Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that acutely causes fever as well as severe joint and muscle pain. Chronic musculoskeletal pain persists in a substantial fraction of patients for months to years after the initial infection, yet we still have a poor understanding of what promotes chronic disease. While replicating virus has not been detected in joint-associated tissues of patients with persistent arthritis nor in various animal models at convalescent time points, viral RNA is detected months after acute infection. To identify the cells that might contribute to pathogenesis during this chronic phase, we developed a recombinant CHIKV that expresses Cre recombinase (CHIKV-3'-Cre). CHIKV-3'-Cre replicated in myoblasts and fibroblasts, and it induced arthritis during the acute phase in mice. Importantly, it also induced chronic disease, including persistent viral RNA and chronic myositis and synovitis similar to wild-type virus. CHIKV-3'-Cre infection of tdTomato reporter mice resulted in a population of tdTomato+ cells that persisted for at least 112 days. Immunofluorescence and flow cytometric profiling revealed that these tdTomato+ cells predominantly were myofibers and dermal and muscle fibroblasts. Treatment with an antibody against Mxra8, a recently defined host receptor for CHIKV, reduced the number of tdTomato+ cells in the chronic phase and diminished the levels of chronic viral RNA, implicating these tdTomato+ cells as the reservoir of chronic viral RNA. Finally, isolation and flow cytometry-based sorting of the tdTomato+ fibroblasts from the skin and ankle and analysis for viral RNA revealed that the tdTomato+ cells harbor most of the persistent CHIKV RNA at chronic time points. Therefore, this CHIKV-3'-Cre and tdTomato reporter mouse system identifies the cells that survive CHIKV infection in vivo and are enriched for persistent CHIKV RNA. This model represents a useful tool for studying CHIKV pathogenesis in the acute and chronic stages of disease

Distinct roles of interferon alpha and beta in controlling chikungunya virus replication and modulating neutrophil-mediated inflammation

Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-β (IFN-β knockout [IFN-β-KO] mice or mice treated with an IFN-β-blocking antibody) or IFN-α (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-α-blocking antibody). Mice lacking either IFN-α or IFN-β developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-α sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-β-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-β had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-β-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-α limiting early viral replication and dissemination and IFN-β modulating neutrophil-mediated inflammation

Age and anatomy of the Gongga Shan batholith, eastern Tibetan Plateau, and its relationship to the active Xianshui-he fault

The Gongga Shan batholith of eastern Tibet, previously documented as a ca. 32–12.8 Ma granite pluton, shows some of the youngest U-Pb granite crystallization ages recorded from the Tibetan Plateau, with major implications for the tectonothermal history of the region. Field observations indicate that the batholith is composite; some localities show at least seven crosscutting phases of granitoids that range in composition from diorite to leucocratic monzogranite. In this study we present U-Pb ages of zircon and allanite dated by laser ablation–inductively coupled plasma–mass spectrometry on seven samples, to further investigate the chronology of the batholith. The age data constrain two striking tectonic-plutonic events: a complex Triassic–Jurassic (ca. 215–159 Ma) record of biotite-hornblende granodiorite, K-feldspar megacrystic granite and leucogranitic plutonism, and a Miocene (ca. 14–5 Ma) record of monzonite-leucogranite emplacement. The former age range is attributed to widespread Indosinian tectonism, related to Paleo-Tethyan subduction zone magmatism along the western Yangtze block of south China. The younger component may be related to localized partial melting (muscovite dehydration) of thickened Triassic flysch-type sediments in the Songpan-Ganze terrane, and are among the youngest crustal melt granites exposed on the Tibetan Plateau. Zircon and allanite ages reflect multiple crustal remelting events; the youngest, ca. 5 Ma, resulted in dissolution and crystallization of zircons and growth and/or resetting of allanites. The young garnet, muscovite, and biotite leucogranites occur mainly in the central part of the batholith and adjacent to the eastern margin of the batholith at Kangding, where they are cut by the left-lateral Xianshui-he fault. The Xianshui-he fault is the most seismically active strike-slip fault in Tibet and is thought to record the eastward extrusion of the central part of the Tibetan Plateau. The fault obliquely cuts all granites of the Gongga Shan massif and has a major transpressional component in the Kangding-Moxi region. The course of the Xianshui Jiang river is offset by ∼62 km along the Xianshui-he fault and in the Kangding area granites as young as ca. 5 Ma are cut by the fault. Our new geochronological data show that only a part of the Gongga Shan granite batholith is composed of young (Miocene) melt, and we surmise that as most of eastern Tibet is composed of Precambrian–Triassic Indosinian rocks, there is no geological evidence to support regional Cenozoic internal thickening or metamorphism and no evidence for eastward-directed lower crustal flow away from Tibet. We suggest that underthrusting of Indian lower crust north as far as the Xianshui-he fault resulted in Cenozoic uplift of the eastern plateau

Validation of an Internet-Based Cohort of Inflammatory Bowel Disease (CCFA Partners):

As traditional methods have become increasingly difficult, the Internet offers a mechanism for conducting survey research quickly and efficiently. The validity of this research, however, depends on the ability of respondents to accurately report health status. We used a large Internet-based inflammatory bowel disease cohort to validate self-reported IBD against physician reports

Developing Standards for Cultural Competency Training for Health Care Providers to Care for Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, and Asexual Persons: Consensus Recommendations from a National Panel

Purpose: Lesbian, gay, bisexual, transgender, queer, intersex, and/or asexual and other sexual and gender diverse persons (LGBTQIA + or SGD persons) experience barriers to equitable health care. The purpose of this article is to describe a collaborative process that resulted in core cultural competency recommendations addressing training for those who provide health care and/or social services to LGBTQIA + patients. Methods: In 2018 and 2019, Whitman-Walker Health, a Federally Qualified Community Health Center in Washing- ton, DC, and the National LGBT Cancer Network purposively selected leaders of community clinics and community-based organizations, cultural competency trainers, and clinicians and researchers with expertise in SGD health with diverse lived experiences to develop consensus-based cultural competency recommendations. Recommendations were developed through a synthesis of peer-reviewed studies, publicly accessible curricula, and evaluations of SGD cultural competency trainings; two in-person convenings; and iterative feedback from diverse stakeholders. Results: Five anchoring recommendations emerged: (1) know your audience; (2) develop and fine-tune the curriculum; (3) employ both adult and transformational learning theories; (4) choose multiple effective trainers; and (5) evaluate impact of training. These recommendations promote an ongoing process of individual and organizational improvement and a stance of humility rather than competence to be mastered. Conclusion: By setting core cultural competency standards for all persons involved in health care and social services, these recommendations complement existing clinical competency recommendations to advance SGD health equity

MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis

MerTK, a receptor tyrosine kinase (RTK) of the TYRO3/AXL/MerTK family, is expressed in myeloid lineage cells in which it acts to suppress proinflammatory cytokines following ingestion of apoptotic material. Using syngeneic mouse models of breast cancer, melanoma, and colon cancer, we found that tumors grew slowly and were poorly metastatic in MerTK–/– mice. Transplantation of MerTK–/– bone marrow, but not wild-type bone marrow, into lethally irradiated MMTV-PyVmT mice (a model of metastatic breast cancer) decreased tumor growth and altered cytokine production by tumor CD11b+ cells. Although MerTK expression was not required for tumor infiltration by leukocytes, MerTK–/– leukocytes exhibited lower tumor cell–induced expression of wound healing cytokines, e.g., IL-10 and growth arrest-specific 6 (GAS6), and enhanced expression of acute inflammatory cytokines, e.g., IL-12 and IL-6. Intratumoral CD8+ T lymphocyte numbers were higher and lymphocyte proliferation was increased in tumor-bearing MerTK–/– mice compared with tumor-bearing wild-type mice. Antibody-mediated CD8+ T lymphocyte depletion restored tumor growth in MerTK–/– mice. These data demonstrate that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines. These results suggest that inhibition of MerTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies

Foot-placement accuracy during planned and reactive target stepping during walking in stroke survivors and healthy adults

Background: The high prevalence of falls due to trips and slips following stroke may signify difficulty adjusting foot-placement in response to the environment. However, little is known about under what circumstances foot-placement adjustment becomes difficult for stroke survivors (SS), making the design of targeted rehabilitation interventions to improve independent community mobility difficult. Research question: To investigate the effect of planned and reactive target-stepping on foot-placement accuracy in stroke survivors and young and older healthy adults? Methods: Young (N=11, 30±6 years) and older (N=10, 64±8 years) healthy adults and SS (N=11, 67±9 years) walked, at preferred pace, on a force instrumented treadmill. Each participant walked to illuminated targets, visible two steps in advance (planned) or appearing at contralateral midstance (reactive). Foot-placement error (magnitude and bias) and number of missed targets were compared. Results: All participants missed more reactive than planned targets (p=0.05), and SS missed more targets than young (p<0.001) and older (p=0.001) adults. But no interaction showing SS missed more reactive targets than other groups was found. For all groups: reactive adaptations to steps in the anterio-posterior plane resulted in lower error than planned adaptations (p=0.027). Lengthening steps where undershot more than shortening (p<0.001) by all groups. Reactive medio-lateral adaptations over all induced larger error (p=0.029) than planned and changed the direction of bias (p=0.018). Significance: SS experience difficulty making all adjustments, they showed increased error in all conditions but less pronounced difference between planned and reactive stepping. SS may use a reactive control strategy for all adjustments, in contrast to healthy young adults who may plan foot-placement in advance. The likelihood of stroke survivors misplacing a step is large, with 9.8% targets missed; possibly leading to falls. Further investigation is needed to understand foot-placement control strategies used by SS and the role of planning in gait adaptability

Auditory temporal resolution of a wild white-beaked dolphin (Lagenorhynchus albirostris)

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology 195 (2009): 375-384, doi:10.1007/s00359-009-0415-x.Adequate temporal resolution is required across taxa to properly utilize amplitude modulated acoustic signals. Among mammals, odontocete marine mammals are considered to have relatively high temporal resolution, which is a selective advantage when processing fast traveling underwater sound. However, multiple methods used to estimate auditory temporal resolution have left comparisons among odontocetes and other mammals somewhat vague. Here we present the estimated auditory temporal resolution of an adult male white-beaked dolphin, (Lagenorhynchus albirostris), using auditory evoked potentials and click stimuli. Ours is the first of such studies performed on a wild dolphin in a capture-and-release scenario. The white-beaked dolphin followed rhythmic clicks up to a rate of approximately 1125-1250 Hz, after which the modulation rate transfer function (MRTF) cut-off steeply. However, 10% of the maximum response was still found at 1450 Hz indicating high temporal resolution. The MRTF was similar in shape and bandwidth to that of other odontocetes. The estimated maximal temporal resolution of white-beaked dolphins and other odontocetes was approximately twice that of pinnipeds and manatees, and more than ten-times faster than humans and gerbils. The exceptionally high temporal resolution abilities of odontocetes are likely due primarily to echolocation capabilities that require rapid processing of acoustic cues.We wish to thank the Danish Natural Science Research Council for major financial support (grant no. 272-05-0395)

Thrive: Success Strategies for the Modern-Day Faculty Member

The THRIVE collection is intended to help faculty thrive in their roles as educators, scholars, researchers, and clinicians. Each section contains a variety of thought-provoking topics that are designed to be easily digested, guide personal reflection, and put into action. Please use the THRIVE collection to help: Individuals study topics on their own, whenever and wherever they want Peer-mentoring or other learning communities study topics in small groups Leaders and planners strategically insert faculty development into existing meetings Faculty identify campus experts for additional learning, grand rounds, etc. If you have questions or want additional information on a topic, simply contact the article author or email [email protected]://digitalcommons.unmc.edu/facdev_books/1000/thumbnail.jp