• The E3 ubiquitin ligase MARCH1 regulates glucose-tolerance and lipid storage in a sex-specific manner

      Bhagwandin, Candida; Ashbeck, Erin L; Whalen, Michael; Bandola-Simon, Joanna; Roche, Paul A; Szajman, Adam; Truong, Sarah Mai; Wertheim, Betsy C; Klimentidis, Yann C; Ishido, Satoshi; et al. (PUBLIC LIBRARY SCIENCE, 2018-10-24)
      Type 2 diabetes is typified by insulin-resistance in adipose tissue, skeletal muscle, and liver, leading to chronic hyperglycemia. Additionally, obesity and type 2 diabetes are characterized by chronic low-grade inflammation. Membrane-associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase best known for suppression of antigen presentation by dendritic and B cells. MARCH1 was recently found to negatively regulate the cell surface levels of the insulin receptor via ubiquitination. This, in turn, impaired insulin sensitivity in mouse models. Here, we report that MARCH1-deficient (knockout; KO) female mice exhibit excessive weight gain and excessive visceral adiposity when reared on standard chow diet, without increased inflammatory cell infiltration of adipose tissue. By contrast, male MARCH1 KO mice had similar weight gain and visceral adiposity to wildtype (WT) male mice. MARCH1 KO mice of both sexes were more glucose tolerant than WT mice. The levels of insulin receptor were generally higher in insulin-responsive tissues (especially the liver) from female MARCH1 KO mice compared to males, with the potential to account in part for the differences between male and female MARCH1 KO mice. We also explored a potential role for MARCH1 in human type 2 diabetes risk through genetic association testing in publicly-available datasets, and found evidence suggestive of association. Collectively, our data indicate an additional link between immune function and diabetes, specifically implicating MARCH1 as a regulator of lipid metabolism and glucose tolerance, whose function is modified by sex-specific factors.
    • Earlier snowmelt reduces atmospheric carbon uptake in midlatitude subalpine forests

      Winchell, Taylor S.; Barnard, David M.; Monson, Russell K.; Burns, Sean P.; Molotch, Noah P.; Univ Arizona, Dept Ecol & Evolutionary Biol; Univ Arizona, Tree Ring Res Lab; Institute of Alpine and Arctic Research; University of Colorado Boulder; Boulder Colorado USA; Institute of Alpine and Arctic Research; University of Colorado Boulder; Boulder Colorado USA; Department of Ecology and Evolutionary Biology and Laboratory for Tree Ring Research; University of Arizona; Tucson Arizona USA; et al. (AMER GEOPHYSICAL UNION, 2016-08-16)
      Previous work demonstrates conflicting evidence regarding the influence of snowmelt timing on forest net ecosystem exchange (NEE). Based on 15years of eddy covariance measurements in Colorado, years with earlier snowmelt exhibited less net carbon uptake during the snow ablation period, which is a period of high potential for productivity. Earlier snowmelt aligned with colder periods of the seasonal air temperature cycle relative to later snowmelt. We found that the colder ablation-period air temperatures during these early snowmelt years lead to reduced rates of daily NEE. Hence, earlier snowmelt associated with climate warming, counterintuitively, leads to colder atmospheric temperatures during the snow ablation period and concomitantly reduced rates of net carbon uptake. Using a multilinear-regression (R-2=0.79, P<0.001) relating snow ablation period mean air temperature and peak snow water equivalent (SWE) to ablation-period NEE, we predict that earlier snowmelt and decreased SWE may cause a 45% reduction in midcentury ablation-period net carbon uptake.
    • Early AMD-like defects in the RPE and retinal degeneration in aged mice with RPE-specific deletion of Atg5 or Atg7

      Zhang, Youwen; Cross, Samuel D.; Stanton, James B.; Marmorstein, Alan D.; Le, Yun Zheng; Marmorstein, Lihua Y.; Univ Arizona, Dept Ophthalmol & Vis Sci (MOLECULAR VISION, 2017-04-14)
      Purpose: To examine the effects of autophagy deficiency induced by RPE-specific deletion of Atg5 or Atg7 in mice as a function of age. Methods: Conditional knockout mice with a floxed allele of Atg5 or Atg7 were crossed with inducible VMD2-rtTA/Cre transgenic mice. VMD2-directed RPE-specific Cre recombinase expression was induced with doxycycline feeding in the resulting mice. Cre-mediated deletion of floxed Atg5 or Atg7 resulted in RPE-specific inactivation of the Atg5 or Atg7 gene. Plastic and thin retinal sections were analyzed with light and electron microscopy for histological changes. Photoreceptor outer segment (POS) thickness in plastic sections was measured using the Adobe Photoshop CS4 extended ruler tool. Autophagic adaptor p62/SQSTM1 and markers for oxidatively damaged lipids, proteins, and DNA were examined with immunofluorescence staining of cryosections. Fluorescence signals were quantified using Image J software. Results: Accumulation of p62/SQSTM1 reflecting autophagy deficiency was observed in the RPE of the Atg5(Delta RPE) and Atg7(Delta RP)E mice. 3-nitrotyrosine, advanced glycation end products (AGEs), and 8-hydroxy-2'-deoxyguanosine (8-OHdG), markers for oxidatively damaged proteins and DNA, were also found to accumulate in the RPE of these mice. We observed retinal degeneration in 35% of the Atg5(Delta RPE) mice and 45% of the Atg7.RPE mice at 8 to 24 months old. Degeneration severity and the number of mice with degeneration increased with age. The mean POS thickness of these mice was 25 mu m at 8-12 months, 15 mu m at 13-18 months, and 3 mu m at 19-24 months, compared to 35 mu m, 30 mu m, and 24 aem in the wildtype mice, respectively. Early age-related macular degeneration (AMD)-like RPE defects were found in all the Atg5(Delta RPE) and Atg7.RPE mice 13 months old or older, including vacuoles, uneven RPE thickness, diminished basal infoldings, RPE hypertrophy/hypotrophy, pigmentary irregularities, and necrosis. The severity of the RPE defects increased with age and in the mice with retinal degeneration. RPE atrophy and choroidal neovascularization (CNV) were occasionally observed in the Atg5(Delta RPE) and Atg7(Delta RPE) mice with advanced age. Conclusions: Autophagy deficiency induced by RPE-specific deletion of Atg5 or Atg7 predisposes but does not necessarily drive the development of AMD-like phenotypes or retinal degeneration.
    • Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury

      Hoffman, Ann N.; Paode, Pooja R.; May, Hazel G.; Ortiz, J. Bryce; Kemmou, Salma; Lifshitz, Jonathan; Conrad, Cheryl D.; Currier Thomas, Theresa; Department of Child Health, University of Arizona College of Medicine-Phoenix (MARY ANN LIEBERT, INC, 2017-01)
      In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury. At post-injury days (PIDs) 1, 7, and 28, brain tissue from sham and brain-injured adult, male rats was processed for Golgi, glial fibrillary acidic protein (GFAP), or silver stain and analyzed to quantify BLA dendritic branch intersections, activated astrocytes, and regional neuropathology, respectively. Compared to sham, brain-injured rats at all PIDs showed enhanced dendritic branch intersections in both pyramidal and stellate BLA neuronal types, as evidenced by Sholl analysis. GFAP staining in the BLA was significantly increased at PID1 and 7 in comparison to sham. However, the BLA was relatively spared from neuropathology, demonstrated by an absence of argyrophilic accumulation over time, in contrast to other brain regions. These data suggest an early and persistent enhancement of dendritic complexity within the BLA after a single diffuse TBI. Increased dendritic complexity would alter information processing into and through the amygdala, contributing to emotional symptoms post-TBI, including PTSD.
    • The Early Detection and Follow-up of the Highly Obscured Type II Supernova 2016ija/DLT16am

      Tartaglia, L.; Sand, David J.; Valenti, S.; Wyatt, S.; Anderson, J. P.; Arcavi, I.; Ashall, C.; Botticella, M. T.; Cartier, R.; Chen, T.-W.; et al. (IOP PUBLISHING LTD, 2018-01-23)
      We present our analysis of the Type II supernova DLT16am (SN 2016ija). The object was discovered during the ongoing D < 40 Mpc (DLT40) one-day cadence supernova search at r similar to 20.1 mag in the "edge-on" nearby (D = 20.0 +/- 4.0 Mpc) galaxy NGC 1532. The subsequent prompt and high-cadenced spectroscopic and photometric follow-up revealed a highly extinguished transient, with E(B - V) = 1.95 +/- 0.15 mag, consistent with a standard extinction law with R-V = 3.1 and a bright (M-V = -18.48 +/- 0.77 mag) absolute peak magnitude. A comparison of the photometric features with those of large samples of SNe II reveals a fast rise for the derived luminosity and a relatively short plateau phase, with a slope of S-50V = 0.84 +/- 0.04 mag/50 days, consistent with the photometric properties typical of those of fast-declining SNe II. Despite the large uncertainties on the distance and the extinction in the direction of DLT16am, the measured photospheric expansion velocity and the derived absolute V-band magnitude at similar to 50 days after the explosion match the existing luminosity-velocity relation for SNe II.
    • Early detection of ovarian cancer using the risk of ovarian cancer algorithm with frequent CA125 testing in women at increased familial risk-combined results from two screening trials

      Skates, Steven J; Greene, Mark H.; Buys, Saundra S; Mai, Phuong L; Brown, Powel; Piedmonte, Marion; Rodriguez, Gustavo; Schorge, John O; Sherman, Mark; Daly, Mary B; et al. (American Association for Cancer Research, 2017-01-31)
      Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6-12 monthly CA125>35U/mL. Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject’s baseline, which triggered transvaginal ultrasound. Specificity and PPV were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls.
    • Early for Everyone: Reconceptualizing Palliative Care in the Neonatal Intensive Care Unit

      Quinn, Megan; Weiss, Alyssa B; Crist, Janice D; Univ Arizona, Coll Nursing (LIPPINCOTT WILLIAMS & WILKINS, 2020-04)
      Background: Palliative care (PC) in the neonatal intensive care unit (NICU) is often provided exclusively to infants expected to die. Standards of care support providing PC early after diagnosis with any condition likely to impact quality of life. Purpose: To determine the state of early PC practice across populations to derive elements of early PC applicable to neonates and their families and demonstrate their application in practice. Search Strategy: Multiple literature searches were conducted from 2016 to 2019. Common keywords used were: palliative care; early PC; end of life, neonate; NICU; perinatal PC; pediatric PC; family-centered care; advanced care planning; palliative care consultant; and shared decision-making. Findings: Early PC is an emerging practice in adult, pediatric, and perinatal populations that has been shown to be helpful for and recommended by families. Three key elements of early PC in the NICU are shared decision-making, care planning, and coping with distress. A hypothetical case of a 24-week infant is presented to illustrate how findings may be applied. Evidence supports expansion of neonatal PC to include infants and families without terminal diagnoses and initiation earlier in care.
    • Early Identification of Autism Spectrum Disorder Among Children Aged 4 Years - Early Autism and Developmental Disabilities Monitoring Network, Six Sites, United States, 2016

      Shaw, Kelly A; Maenner, Matthew J; Baio, Jon; Washington, Anita; Christensen, Deborah L; Wiggins, Lisa D; Pettygrove, Sydney; Andrews, Jennifer G; White, Tiffany; Rosenberg, Cordelia Robinson; et al. (CENTERS DISEASE CONTROL & PREVENTION, 2020-03-27)
      Problem/Condition: Autism spectrum disorder (ASD). Period Covered: 2016. Description of System: The Early Autism and Developmental Disabilities Monitoring (Early ADDM) Network, a subset of the overall ADDM Network, is an active surveillance program that estimates ASD prevalence and monitors early identification of ASD among children aged 4 years. Children included in surveillance year 2016 were born in 2012 and had a parent or guardian who lived in the surveillance area in Arizona, Colorado, Missouri, New Jersey, North Carolina, or Wisconsin, at any time during 2016. Children were identified from records of community sources including general pediatric health clinics, special education programs, and early intervention programs. Data from comprehensive evaluations performed by community professionals were abstracted and reviewed by trained clinicians using a standardized ASD surveillance case definition with criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Results: In 2016, the overall ASD prevalence was 15.6 per 1,000 (one in 64) children aged 4 years for Early ADDM Network sites. Prevalence varied from 8.8 per 1,000 in Missouri to 25.3 per 1,000 in New Jersey. At every site, prevalence was higher among boys than among girls, with an overall male-to-female prevalence ratio of 3.5 (95% confidence interval [CI] = 3.1-4.1). Prevalence of ASD between non-Hispanic white (white) and non-Hispanic black (black) children was similar at each site (overall prevalence ratio: 0.9; 95% CI = 0.8-1.1). The prevalence of ASD using DSM-5 criteria was lower than the prevalence using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria at one of four sites that used criteria from both editions. Among sites where 1.60% of children aged 4 years had information about intellectual disability (intelligence quotient <= 70 or examiner's statement of intellectual disability documented in an evaluation), 53% of children with ASD had co-occurring intellectual disability. Of all children aged 4 years with ASD, 84% had a first evaluation at age <= 36 months and 71% of children who met the surveillance case definition had a previous ASD diagnosis from a community provider. Median age at first evaluation and diagnosis for this age group was 26 months and 33 months, respectively. Cumulative incidence of autism diagnoses received by age 48 months was higher for children aged 4 years than for those aged 8 years identified in Early ADDM Network surveillance areas in 2016. Interpretation: In 2016, the overall prevalence ofASD in the Early ADDM Network using DSM-5 criteria (15.6 per 1,000 children aged 4 years) was higher than the 2014 estimate using DSM-5 criteria (14.1 per 1,000). Children born in 2012 had a higher cumulative incidence of ASD diagnoses by age 48 months compared with children born in 2008, which indicates more early identification of ASD in the younger group. The disparity in ASD prevalence has decreased between white and black children. Prevalence of co-occurring intellectual disability was higher than in 2014, suggesting children with intellectual disability continue to be identified at younger ages. More children received evaluations by age 36 months in 2016 than in 2014, which is consistent with Healthy People 2020 goals. Median age at earliest ASD diagnosis has not changed considerably since 2014. Public Health Action: More children aged 4 years with ASD are being evaluated by age 36 months and diagnosed by age 48 months, but there is still room for improvement in early identification. Timely evaluation of children by community providers as soon as developmental concerns have been identified might result in earlier ASD diagnoses, earlier receipt of evidence-based interventions, and improved developmental outcomes.
    • Early Inception of the Laramide Orogeny in Southwestern Montana and Northern Wyoming: Implications for Models of Flat‐Slab Subduction

      Carrapa, B.; DeCelles, P. G.; Romero, M.; Univ Arizona, Dept Geosci (AMER GEOPHYSICAL UNION, 2019-02-16)
      Timing and distribution of magmatism, deformation, exhumation, and basin development have been used to reconstruct the history of Laramide flat-slab subduction under North America during Late Cretaceous-early Cenozoic time. Existing geodynamic models, however, ignore a large (40,000-km(2)) sector of the Laramide foreland in southwestern Montana. The Montana Laramide ranges consist of Archean basement arches (fault-propagation folds) that were elevated by thrust and reverse faults. We present new thermochronological and geochronological data from six Laramide ranges in southwestern Montana (the Beartooth, Gravelly, Ruby and Madison Ranges, and the Tobacco Root and Highland Mountains) that show significant cooling and exhumation during the Early to mid-Cretaceous, much earlier than the record of Laramide exhumation in Wyoming. These data suggest that Laramide-style deformation-driven exhumation slightly predates the eastward sweep of magmatism in western Montana, consistent with geodynamic models involving initial strain propagation into North American cratonic rocks due to stresses associated with a northeastward expanding region of flat-slab subduction. Our results also indicate various degrees of Cenozoic heating and cooling possibly associated with westward rollback of the subducting Farallon slab, followed by Basin-and-Range extension. Plain Language Summary The Laramide region in the western U.S. is characterized by some of the highest topography in North America including the Wind River Range in WY and the Beartooth Range of WY and Montana. These ranges have fed detritus to surrounding basins for millions of years and contributed to modern ecosystems. These high topographic features and basins have significantly impacted paleoenvironmental conditions over geological time. The formation of these high-relief ranges has been linked to deep Earth, geodynamic, processes involving subduction of a flat slab under the North American Plate. Models of flat-slab subduction rely on the timing and pattern of deformation and exhumation of Laramide ranges, which remains poorly understood. Our study provides new data on the timing of deformation and exhumation of Laramide ranges in SW Montana and northern WY capable of testing current models of flat-slab subduction.
    • Early life history responses and phenotypic shifts in a rare endemic plant responding to climate change

      Winkler, Daniel E; Lin, Michelle Yu-Chan; Delgadillo, José; Chapin, Kenneth J; Huxman, Travis E; Univ Arizona, Ecol & Evolutionary Biol (OXFORD UNIV PRESS, 2019-10-31)
      Changes in species ranges are anticipated with climate change, where in alpine settings, fragmentation and contraction are likely. This is especially true in high altitude biodiversity hotspots, where warmer growing seasons and increased drought events may negatively impact populations by limiting regeneration. Here, we test for high-altitude species responses to the interactive effects of warming and drought in Heterotheca brandegeei, a perennial cushion plant endemic to alpine outcroppings in Sierra de San Pedro Mártir National Park, Baja California, México. We exposed H. brandegeei seedlings to experimental warming and drought conditions to document early life history responses and the species ability to tolerate climate change. Drought negatively influenced seedling growth, with overall reductions in above- and belowground biomass. Warming and drought each led to substantial reductions in leaf development. At the same time, individuals maintained high specific leaf area and carbon investment in leaves across treatments, suggesting that existing phenotypic variation within populations may be high enough to withstand climate change. However, warming and drought interacted to negatively influence leaf-level water-use efficiency (WUE). Seedling mortality rates were nearly three times higher in warming and drought treatments, suggesting bleak prospects for H. brandegeei populations in future climate conditions. Overall, our results suggest H. brandegeei populations may experience substantial declines under future warmer and drier conditions. Some individuals may be able to establish, albeit, as smaller, more stressed plants. These results further suggest that warming alone may not be as consequential to populations as drought will be in this already water-limited system.
    • Early life risk factors for chronic sinusitis: A longitudinal birth cohort study

      Chang, Eugene H.; Stern, Debra A.; Willis, Amanda L.; Guerra, Stefano; Wright, Anne L.; Martinez, Fernando D.; Univ Arizona, Dept Otolaryngol; Univ Arizona, Asthma & Airway Dis Res Ctr (MOSBY-ELSEVIER, 2018-04)
      Background: Chronic sinusitis is a commonly diagnosed condition in adults who frequently present with late-stage disease and irreversible changes to the sinus mucosa. Understanding the natural history of chronic sinusitis is critical in developing therapies designed to prevent or slow the progression of disease. Objective: We sought to determine early life risk factors for adult sinusitis in a longitudinal cohort study (Tucson Children's Respiratory Study). Methods: Physician-diagnosed sinusitis was reported at age 6. Adult sinusitis between 22 and 32 years was defined as self-reported sinusitis plus physician-ordered sinus radiologic films. Atopy was assessed by skin prick test. Individuals were grouped into 4 phenotypes: no sinusitis (n = 621), transient childhood sinusitis only (n = 57), late-onset adult sinusitis only (n = 68), and early onset chronic sinusitis (childhood and adult sinusitis, n = 26). Results: Sinusitis was present in 10.8% of children and 12.2% of adults. Childhood sinusitis was the strongest independent risk factor for adult sinusitis (odds ratio = 4.2; 95% CI: 2.5-7.1; P < .0001; n = 772). Early onset chronic sinusitis was associated with increased serum IgE levels as early as at 9 months of age, atopy (assessed by skin prick test reactivity), childhood eczema and allergic rhinitis, frequent childhood colds, maternal asthma, and with increased prevalence of concurrent asthma. No association was found between late-onset adult sinusitis and any of the early life risk factors studied. Conclusions: We identified an early onset chronic sinusitis phenotype associated with a predisposition to viral infections/colds in early life, allergies, and asthma. Elucidation of the molecular mechanisms for this phenotype may lead to future therapies to prevent the progression of the disease into adult sinusitis.
    • Early Linguistic Markers of Trauma-Specific Processing Predict Post-trauma Adjustment

      Kleim, Birgit; Horn, Andrea B; Kraehenmann, Rainer; Mehl, Matthias R; Ehlers, Anke; Univ Arizona, Dept Psychol (FRONTIERS MEDIA SA, 2018-12-05)
      Identifying early predictors for psychiatric disorders, such as post-traumatic stress disorder (PTSD), is crucial for effective treatment and prevention efforts. Obtaining such predictors is challenging and methodologically limited, for example by individuals' distress, arousal, and reduced introspective ability. We investigated the predictive power of language-based, implicit markers of psychological processes (N = 163) derived from computerized text-analysis of trauma and control narratives provided within 18 days post-trauma. Trauma narratives with fewer cognitive processing words (indicating less cognitive elaboration), more death-related words (indicating perceived threat to life), and more first-person singular pronouns (indicating self-immersed processing) predicted greater PTSD symptoms at 6 months. These effects were specific to trauma narratives and held after controlling for early PTSD symptom severity and verbal intelligence. When self-report questionnaires of related processes were considered together with the trauma narrative linguistic predictors, use of more first-person singular pronouns remained a significant predictor alongside self-reported mental defeat. Language-based processing markers may complement questionnaire measures in early forecasting of post-trauma adjustment.
    • Early Marine Isotope Stage 3 human occupation of the Shandong Peninsula, coastal North China

      Li, Feng; Wang, Jian; Zhou, Xinying; Wang, Xiaomin; Long, Hao; Chen, Yupeng; Olsen, John W.; Chen, Fuyou; Univ Arizona, Sch Anthropol (WILEY, 2018-11)
      Archeological studies of coastal sites have yielded a large body of information regarding the dispersal of modern humans from Africa and the coastal adaptations of various hominin groups. Coastal areas have been attractive to humans since at least the late Middle Pleistocene, according to research conducted in Africa and the circum-Mediterranean region. However, little information concerning Paleolithic occupations has come to light in coastal areas of China. Here, we report on the chronology, archeology and paleoenvironmental reconstruction of the Pleistocene Dazhushan site on the east coast of the Shandong Peninsula in North China. Evidence indicates that prehistoric humans employing a flake technology occupied the current coastal area of the peninsula by at least early Marine Isotope Stage 3 (MIS 3; c. 57-29 ka) when the region was an inland area dominated by a mixed broadleaved forest and grassland environment occupied by terrestrial herbivores. Based on archeological evidence brought to light along the current Chinese coastline, correlated with sea level changes that have occurred since MIS 3, we suggest that future studies of coastal migrations and adaptations in eastern China will be considerably enhanced by a deeper understanding of the geomorphological evolution of those coastal regions.
    • Early musculoskeletal classroom education confers little advantage to medical student knowledge and competency in the absence of clinical experiences: a retrospective comparison study

      Khorsand, Derek; Khwaja, Ansab; Schmale, Gregory A.; Univ Arizona, Dept Orthopaed Surg (BIOMED CENTRAL LTD, 2018-03-27)
      Background: Deficiencies in medical student knowledge in musculoskeletal medicine have been well documented. To address these deficiencies, numerous curricular changes at our institution were instituted. The objective of this study was to determine whether medical students in their preclinical years benefit from early exposure to musculoskeletal medicine when compared to students exposed to musculoskeletal medicine just prior to completion of their preclinical curriculum. Methods: United States Medical Licensing Examination (USMLE) Step 1 and 2 scores were compared for periods of time before and after institution of the new curriculum. Scores on the previously validated 24-question short answer survey from Freedman and Bernstein were also compared over these same periods of time between these two groups and to established standards for competency, using a student's two-tailed unpaired t-test for significance. Entering Medical College Admission Test (MCAT) scores were used to compare baseline preparation of students. Results: Overall USMLE scores as well as scores on the USMLE subtest on Musculoskeletal, Skin and Connective Tissue Disease showed no improvement when scores were compared between the two groups of students. There was a statistically significant lower performance on the Freedman and Bernstein knowledge assessment exam for students in the new pre-clinical curriculum as compared to those introduced under the old model, considering both musculoskeletal knowledge (p < 0.001) and proficiency (p < 0.01), though the response rate on the recent survey was low (112/986 or 11%). Spine remained the least understood sub-topic, while a dedicated course in rheumatology likely contributed to increased student knowledge in that area. Additional exposure to musculoskeletal topics during the clinical years increased student knowledge. There was no difference between groups when comparing entering MCAT scores. Conclusions: Classroom curricular changes, including moving the introductory musculoskeletal course to the first year, intended to optimize musculoskeletal medicine education in the pre-clinical years of medical school did not appear to improve student musculoskeletal knowledge at any year of training. Further efforts to improve the education of medical students in musculoskeletal medicine should be directed towards providing more clinical experiences with patients having musculoskeletal concerns. This was a retrospective comparative study, level III evidence.
    • Early null and overt subjects in the Spanish of simultaneous English-Spanish bilinguals and Crosslinguistic Influence

      Villa-García, Julio; Suárez-Palma, Imanol; Department of Spanish & Portuguese, University of Arizona; University of Manchester; University of Arizona (JOHN BENJAMINS PUBLISHING CO, 2016)
      This study assesses the scope of the Crosslinguistic Influence (CLI) hypothesis’ predictions with regard to early bilingual acquisition. To this end, we analyze longitudinal corpus data from four bilinguals attesting the acquisition of subjecthood (null versus overt; preverbal versus postverbal) and the pragmatic adequacy of early null and overt subjects in a null-subject language (i.e., Spanish) in combination with a language differing in its pro-drop parameter setting (i.e., English). Our results indicate that CLI barely affects the development of subjects in the null-subject language at the initial stages, namely at the outset of null and overt subjects, and in turn support the Separate Development Hypothesis. Our bilingual cohort patterns with their Spanish-acquiring monolingual peer in that both groups display comparable proportions of null subjects as well as acquisitional trajectories of null and overt subjects at the early stages of acquisition. Much like monolinguals, bilinguals begin to produce preverbal and postverbal subjects concurrently. The bilingual children and the monolingual child of this study actually produce extremely high rates of pragmatically appropriate covert and overt subjects, which are for the most part target-like from the start, thus pointing to the absence of CLI effects. In light of monolingual and bilingual data, the paper also revisits the hotly debated issue of the ‘no overt subject’ stage of Grinstead (1998, et seq.), its existence in child Spanish being questionable.
    • Early progression of pulmonary hypertension in the monocrotaline model in males is associated with increased lung permeability

      Rafikova, Olga; James, Joel; Eccles, Cody A; Kurdyukov, Sergey; Niihori, Maki; Varghese, Mathews Valuparampil; Rafikov, Ruslan; Univ Arizona, Dept Med, Div Endocrinol (BMC, 2020-03-18)
      Background The mechanisms involved in pulmonary hypertension (PH) development in patients and pre-clinical models are poorly understood. PH has a well-established sex dimorphism in patients with increased frequency of PH in females, and more severe disease with poor survival prognosis in males. Previously, we found that heme signaling plays an essential role in the development phase of the Sugen/Hypoxia (SU/Hx) model. This study is focused on the elucidation of sex differences in mechanisms of PH development related to heme action at the early stage of the monocrotaline (MCT) PH model. Methods Rats received MCT injection (60 mg/kg, i.p.) and followed for 14 days to investigate early disease changes. Hemodynamic parameters were recorded at the end of the study; plasma, lung homogenates, and nuclear fractions were used for the evaluation of protein levels. Results Our data indicate that on day 14, rats did not show any significant increase in the Fulton index due to the early disease phase. However, the right ventricular systolic pressure was significantly increased in male rats, while female rats showed only a trend. Interestingly, only males demonstrated an increased lung-to-bodyweight ratio that indicated lung edema. Indeed, lung histology confirmed severe perivascular edema in males. Previously, we have reported that the increased perivascular edema in SU/Hx model correlated with intravascular hemolysis and activated heme signaling. Here, we found that elevated free hemoglobin levels and perivascular edema were increased, specifically in males showing more rapid progress of PH. A high level of heme carrier protein 1 (HCP-1), which is involved in heme uptake from the bloodstream into the cells, was also found elevated in the lungs of males. The upregulation of heme oxygenase in males indicated increased intracellular heme catabolism. Increased heme signaling resulted in the activation of heme-mediated barrier-disruptive mechanisms. Thus, hemolysis in males can be responsible for increased permeability of the lungs and early disease development. Conclusions Our study indicates the importance of barrier-disruptive mechanisms as an earlier event in the induction of pulmonary hypertension. Importantly, males are more susceptible to hemolysis and develop PH earlier than females.
    • The Early Psychosis Intervention Center (EPICENTER): development and six-month outcomes of an American first-episode psychosis clinical service

      Breitborde, Nicholas JK; Bell, Emily K.; Dawley, David; Woolverton, Cindy; Ceaser, Alan; Waters, Allison C.; Dawson, Spencer C.; Bismark, Andrew W.; Polsinelli, Angelina J.; Bartolomeo, Lisa; et al. (BioMed Central Ltd, 2015)
      BACKGROUND: There is growing evidence that specialized clinical services targeted toward individuals early in the course of a psychotic illness may be effective in reducing both the clinical and economic burden associated with these illnesses. Unfortunately, the United States has lagged behind other countries in the delivery of specialized, multi-component care to individuals early in the course of a psychotic illness. A key factor contributing to this lag is the limited available data demonstrating the clinical benefits and cost-effectiveness of early intervention for psychosis among individuals served by the American mental health system. Thus, the goal of this study is to present clinical and cost outcome data with regard to a first-episode psychosis treatment center within the American mental health system: the Early Psychosis Intervention Center (EPICENTER). METHODS: Sixty-eight consecutively enrolled individuals with first-episode psychosis completed assessments of symptomatology, social functioning, educational/vocational functioning, cognitive functioning, substance use, and service utilization upon enrollment in EPICENTER and after 6 months of EPICENTER care. All participants were provided with access to a multi-component treatment package comprised of cognitive behavioral therapy, family psychoeducation, and metacognitive remediation. RESULTS: Over the first 6 months of EPICENTER care, participants experienced improvements in symptomatology, social functioning, educational/vocational functioning, cognitive functioning, and substance abuse. The average cost of care during the first 6 months of EPICENTER participation was lower than the average cost during the 6-months prior to joining EPICENTER. These savings occurred despite the additional costs associated with the receipt of EPICENTER care and were driven primarily by reductions in the utilization of inpatient psychiatric services and contacts with the legal system. CONCLUSIONS: The results of our study suggest that multi-component interventions for first-episode psychosis provided in the US mental health system may be both clinically-beneficial and cost-effective. Although additional research is needed, these findings provide preliminary support for the growing delivery of specialized multi-component interventions for first-episode psychosis within the United States. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01570972; Date of Trial Registration: November 7, 2011
    • Early Retinal Neuronal Dysfunction in Diabetic Mice: Reduced Light-Evoked Inhibition Increases Rod Pathway Signaling.

      Moore-Dotson, Johnnie M.; Beckman, Jamie J.; Mazade, Reece E.; Hoon, Mrinalini; Bernstein, Adam S.; Romero-Aleshire, Melissa J.; Brooks, Heddwen L.; Eggers, Erika D.; Department of Physiology, University of Arizona; Graduate Interdisciplinary Program in Physiological Sciences, University of Arizona; et al. (Association for Research in Vision and Ophthalmology (ARVO), 2016-03-01)
      Recent studies suggest that the neural retinal response to light is compromised in diabetes. Electroretinogram studies suggest that the dim light retinal rod pathway is especially susceptible to diabetic damage. The purpose of this study was to determine whether diabetes alters rod pathway signaling.
    • Early Science with the Large Millimeter Telescope: Detection of Dust Emission in Multiple Images of a Normal Galaxy at z > 4 Lensed by a Frontier Fields Cluster

      Pope, Alexandra; Montaña, Alfredo; Battisti, A.; Limousin, Marceau; Marchesini, Danilo; Wilson, G. W.; Alberts, Stacey; Aretxaga, Itziar; Avila-Reese, Vladimir; Bermejo-Climent, José Ramón; et al. (IOP PUBLISHING LTD, 2017-04-03)
      We directly detect dust emission in an optically detected, multiply imaged galaxy lensed by the Frontier Fields cluster MACSJ0717.5+3745. We detect two images of the same galaxy at 1.1 mm with the AzTEC camera on the Large Millimeter Telescope leaving no ambiguity in the counterpart identification. This galaxy, MACS0717_Az9, is at z > 4 and the strong lensing model (mu = 7.5) allows us to calculate an intrinsic IR luminosity of 9.7 x 10(10) L-circle dot and an obscured star formation rate of 14.6 +/- 4.5 M-circle dot yr(-1). The unobscured star formation rate from the UV is only 4.1 +/- 0.3 M-circle dot yr(-1), which means the total star formation rate (18.7 +/- 4.5 M-circle dot yr(-1)) is dominated (75%-80%) by the obscured component. With an intrinsic stellar mass of only 6.9 x 10(9) M circle dot, MACS0717_Az9 is one of only a handful of z. >. 4 galaxies at these lower masses that is detected in dust emission. This galaxy lies close to the estimated star formation sequence at this epoch. However, it does not lie on the dust obscuration relation (IRX-beta) for local starburst galaxies and is instead consistent with the Small Magellanic Cloud attenuation law. This remarkable lower mass galaxy, showing signs of both low metallicity and high dust content, may challenge our picture of dust production in the early universe.
    • Early Sibling Conflict May Ultimately Benefit the Family

      Smith, Alyssa Laney; Atwater, Daniel Z; Callaway, Ragan M; Univ Arizona, Dept Ecol & Evolutionary Biol (UNIV CHICAGO PRESS, 2019-04-14)
      Relatives often interact differently with each other than with nonrelatives, and whether kin cooperate or compete has important consequences for the evolution of mating systems, seed size, dispersal, and competition. Previous research found that the larger of the size dimorphic seeds produced by the annual plant Aegilops triuncialis suppressed germination of their smaller sibs by 25%-60%. Here, we found evidence for kin recognition and sibling rivalry later in life among Aegilops seedlings that places seed-seed interactions in a broader context. In experiments with size dimorphic seeds, seedlings reduced the growth of sibling seedlings by ∼40% but that of nonsibling seedlings by ∼25%. These sequential antagonistic interactions between seeds and then seedlings provide insight into conflict and cooperation among kin. Kin-based conflict among seeds may maintain dormancy for some seeds until the coast is clear of more competitive siblings. If so, biotically induced seed dormancy may be a unique form of cooperation, which increases the inclusive fitness of maternal plants and offspring by minimizing competition among kin.