If Established by Law, Then an Administrative Judge is an Officer

Administrative Judges (AJs) are a large and often overlooked group of federal agency adjudicators. While courts have examined Article II Appointments Clause challenges to Administrative Law Judges (ALJs), courts have yet to encounter a legal challenge to the constitutionality of AJs’ appointment procedures. The constitutionality of any federal government actor’s appointment is dependent upon whether that actor is an “officer” or an “employee” under the Article II Appointments clause. It is apparent that the current “significant authority” test that the Supreme Court has espoused to distinguish between officers and employees is unworkable. This Note endeavors to set forth a bright-line test to distinguish between officers and employees that better serves the purposes of the Appointments Clause and is more easily applicable. The test is simple: if an AJ is “established by Law,” then that AJ is an officer and must be appointed according to the Appointments Clause

Requirement and Function of Hippo Pathway Signaling in the Mammalian Gastrointestinal Tract: A Dissertation

In cancer, aberrant activation of developmental signaling pathways such as the Hippo Pathway has been shown to drive proliferation and invasion of cancer cells. Therefore, understanding the normal function of the Hippo Pathway during embryonic development can provide critical insight into how aberrant activity contributes to tumorigenesis. This dissertation explores the role of the Hippo Pathway members YAP and TAZ in gastrointestinal (GI) development and tumorigenesis. I use mouse genetics to systematically dissect the roles of YAP/TAZ in the endoderm-derived gastrointestinal epithelia and mesoderm-derived gastrointestinal mesenchyme during mammalian development. In the GI epithelium, I demonstrate that YAP/TAZ are dispensable for development and homeostasis. However, YAP/TAZ are required for Wnt pathway-driven tumorigenesis. I find that YAP/TAZ are direct transcriptional targets of Wnt/TCF4 signaling. In the GI mesenchyme, I describe a previously unknown requirement for YAP/TAZ activity during mammalian GI development. YAP/TAZ are involved in normal GI mesenchymal differentiation and function as transcriptional co-repressors in a progenitor cell population. In this way, YAP/TAZ act as molecular gatekeepers prior to Hedgehog-mediated differentiation into smooth muscle cells. This work unveils a previously unknown requirement for Hippo pathway signaling in the mammalian GI tract and a novel mechanism wherein YAP/TAZ function as transcriptional co-repressors to maintain a mesenchymal progenitor cell population

The norovirus NS3 protein is a dynamic lipid- and microtubule-associated protein involved in viral RNA replication

Norovirus (NoV) infections are a significant health burden to society, yet the lack of reliable tissue culture systems has hampered the development of appropriate antiviral therapies. Here we show that the NoV NS3 protein, derived from murine NoV (MNV), is intimately associated with the MNV replication complex and the viral replication intermediate double-stranded RNA (dsRNA). We observed that when expressed individually, MNV NS3 and NS3 encoded by human Norwalk virus (NV) induced the formation of distinct vesicle-like structures that did not colocalize with any particular protein markers to cellular organelles but localized to cellular membranes, in particular those with a high cholesterol content. Both proteins also showed some degree of colocalization with the cytoskeleton marker β-tubulin. Although the distribution of MNV and NV NS3s were similar, NV NS3 displayed a higher level of colocalization with the Golgi apparatus and the endoplasmic reticulum (ER). However, we observed that although both proteins colocalized in membranes counterstained with filipin, an indicator of cholesterol content, MNV NS3 displayed a greater association with flotillin and stomatin, proteins known to associate with sphingolipid- and cholesterol-rich microdomains. Utilizing time-lapse epifluorescence microscopy, we observed that the membrane-derived vesicular structures induced by MNV NS3 were highly motile and dynamic in nature, and their movement was dependent on intact microtubules. These results begin to interrogate the functions of NoV proteins during virus replication and highlight the conserved properties of the NoV NS3 proteins among the seven Norovirus genogroups

Extracorporeal life support in pediatric trauma: a systematic review

Introduction Extracorporeal membrane oxygenation (ECMO) was once thought to be contraindicated in trauma patients, however ECMO is now used in adult patients with post-traumatic acute respiratory distress syndrome (ARDS) and multisystem trauma. Despite acceptance as a therapy for the severely injured adult, there is a paucity of evidence supporting ECMO use in pediatric trauma patients. Methods An electronic literature search of PubMed, MEDLINE, and the Cochrane Database of Collected Reviews from 1972 to 2018 was performed. Included studies reported on ECMO use after trauma in patients ≤18 years of age and reported outcome data. The Institute of Health Economics quality appraisal tool for case series was used to assess study quality. Results From 745 studies, four met inclusion criteria, reporting on 58 pediatric trauma patients. The age range was <1–18 years. Overall study quality was poor with only a single article of adequate quality. Twenty-nine percent of patients were cannulated at adult centers, the remaining at pediatric centers. Ninety-one percent were cannulated for ARDS and the remaining for cardiovascular collapse. Overall 60% of patients survived and the survival rate ranged from 50% to 100%. Seventy-seven percent underwent venoarterial cannulation and the remaining underwent veno-venous cannulation. Conclusion ECMO may be a therapeutic option in critically ill pediatric trauma patients. Consideration should be made for the expansion of ECMO utilization in pediatric trauma patients including its application for pediatric patients at adult trauma centers with ECMO capabilities

Multi‐century stasis in C3 and C4 grass distributions across the contiguous United States since the industrial revolution

AimsUnderstanding the functional response of ecosystems to past global change is crucial to predicting performance in future environments. One sensitive and functionally significant attribute of grassland ecosystems is the percentage of species that use the C4 versus C3 photosynthetic pathway. Grasses using C3 and C4 pathways are expected to have different responses to many aspects of anthropogenic environmental change that have followed the industrial revolution, including increases in temperature and atmospheric CO2, changes to land management and fire regimes, precipitation seasonality, and nitrogen deposition. In spite of dramatic environmental changes over the past 300 years, it is unknown if the C4 grass percentage in grasslands has shifted.LocationContiguous United States of America.MethodsHere, we used stable carbon isotope data (i.e. δ13C) from 30 years of soil samples, as well as herbivore tissues that date to 1739 CE, to reconstruct coarse‐grain C3 and C4 grass composition in North American grassland sites to compare with modern vegetation. We spatially resampled these three datasets to a shared 100‐km grid, allowing comparison of δ13C values at a resolution and extent common for climate model outputs and biogeographical studies.ResultsAt this spatial grain, the bison tissue proxy was superior to the soil proxy because the soils reflect integration of local carbon inputs, whereas bison sample vegetation across landscapes. Bison isotope values indicate that historical grassland photosynthetic‐type composition was similar to modern vegetation.Main conclusionsDespite major environmental change, comparing modern plot vegetation data to three centuries of bison δ13C data revealed that the biogeographical distribution of C3 and C4 grasses has not changed significantly since the 1700s. This is particularly surprising given the expected CO2 fertilization of C3 grasses. Our findings highlight the critical importance of capturing the full range of physiological, ecological and demographical processes in biosphere models predicting future climates and ecosystems.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139065/1/jbi13061.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139065/2/jbi13061_am.pd

Sustainable Agriculture Education and Civic Engagement: The Significance of Community-University Partnerships in the New Agricultural Paradigm

Universities and colleges across the United States are making innovative strides in higher education programming to catalyze a more sustainable era of agriculture. This is clearly exemplified through the formation of community-university partnerships as critical illustrations of civic engagement (CE) for sustainable agriculture (SA) education. This paper explores the praxis of CE for SA education by focusing on the ways in which five land-grant universities (LGUs) with undergraduate programs in SA have developed and put into practice community-university partnerships. Drawing upon these programs and supportive literature, this article specifically attempts to describe the role and significance of CE for SA education, emerging community-university partnership models and their implications for prompting food and agriculture sustainability, and student learning and program assessment outcomes. We also reveal the many challenges and opportunities encountered by stakeholders involved in the creation and continuation of these programs and their subsequent coursework. Conclusions offer real world recommendations for other faculty, staff, student, and community stakeholders to implement and generate action-oriented scholarship for and with communities as a viable thread of SA education

YAP/TAZ Activation Drives Uveal Melanoma Initiation and Progression

Uveal melanoma (UM), the most common ocular malignancy, is characterized by GNAQ/11 mutations. Hippo/YAP and Ras/mitogen-activated protein kinase (MAPK) emerge as two important signaling pathways downstream of G protein alpha subunits of the Q class (GalphaQ/11)-mediated transformation, although whether and how they contribute to UM genesis in vivo remain unclear. Here, we adapt an adeno-associated virus (AAV)-based ocular injection method to directly deliver Cre recombinase into the mouse uveal tract and demonstrate that Lats1/2 kinases suppress UM formation specifically in uveal melanocytes. We find that genetic activation of YAP, but not Kras, is sufficient to initiate UM. We show that YAP/TAZ activation induced by Lats1/2 deletion cooperates with Kras to promote UM progression via downstream transcriptional reinforcement. Furthermore, dual inhibition of YAP/TAZ and Ras/MAPK synergizes to suppress oncogenic growth of human UM cells. Our data highlight the functional significance of Lats-YAP/TAZ in UM initiation and progression in vivo and suggest combination inhibition of YAP/TAZ and Ras/MAPK as a new therapeutic strategy for UM

The reductive activation of CO2 across a Ti═Ti double bond: synthetic, structural, and mechanistic studies

[Image: see text] The reactivity of the bis(pentalene)dititanium double-sandwich compound Ti(2)Pn(†)(2) (1) (Pn(†) = 1,4-{Si(i)Pr(3)}(2)C(8)H(4)) with CO(2) is investigated in detail using spectroscopic, X-ray crystallographic, and computational studies. When the CO(2) reaction is performed at −78 °C, the 1:1 adduct 4 is formed, and low-temperature spectroscopic measurements are consistent with a CO(2) molecule bound symmetrically to the two Ti centers in a μ:η(2),η(2) binding mode, a structure also indicated by theory. Upon warming to room temperature the coordinated CO(2) is quantitatively reduced over a period of minutes to give the bis(oxo)-bridged dimer 2 and the dicarbonyl complex 3. In situ NMR studies indicated that this decomposition proceeds in a stepwise process via monooxo (5) and monocarbonyl (7) double-sandwich complexes, which have been independently synthesized and structurally characterized. 5 is thermally unstable with respect to a μ-O dimer in which the Ti–Ti bond has been cleaved and one pentalene ligand binds in an η(8) fashion to each of the formally Ti(III) centers. The molecular structure of 7 shows a “side-on” bound carbonyl ligand. Bonding of the double-sandwich species Ti(2)Pn(2) (Pn = C(8)H(6)) to other fragments has been investigated by density functional theory calculations and fragment analysis, providing insight into the CO(2) reaction pathway consistent with the experimentally observed intermediates. A key step in the proposed mechanism is disproportionation of a mono(oxo) di-Ti(III) species to yield di-Ti(II) and di-Ti(IV) products. 1 forms a structurally characterized, thermally stable CS(2) adduct 8 that shows symmetrical binding to the Ti(2) unit and supports the formulation of 4. The reaction of 1 with COS forms a thermally unstable complex 9 that undergoes scission to give mono(μ-S) mono(CO) species 10. Ph(3)PS is an effective sulfur transfer agent for 1, enabling the synthesis of mono(μ-S) complex 11 with a double-sandwich structure and bis(μ-S) dimer 12 in which the Ti–Ti bond has been cleaved

Genomic and transcriptomic variation defines the chromosome-scale assembly of Haemonchus contortus, a model gastrointestinal worm

International audienceHaemonchus contortus is a globally distributed and economically important gastrointestinal pathogen of small ruminants and has become a key nematode model for studying anthelmintic resistance and other parasite-specific traits among a wider group of parasites including major human pathogens. Here, we report using PacBio long-read and OpGen and 10X Genomics long-molecule methods to generate a highly contiguous 283.4 Mbp chromosome-scale genome assembly including a resolved sex chromosome for the MHco3(ISE).N1 isolate. We show a remarkable pattern of conservation of chromosome content with Caenorhabditis elegans, but almost no conservation of gene order. Short and long-read transcriptome sequencing allowed us to define coordinated transcriptional regulation throughout the parasite’s life cycle and refine our understanding of cis- and trans-splicing. Finally, we provide a comprehensive picture of chromosome-wide genetic diversity both within a single isolate and globally. These data provide a high-quality comparison for understanding the evolution and genomics of Caenorhabditis and other nematodes and extend the experimental tractability of this model parasitic nematode in understanding helminth biology, drug discovery and vaccine development, as well as important adaptive traits such as drug resistance

Chronic comorbidities in children and adolescents with perinatally acquired HIV infection in sub-Saharan Africa in the era of antiretroviral therapy.

Globally, 1·7 million children are living with HIV, of which 90% are in sub-Saharan Africa. The remarkable scale-up of combination antiretroviral therapy has resulted in increasing numbers of children with HIV surviving to adolescence. Unfortunately, in sub-Saharan Africa, HIV diagnosis is often delayed with children starting antiretroviral therapy late in childhood. There have been increasing reports from low-income settings of children with HIV who have multisystem chronic comorbidities despite antiretroviral therapy. Many of these chronic conditions show clinical phenotypes distinct from those in adults with HIV, and result in disability and reduced quality of life. In this Review, we discuss the spectrum and pathogenesis of comorbidities in children with HIV in sub-Saharan Africa. Prompt diagnosis and treatment of perinatally acquired HIV infection is a priority. Additionally, there is a need for increased awareness of the burden of chronic comorbidities. Diagnostic and therapeutic strategies need to be collectively developed if children with HIV are to achieve their full potential