Local lung hypoxia determines epithelial fate decisions during alveolar regeneration.

After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/β-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair

Targeting glutamine synthesis inhibits stem cell adipogenesis in vitro

Background/Aims: Glutamine is the most abundant amino acid in the body and has a metabolic role as a precursor for protein, amino sugar and nucleotide synthesis. After glucose, glutamine is the main source of energy in cells and has recently been shown to be an important carbon source for de novo lipogenesis. Glutamine is synthesized by the enzyme glutamine synthetase, a mitochondrial enzyme that is active during adipocyte differentiation suggesting a regulatory role in this process. The aim of our study was therefore to investigate whether glutamine status impacts on differentiation of adipocytes and lipid droplet accumulation. Methods: Mouse mesenchymal stem cells (MSCs) were submitted to glutamine deprivation (i.e. glutamine-free adipogenic medium in conjunction with irreversible glutamine synthetase inhibitor, methionine sulfoximine – MSO) during differentiation and their response compared with MSCs differentiated in glutamine-supplemented medium (5, 10 and 20 mM). Differentiated MSCs were assessed for lipid content using Oil Red O (ORO) staining and gene expression was analysed by qPCR. Intracellular glutamine levels were determined using a colorimetric assay, while extracellular glutamine was measured using liquid chromatography-mass spectrometry (LC-MS). Results: Glutamine deprivation largely abolished adipogenic differentiation and lipid droplet formation. This was accompanied with a reduction in intracellular glutamine concentration, and downregulation of gene expression for classical adipogenic markers including PPARγ. Furthermore, glutamine restriction suppressed isocitrate dehydrogenase 1 (IDH1) gene expression, an enzyme which produces citrate for lipid synthesis. In contrast, glutamine supplementation promoted adipogenic differentiation in a dose-dependent manner. Conclusion: These results suggest that the glutamine pathway may have a previously overlooked role in adipogenesis. The underlying mechanism involved the glutamine-IDH1 pathway and could represent a potential therapeutic strategy to treat excessive lipid accumulation and thus obesity

CD39 activity correlates with stage and inhibits platelet reactivity in chronic lymphocytic leukemia

<p>Abstract</p> <p>Background</p> <p>Chronic lymphocytic leukemia (CLL) is characterized by accumulation of mature appearing lymphocytes and is rarely complicated by thrombosis. One possible explanation for the paucity of thrombotic events in these patients may be the presence of the ecto-nucleotidase CD39/NTDPase-1 on the surface of the malignant cells in CLL. CD39 is the major promoter of platelet inhibition <it>in vivo </it>via its metabolism of ADP to AMP. We hypothesize that if CD39 is observed on CLL cells, then patients with CLL may be relatively protected against platelet aggregation and recruitment and that CD39 may have other effects on CLL, including modulation of the disease, via its metabolism of ATP.</p> <p>Methods</p> <p>Normal and malignant lymphocytes were isolated from whole blood from patients with CLL and healthy volunteers. Enzyme activity was measured via radio-TLC assay and expression via FACS. Semi-quantititative RT-PCR for CD39 splice variants and platelet function tests were performed on several samples.</p> <p>Results</p> <p>Functional assays demonstrated that ADPase and ATPase activities were much higher in CLL cells than in total lymphocytes from the normal population on a per cell basis (p-value < 0.00001). CD39 activity was elevated in stage 0–2 CLL compared to stage 3–4 (p < 0.01). FACS of lymphocytes demonstrated CD39 expression on > 90% of normal and malignant B-lymphocytes and ~8% of normal T-lymphocytes. RT-PCR showed increased full length CD39 and splice variant 1.5, but decreased variant 1.3 in CLL cells. Platelet function tests showed inhibition of platelet activation and recruitment to ADP by CLL cells.</p> <p>Conclusion</p> <p>CD39 is expressed and active on CLL cells. Enzyme activity is higher in earlier stages of CLL and decreased enzyme activity may be associated with worsening disease. These results suggest that CD39 may play a role in the pathogenesis of malignancy and protect CLL patients from thrombotic events.</p

Decoherence produces coherent states: an explicit proof for harmonic chains

We study the behavior of infinite systems of coupled harmonic oscillators as t->infinity, and generalize the Central Limit Theorem (CLT) to show that their reduced Wigner distributions become Gaussian under quite general conditions. This shows that generalized coherent states tend to be produced naturally. A sufficient condition for this to happen is shown to be that the spectral function is analytic and nonlinear. For a rectangular lattice of coupled oscillators, the nonlinearity requirement means that waves must be dispersive, so that localized wave-packets become suppressed. Virtually all harmonic heat-bath models in the literature satisfy this constraint, and we have good reason to believe that coherent states and their generalizations are not merely a useful analytical tool, but that nature is indeed full of them. Standard proofs of the CLT rely heavily on the fact that probability densities are non-negative. Although the CLT generally fails if the probability densities are allowed to take negative values, we show that a CLT does indeed hold for a special class of such functions. We find that, intriguingly, nature has arranged things so that all Wigner functions belong to this class.Comment: Final published version. 17 pages, Plain TeX, no figures. Online at http://astro.berkeley.edu/~max/gaussians.html (faster from the US), from http://www.mpa-garching.mpg.de/~max/gaussians.html (faster from Europe) or from [email protected]

Robustness in large-scale random networks

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2003.Includes bibliographical references (p. 73-76).This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.We consider the issue of protection in very large networks displaying randomness in topology. We employ random graph models to describe such networks, and obtain probabilistic bounds on several parameters related to various protection schemes. In particular, we take the case of random regular networks for simplicity, where the degree of each node is the same, and consider the length of primary and backup paths in terms of the number of hops. First, for a randomly picked pair of nodes, we derive a lower bound on the average distance between the pair and discuss the tightness of the bound. In addition, noting that primary and protection paths form cycles, we obtain a lower bound on the average length of the shortest cycle around the pair. Finally, we show that the protected connections of a given maximum finite length are rare. We then generalize our network model so that different degrees are allowed according to some arbitrary distribution. Notably, we derive an upper bound on the mean number of non-finite length cycles in generalized random networks. More importantly, we show that most of the results in regular networks carry over with minor modifications, which significantly broadens the scope of networks to which our approach applies. Our main contributions are the following. First, we take an analytical approach by bringing the concept of randomness into network topologies that can provide concise rules to relate basic network parameters to robustness. Second, we establish analytical results for the length of backup paths for path and link-based protection schemes rather than for the efficiency of backup capacity, upon which most studies concentrate. Finally, we develop a unified framework for studying the issue of robustness in very general random networks with arbitrary degree distributions.by Minkyu Kim.S.M

RTOG 0518: Randomized Phase III Trial to Evaluate Zoledronic Acid for Prevention of Osteoporosis and Associated Fractures in Prostate Cancer Patients

Background: RTOG 0518 evaluated the potential benefit of zoledronic acid therapy in preventing bone fractures for patients with high grade and/or locally advanced, non-metastatic prostate adenocarcinoma receiving luteinizing hormone-releasing hormone (LHRH) agonist and radiotherapy (RT). Methods: Eligible patients with T-scores of the hip ( −2.5 vs. > −1.0) and negative bone scans were prospectively randomized to either zoledronic acid, 4 mg, concurrently with the start of RT and then every six months for a total of 6 infusions (Arm 1) or observation (Arm 2). Vitamin D and calcium supplements were given to all patients. Secondary objectives included quality of life (QOL) and bone mineral density (BMD) changes over a period of three years. Results: Of 109 patients accrued before early closure, 96 were eligible. Median follow-up was 36.3 months for Arm I and 34.8 months for Arm 2. Only two patients experienced a bone fracture (1 in each arm) resulting in no difference in freedom from any bone fracture (p=0.95), nor in QOL. BMD percent changes from baseline to 36 months were statistically improved with the use of zoledronic acid compared to observation for the lumbar spine (6% vs. −5%, p<0.0001), left total hip (1% vs. −8%, p=0.0002), and left femoral neck (3% vs. −8%, p=0.0007). Conclusions: For patients with advanced, non-metastatic prostate cancer receiving LHRH agonist and RT, the use of zoledronic acid was associated with statistically improved BMD percent changes. The small number of accrued patients resulted in decreased statistical power to detect any differences in the incidence of bone fractures or QOL

A Nuclear Cryogenic Propulsion Stage for Near-Term Space Missions

Development efforts in the United States have demonstrated the viability and performance potential of NTP systems. For example, Project Rover (1955 - 1973) completed 22 high power rocket reactor tests. Peak performances included operating at an average hydrogen exhaust temperature of 2550 K and a peak fuel power density of 5200 MW/m3 (Pewee test), operating at a thrust of 930 kN (Phoebus-2A test), and operating for 62.7 minutes on a single burn (NRXA6 test). Results from Project Rover indicated that an NTP system with a high thrust-toweight ratio and a specific impulse greater than 900 s would be feasible. Excellent results have also been obtained by Russia. Ternary carbide fuels developed in Russia may have the potential for providing even higher specific impulses

Bridging Alone: Religious Conservatism, Marital Homogamy, and Voluntary Association Membership

This study characterizes social insularity of religiously conservative American married couples by examining patterns of voluntary associationmembership. Constructing a dataset of 3938 marital dyads from the second wave of the National Survey of Families and Households, the author investigates whether conservative religious homogamy encourages membership in religious voluntary groups and discourages membership in secular voluntary groups. Results indicate that couples’ shared affiliation with conservative denominations, paired with beliefs in biblical authority and inerrancy, increases the likelihood of religious group membership for husbands and wives and reduces the likelihood of secular group membership for wives, but not for husbands. The social insularity of conservative religious groups appears to be reinforced by homogamy—particularly by wives who share faith with husbands

Allergic rhinitis

Allergic rhinitis is a common disorder that is strongly linked to asthma and conjunctivitis. It is usually a long-standing condition that often goes undetected in the primary-care setting. The classic symptoms of the disorder are nasal congestion, nasal itch, rhinorrhea and sneezing. A thorough history, physical examination and allergen skin testing are important for establishing the diagnosis of allergic rhinitis. Second-generation oral antihistamines and intranasal corticosteroids are the mainstay of treatment. Allergen immunotherapy is an effective immune-modulating treatment that should be recommended if pharmacologic therapy for allergic rhinitis is not effective or is not tolerated. This article provides an overview of the pathophysiology, diagnosis, and appropriate management of this disorder