: (1) emotional intelligence buffers stress; (2) emotional intelligence reduces anxiety associated with end of life care; (3) emotional intelligence promotes effective communication; and (4) emotional intelligence improves nursing performance., Conclusions: The articles we analysed adopted a variety of emotional intelligence models. Using the Ashkanasy and Daus "three-stream" taxonomy (Stream 1: ability models; 2: self-report; 3: mixed models), we found that Stream 2 self-report measures were the most popular followed by Stream 3 mixed model measures. None of the studies we surveyed used the Stream 1 approach. Findings nonetheless indicated that emotional intelligence was important in maintaining physical and psychological well-being. We concluded that developing emotional intelligence should be a useful adjunct to improve academic and clinical performance and to reduce the risk of emotional distress during clinical placement experiences. We call for more consistency in the use of emotional intelligence tests as a means to create an empirical evidence base in the field of nurse education., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Precisely orchestrated interactions between spinal motor axons and their ensheathing glia are vital for forming and maintaining functional spinal motor nerves. Following perturbations to peripheral myelinating glial cells, centrally derived oligodendrocyte progenitor cells (OPCs) ectopically exit the spinal cord and myelinate peripheral nerves in myelin with CNS characteristics. However, whether remaining peripheral ensheathing glia, such as perineurial glia, properly encase the motor nerve despite this change in glial cell and myelin composition, remains unknown. Using zebrafish mutants in which OPCs migrate out of the spinal cord and myelinate peripheral motor axons, we assayed perineurial glial development, maturation, and response to injury. Surprisingly, in the presence of OPCs, perineurial glia exited the CNS normally. However, aspects of their development, response to injury, and function were altered compared with wildtype larvae. In an effort to better understand the plasticity of perineurial glia in response to myelin perturbations, we identified transforming growth factor-β1 as a partial mediator of perineurial glial development. Together, these results demonstrate the incredible plasticity of perineurial glia in the presence of myelin perturbations. SIGNIFICANCE STATEMENT Peripheral neuropathies can result from damage or dysregulation of the insulating myelin sheath surrounding spinal motor axons, causing pain, inefficient nerve conduction, and the ectopic migration of oligodendrocyte progenitor cells (OPCs), the resident myelinating glial cell of the CNS, into the periphery. How perineurial glia, the ensheathing cells that form the protective blood-nerve barrier, are impacted by this myelin composition change is unknown. Here, we report that certain aspects of perineurial glial development and injury responses are mostly unaffected in the presence of ectopic OPCs. However, perineurial glial function is disrupted along nerves containing centrally derived myelin, demonstrating that, although perineurial glial cells display plasticity despite myelin perturbations, the blood-nerve barrier is compromised in the presence of ectopic OPCs., (Copyright © 2017 the authors 0270-6474/17/374790-18$15.00/0.)

Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells. TGF-β signaling also inhibited a cytotoxic program that includes granzymes and perforin expression at both early and late stages of infection in vivo and repressed the transcription factor eomesodermin. Overexpression of eomesodermin was sufficient to recapitulate in great part the phenotype of TGF-β receptor-deficient CD4 T cells, while SMAD4 was necessary for CD4 T cell accumulation and differentiation. TGF-β signaling also restricted accumulation and differentiation of CD4 T cells and reduced the expression of cytotoxic molecules in mice and humans infected with other persistent viruses. These data uncovered an eomesodermin-driven CD4 T cell program that is continuously suppressed by TGF-β signaling. During chronic viral infection, this program limits CD4 T cell responses while maintaining CD4 T helper cell identity.

Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8(+) T cell functions, and specialization of CD4(+) T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.

Unlabelled: Rapid innate responses to viral encounters are crucial to shaping the outcome of infection, from viral clearance to persistence. Transforming growth factor β (TGF-β) is a potent immune suppressor that is upregulated early upon viral infection and maintained during chronic infections in both mice and humans. However, the role of TGF-β signaling in regulating individual cell types in vivo is still unclear. Using infections with two different persistent viruses, murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV; Cl13), in their natural rodent host, we observed that TGF-β signaling on dendritic cells (DCs) did not dampen DC maturation or cytokine production in the early stages of chronic infection with either virus in vivo. In contrast, TGF-β signaling prior to (but not during) chronic viral infection directly restricted the natural killer (NK) cell number and effector function. This restriction likely compromised both the early control of and host survival upon MCMV infection but not the long-term control of LCMV infection. These data highlight the context and timing of TGF-β signaling on different innate cells that contribute to the early host response, which ultimately influences the outcome of chronic viral infection in vivo., Importance: In vivo host responses to pathogens are complex processes involving the cooperation of many different immune cells migrating to specific tissues over time, but these events cannot be replicated in vitro. Viruses causing chronic infections are able to subvert this immune response and represent a human health burden. Here we used two well-characterized viruses that are able to persist in their natural mouse host to dissect the role of the suppressive molecule TGF-β in dampening host responses to infection in vivo. This report presents information that allows an increased understanding of long-studied TGF-β signaling by examining its direct effect on different immune cells that are activated very early after in vivo viral infection and may aid with the development of new antiviral therapeutic strategies., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Development and maintenance of the peripheral nervous system (PNS) are essential for an organism to survive and reproduce, and damage to the PNS by disease or injury is often debilitating. Remarkably, the nerves of the PNS are capable of regenerating after trauma. However, full functional recovery after nerve injuries remains poor. Peripheral nerve regeneration has been studied extensively, with particular emphasis on elucidating the roles of Schwann cells and macrophages during degeneration and subsequent regeneration. In contrast, the roles of other essential nerve components, including perineurial glia, are poorly understood. Here, we use laser nerve transection and in vivo, time-lapse imaging in zebrafish to investigate the role and requirement of perineurial glia after nerve injury. We show that perineurial glia respond rapidly and dynamically to nerve transections by extending processes into injury sites and phagocytizing debris. Perineurial glia also bridge injury gaps before Schwann cells and axons, and we demonstrate that these bridges are essential for axon regrowth. Additionally, we show that perineurial glia and macrophages spatially coordinate early debris clearance and that perineurial glia require Schwann cells for their attraction to injury sites. This work highlights the complex nature of cell-cell interactions after injury and introduces perineurial glia as integral players in the regenerative process., (Copyright © 2014 the authors 0270-6474/14/3412762-16$15.00/0.)

The nervous system is often described as a hard-wired component of the body even though it is a considerably fluid organ system that reacts to external stimuli in a consistent, stereotyped manner, while maintaining incredible flexibility and plasticity. Unlike the central nervous system (CNS), the peripheral nervous system (PNS) is capable of significant repair, but we have only just begun to understand the cellular and molecular mechanisms that govern this phenomenon. Using zebrafish as a model system, we have the unprecedented opportunity to couple regenerative studies with in vivo imaging and genetic manipulation. Peripheral nerves are composed of axons surrounded by layers of glia and connective tissue. Axons are ensheathed by myelinating or non-myelinating Schwann cells, which are in turn wrapped into a fascicle by a cellular sheath called the perineurium. Following an injury, adult peripheral nerves have the remarkable capacity to remove damaged axonal debris and re-innervate targets. To investigate the roles of all peripheral glia in PNS regeneration, we describe here an axon transection assay that uses a commercially available nitrogen-pumped dye laser to axotomize motor nerves in live transgenic zebrafish. We further describe the methods to couple these experiments to time-lapse imaging of injured and control nerves. This experimental paradigm can be used to not only assess the role that glia play in nerve regeneration, but can also be the platform for elucidating the molecular mechanisms that govern nervous system repair.

Motor nerves play the critical role of shunting information out of the CNS to targets in the periphery. Their formation requires the coordinated development of distinct cellular components, including motor axons and the Schwann cells and perineurial glia that ensheath them. During nervous system assembly, these glial cells must migrate long distances and terminally differentiate, ensuring the efficient propagation of action potentials. Although we know quite a bit about the mechanisms that control Schwann cell development during this process, nothing is known about the mechanisms that mediate the migration and differentiation of perineurial glia. Using in vivo imaging in zebrafish, we demonstrate that Notch signaling is required for both perineurial migration and differentiation during nerve formation, but not regeneration. Interestingly, loss of Notch signaling in perineurial cells also causes a failure of Schwann cell differentiation, demonstrating that Schwann cells require perineurial glia for aspects of their own development. These studies describe a novel mechanism that mediates multiple aspects of perineurial development and reveal the critical importance of perineurial glia for Schwann cell maturation and nerve formation.

Risk and incidence of pressure ulcers (PUs) in the burn population remain poorly understood. The purpose of this study was to determine the timing and incidence of PUs at our regional burn center and to identify early risk factors for PU development in burn patients. A retrospective review of 40 charts was performed from among the 1489 patients admitted to our regional burn center between January 2008 and December 2009. Twenty patients acquired PUs during their admission and were identified on the basis of International Classification of Diseases, ninth revision, designation, hospital stay >7 days, and thermal injury (excluding toxic epidermal necrolysis and purpura fulminans). The remaining 20 patients were matched controls based on ±5 years in age and ±8% TBSA. Patient, injury, and outcome characteristics were compared among patient groups using χ for categorical variables and Mann-Whitney for continuous variables. The incidence of PU was 1.3% of all admissions. PU most commonly occurred at the sacrum/coccyx (eight), lower extremity (seven), and occiput (six). A majority of PU presented at stage 2 (33%), stage 3 (26%), and unstageable (30%). Thirteen were splint or device related and reportable. Ninety percent of patients with PUs presented with a Braden score of 16 or less (P = .03), although 60% of controls also had admission Braden scores less than 16. On an average, PUs were acquired within 17 days of admission. Data suggest burn patients are particularly at risk of developing PU based on admission Braden scores. However, low Braden scores do not necessarily correlate with eventual development of PU. Therefore, early and aggressive PU prevention and risk assessment tools must be used to diagnose PUs at an early and reversible stage.

The antiviral response is largely mediated by dendritic cells (DCs), including conventional (c) DCs that function as antigen-presenting cells, and plasmacytoid (p) DCs that produce type I interferons, making them an attractive target for viruses. We find that the Old World arenaviruses lymphocytic choriomeningitis virus clone 13 (LCMV Cl13) and Lassa virus bind pDCs to a greater extent than cDCs. Consistently, LCMV Cl13 targets pDCs early after in vivo infection of its natural murine host and establishes a productive and robust replication cycle. pDCs coproduce type I interferons and proinflammatory cytokines, with the former being induced in both infected and uninfected pDCs, demonstrating a dissociation from intrinsic virus replication. TLR7 globally mediates pDC responses, limits pDC viral load, and promotes rapid innate and adaptive immune cell activation. These early events likely help dictate the outcome of infections with arenaviruses and other DC-replicating viruses and shed light on potential therapeutic targets., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice. Therefore, eliciting effective immunity in this context represents a challenge. Here, we report that during a murine chronic viral infection, interleukin-6 (IL-6) was produced by irradiation-resistant cells in a biphasic manner, with late IL-6 being absolutely essential for viral control. The underlying mechanism involved IL-6 signaling on virus-specific CD4 T cells that caused up-regulation of the transcription factor Bcl6 and enhanced T follicular helper cell responses at late, but not early, stages of chronic viral infection. This resulted in escalation of germinal center reactions and improved antibody responses. Our results uncover an antiviral strategy that helps to safely resolve a persistent infection in vivo.

The serpin mechanism of protease inhibition involves the rapid and stable incorporation of the reactive center loop (RCL) into central β-sheet A. Serpins therefore require a folding mechanism that bypasses the most stable "loop-inserted" conformation to trap the RCL in an exposed and metastable state. This unusual feature of serpins renders them highly susceptible to point mutations that lead to the accumulation of hyperstable misfolded polymers in the endoplasmic reticulum of secretory cells. The ordered and stable protomer-protomer association in serpin polymers has led to the acceptance of the "loop-sheet" hypothesis of polymerization, where a portion of the RCL of one protomer incorporates in register into sheet A of another. Although this mechanism was proposed 20 years ago, no study has ever been conducted to test its validity. Here, we describe the properties of a variant of α(1)-antitrypsin with a critical hydrophobic section of the RCL substituted with aspartic acid (P8-P6). In contrast to the control, the variant was unable to polymerize when incubated with small peptides or when cleaved in the middle of the RCL (accepted models of loop-sheet polymerization). However, when induced by guanidine HCl or heat, the variant polymerized in a manner indistinguishable from the control. Importantly, the Asp mutations did not affect the ability of the Z or Siiyama α(1)-antitrypsin variants to polymerize in COS-7 cells. These results argue strongly against the loop-sheet hypothesis and suggest that, in serpin polymers, the P8-P6 region is only a small part of an extensive domain swap.

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by progressive cognitive, behavioral, and motor deficits and caused by expansion of a polyglutamine repeat in the Huntingtin protein (Htt). Despite its monogenic nature, HD pathogenesis includes obligatory non-cell-autonomous pathways involving both the cortex and the striatum, and therefore effective recapitulation of relevant HD disease pathways in cell lines and primary neuronal monocultures is intrinsically limited. To address this, the authors developed an automated high-content imaging screen in high-density primary cultures of cortical and striatal neurons together with supporting glial cells. Cortical and striatal neurons are transfected separately with different fluorescent protein markers such that image-based high-content analysis can be used to assay these neuronal populations separately but still supporting their intercellular interactions, including abundant synaptic interconnectivity. This assay was reduced to practice using transfection of a mutant N-terminal Htt domain and validated via a screen of ~400 selected small molecules. Both expected as well as novel candidate targets for HD emerged from this screen; of particular interest were target classes with close relative proximity to clinical testing. These findings suggest that composite primary cultures incorporating increased levels of biological complexity can be used for high-content imaging and "high-context" screening to represent molecular targets that otherwise may be operant only in the complex tissue environment found in vivo during disease pathogenesis.

The mitogen-activated protein kinases (MAPKs) ERK1/2, p38, and JNK are thought to determine survival-versus-death fate in developing thymocytes. However, this view was challenged by studies using 'MEK1-ERK1/2-specific' pharmacological inhibitors, which block both positive and negative selection. Recently, these inhibitors were also shown to affect MEK5, an upstream activator of ERK5, another class of MAPK with homology to ERK1/2. To define the contribution of the MEK5-ERK5 pathway in T-cell development, we retrovirally expressed dominant-negative or constitutively activated form of MEK5 to inhibit or activate the MEK5-ERK5 pathway. We demonstrate that MEK5 regulates apoptosis of developing thymocytes but has no function in positive selection. ERK5 activity correlates with the levels of Nur77 family members but not that of Bim, two effector pathways of thymocyte apoptosis. These results illustrate the critical involvement of the MEK5-ERK5 pathway in thymocyte development distinct from that of ERK1/2 and highlight the importance of the MAPK network in mediating differential effects pertaining to T-cell differentiation and apoptosis.

Background: Based on prior success of virtual-reality (VR) trainers in imparting surgical skills, a randomized and controlled study was designed to determine whether VR training improves angled-telescope operative performance., Methods: Third-year medical students received instruction on the use of an angled laparoscope and subsequently underwent performance assessment of angled telescope navigational tasks in an anesthetized porcine model. Subjects were then randomized to objective-based training with an angled-telescope simulator (EndoTower; Verefi Technologies, Elizabethtown, PA) versus no training, followed by reassessment of performance., Results: Initially, there were no significant differences between VR-trained (n = 9) and control (n = 10) groups. After training, object visualization, scope orientation, and horizon error scores were significantly better in VR-trained than control groups; subject-matched improvement in orientation score was 50.9% versus 10.8% (P < .05)., Conclusions: VR training in angled laparoscope use improves operative performance of novices. These data support growing evidence that VR training is highly effective in improving surgical skills outside of the clinical setting.