Transformation of Undifferentiated Thy-1lo B220+ Thymic Lymphoid Cells by the Abelson Murine Leukemia Virus

Intrathymic injection of the Abelson murine leukemia virus (A-MuLV) results in transformation of immature T and B lymphoid cells. In this report we demonstrate that the concentration of A-MuLV injected into murine thymi influences the selection of the transformation target. Thus, concentrated A-MuLV gives rise to Thy-1+ B220- thymomas. In contrast, dilute virus induces B220+ thymomas that also express low levels of Thy- 1 (Thy-1lo), a phenotype that is similar to marrow-derived progenitor B-lymphoid cells (pro-B cells) that are highly susceptible to A-MuLV transformation in vitro. However, rare B220+ lymphoid cells isolated from normal adult thymi were not transformed by A-MuLV in vitro, while B220+ cells isolated from bone marrow were highly susceptible to transformation by A-MuLV. The Thy-1lo B220+population in the primary thymomas had not rearranged TCRγ, TCRβ, or Igκ genes, but contained subpopulations that assembled Ig DJH or VDJH genes and were therefore similar to transformed pro- and pre-B cells obtained from A-MuLV infected fetal liver and adult bone marrow, respectively. However, unlike A-MuLV-transformed pro- and pre-B cells, many (40– 70%) of the Thy-1lo B220+ transformed thymoma cells had not rearranged Igh genes, and therefore appear to represent undifferentiated lymphoid cells. We conclude that A-MuLV may transform an undifferentiated lymphoid target in the thymus

Resolution of Clinical Signs in Trauma Intensive Care Unit Patients Following Diagnosis of Ventilator-Associated Pneumonia

PURPOSE: The ATS/IDSA Ventilator-Associated Pneumonia (VAP) guidelines suggest that clinical improvement of VAP should be apparent within 3-6 days. Anecdotally, such improvement has not been noted in trauma patients at our institution. The current study was conducted to evaluate resolution of clinical signs of VAP following diagnosis. METHODS: Critically injured adults admitted to the trauma intensive care unit (TICU) from 6/1/06-12/31/07 and subsequently diagnosed with VAP were retrospectively reviewed. Clinical signs, including derangements of maximum temperature (Tmax), white blood cell (WBC) count and Pa02/FiO2, were evaluated on days 1-16 following VAP diagnosis. Data are presented as mean ± SD unless otherwise stated. Clinical parameters following VAP were compared using repeated measures ANOVA with the Tukey test for multiple comparisons. RESULTS: A total of 82 patients were identified. Data for the 34 patients without concurrent infections are presented. Demographic data include: Age 46 ± 17 years; 71% males; 94% blunt trauma; median (IQR) Injury Severity Score 29.5 (24 to 38); duration of mechanical ventilation 33 ± 27 days; ICU length of stay (LOS) 39 ± 25 days; hospital LOS 53 ± 33 days. Clinical signs following VAP diagnosis (Figure): Tmax (°F): Day 1=101.8 ± 1.3, Day 3=101.1 ± 1.1, Day 6=101.1 ± 1.4, Day 16=100.1 ± 3. Compared to Day 1, there was a significant reduction in Tmax at Days 10, 11, 12, 13, 14 and 16 (p \u3c 0.05 for all). WBC count (cells/μL): Day 1=12.9 ± 5, Day 3=13.7 ± 5, Day 6=14.4 ± 5, Day 16=13.8 ± 6. There was no significant difference in WBC count on Days 1-16 (p=0.42). PaO2/FiO2: Day 1=232 ± 108, Day 3=200 ± 87, Day 6=218 ± 104, Day 16=246 ± 126. Differences in PaO2/FiO2 on Days 1-16 did not reach statistical significance (p=0.06). CONCLUSIONS: In trauma patients, improvement of clinical parameters following diagnosis of VAP is delayed beyond the 3-6 day timeframe suggested in the ATS/IDSA guidelines. Alternative methods for determining resolution of VAP in trauma patients should be investigated. METHODS INTRODUCTIO

Electroluminescence-detected magnetic-resonance study of polyparaphenylenevinylene (PPV)-based light-emitting diodes

The strong electroluminescence (EL)-detected magnetic resonance of PPV-based light emitting diodes is compared to the conductivity (sigma)- and photoluminescence (PL)-detected resonances. It provides direct evidence that polaron-to-singlet exciton conversion is responsible for the EL. In contrast to the narrow PL-enhancing resonance assigned to polaron recombination, strong EL- and sigma-quenching resonances are attributed to the spin-dependent polaron-to-bipolaron decay. The half-field EL- and sigma-detected resonances of two distinct triplet excitons is believed to result from triplet-triplet fusion to singlets

Essential role of Notch signaling in effector memory CD8+ T cell–mediated airway hyperresponsiveness and inflammation

Adoptive transfer of in vivo–primed CD8+ T cells or in vitro–generated effector memory CD8+ T (TEFF) cells restores airway hyperresponsiveness (AHR) and airway inflammation in CD8-deficient (CD8−/−) mice. Examining transcription levels, there was a strong induction of Notch1 in TEFF cells compared with central memory CD8+ T cells. Treatment of TEFF cells with a γ-secretase inhibitor (GSI) strongly inhibited Notch signaling in these cells, and after adoptive transfer, GSI-treated TEFF cells failed to restore AHR and airway inflammation in sensitized and challenged recipient CD8−/− mice, or to enhance these responses in recipient wild-type (WT) mice. These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in TEFF cells. Treatment of sensitized and challenged WT mice with Delta1-Fc resulted in decreased AHR and airway inflammation accompanied by higher levels of interferon γ in bronchoalveolar lavage fluid. These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1. These data are the first to show a functional role for Notch in the challenge phase of CD8+ T cell–mediated development of AHR and airway inflammation, and identify Delta1 as an important regulator of allergic airway inflammation

Photoinduced absorption and photoluminescence in poly(2,5-dimethoxy-p- phenylene vinylene)

We report a study of the photoexcited states in the conjugated polymer poly(2,5-dimethoxy-p-phenylene vinylene). Photoluminescence due to radiative recombination of singlet excitons is observed at energiesjust below the onset of the pi-pi* absorption band at 2.1 eV. Photoinduced absorption at 80 K shows bands peaking at 0.68, 1.35, and 1.80 eV. The features at 0.68 and 1.8 eV are associated with the same excited state which we propose is a doubly charged bipolaron, while the third at 1.35 eV is unrelated. We assign this 1.35-eV absorption to a triplet-triplet transition of a triplet exciton. The bipolarons are long lived with significant numbers surviving in excess of 100 ms at 80 K, and have a weak temperature dependence such that photoinduced absorption is readily detectable even at room temperature. The triplet exciton has a lifetime of order 2.5 ms at 80 K but this falls rapidly at higher temperature and the response is not detected at room temperature. We contrast these results with those obtained previously for the related poly(arylene vinylene) polymers poly(p-phenylene vinylene), and poly(2,5-thienylene vinylene) and for other conjugated polymers, and draw attention to the important role played in the photophysics of these materials by neutral excited states

Toward a Consensus on Guiding Principles for Health Systems Strengthening

Based upon a review of the literature, Robert Chad Swanson and colleagues present a set of guiding principles for health systems strengthening

Hopanoid-free Methylobacterium extorquens DM4 overproduces carotenoids and has widespread growth impairment

Hopanoids are sterol-like membrane lipids widely used as geochemical proxies for bacteria. Currently, the physiological role of hopanoids is not well understood, and this represents one of the major limitations in interpreting the significance of their presence in ancient or contemporary sediments. Previous analyses of mutants lacking hopanoids in a range of bacteria have revealed a range of phenotypes under normal growth conditions, but with most having at least an increased sensitivity to toxins and osmotic stress. We employed hopanoid-free strains of Methylobacterium extorquens DM4, uncovering severe growth defects relative to the wild-type under many tested conditions, including normal growth conditions without additional stressors. Mutants overproduce carotenoids–the other major isoprenoid product of this strain–and show an altered fatty acid profile, pronounced flocculation in liquid media, and lower growth yields than for the wild-type strain. The flocculation phenotype can be mitigated by addition of cellulase to the medium, suggesting a link between the function of hopanoids and the secretion of cellulose in M. extorquens DM4. On solid media, colonies of the hopanoid-free mutant strain were smaller than wild-type, and were more sensitive to osmotic or pH stress, as well as to a variety of toxins. The results for M. extorquens DM4 are consistent with the hypothesis that hopanoids are important for membrane fluidity and lipid packing, but also indicate that the specific physiological processes that require hopanoids vary across bacterial lineages. Our work provides further support to emerging observations that the role of hopanoids in membrane robustness and barrier function may be important across lineages, possibly mediated through an interaction with lipid A in the outer membrane

Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137575/1/ajmgb32527.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137575/2/ajmgb32527_am.pd

Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD