The Chromatic Structure of Dense Graphs

This thesis focusses on extremal graph theory, the study of how local constraints on a graph affect its macroscopic structure. We primarily consider the chromatic structure: whether a graph has or is close to having some (low) chromatic number. Chapter 2 is the slight exception. We consider an induced version of the classical Turán problem. Introduced by Loh, Tait, Timmons, and Zhou, the induced Turán number ex(n, {H, F-ind}) is the greatest number of edges in an n-vertex graph with no copy of H and no induced copy of F. We asymptotically determine ex(n, {H, F-ind}) for H not bipartite and F neither an independent set nor a complete bipartite graph. We also improve the upper bound for ex(n, {H, K_{2, t}-ind}) as well as the lower bound for the clique number of graphs that have some fixed edge density and no induced K_{2, t}. The next three chapters form the heart of the thesis. Chapters 3 and 4 consider the Erdős-Simonovits question for locally r-colourable graphs: what are the structure and chromatic number of graphs with large minimum degree and where every neighbourhood is r-colourable? Chapter 3 deals with the locally bipartite case and Chapter 4 with the general case. While the subject of Chapters 3 and 4 is a natural local to global colouring question, it is also essential for determining the minimum degree stability of H-free graphs, the focus of Chapter 5. Given a graph H of chromatic number r + 1, this asks for the minimum degree that guarantees that an H-free graph is close to r-partite. This is analogous to the classical edge stability of Erdős and Simonovits. We also consider the question for the family of graphs to which H is not homomorphic, showing that it has the same answer. Chapter 6 considers sparse analogues of the results of Chapters 3 to 5 obtaining the thresholds at which the sparse problem degenerates away from the dense one. Finally, Chapter 7 considers a chromatic Ramsey problem first posed by Erdős: what is the greatest chromatic number of a triangle-free graph on $n$ vertices or with m edges? We improve the best known bounds and obtain tight (up to a constant factor) bounds for the list chromatic number, answering a question of Cames van Batenburg, de Joannis de Verclos, Kang, and Pirot

Cholesterosis of the gall-bladder: a clinical and experimental study

The occurrence of cholesterol deposits in the wall of the gall- bladder has appeared to the writer to be of more than passing interest, for the following reasons:- (i) Although cholesterol is of widespread distribution and may be laid down in many sites throughout the body in large collections, yet little is known either of its real function in regard to the general body economy or of the conditions which control its deposition, Such deposits consequently attract interest in inverse proportion to our knowledge of their causation. (2) The biliary tract is known to bear very particular relationship to cholesterol, for, with the exception of the milk during lactation, the bile forms by far the most important vehicle for its excretion, and it therefore becomes a very attractive hypothesis that the gall- bladder, as a specialised part of the biliary tract, bears some close relationship to this excretory process and that this relationship renders it particularly subject to the deposition of cholesterol.Part II. of this thesis is devoted to a consideration of these and other aspects of the disease, and to a description of experimental work which.has been carried out in relation to them, Firstly, Cholesterosis of the Gall-bladder will be considered in its relation to similar deposits of cholesterol in other organs. Secondly, an excursion will be made into the realms of Comparative Pathology, to describe a similar. change which it has been the writer's good fortune to observe in the gall-bladder of a cat.Thirdly, the possible causes of Cholesterosis in the human being will be considered, and the experimental production of the disease in animals under controlled conditions will be described. And lastly, experimental work will be recorded which goes to indicate the relation of Cholesterosis to the function of the gall-bladder and biliary tract.Whatever may be the pathogenesis of Cholesterosis of the Gall-bladder, a feature of very practical interest is its relation to the formation of gall-stones. It is well recognised that Cholesterol forms the chief constituent of the great majority of gall-stones, and it will be shown later that those stones which consist almost entirely of Cholesterol seem particularly apt to be associated with Cholesterosis of the Gall-bladder. The relationship between these two conditions therefore invites examination.In Part III, the present-day views as to the formation of gall-stones are considered, and in this connection several cases from the series here reported are described, which indicate the relationship existing between the origin of stones and cholesterol deposition in the gall-bladder wall

Haemorrhage in jaundice

It is established that in toxiinfective and obstructive forms of jaundice there commonly develops a state characterised by an undue liability to haemorrhage.The bleeding may occur from a mucous or serous surface or into the skin. It commonly gives rise to epistaxis, haematemesis, melaena, purpura. The danger of haemorrhage is greatest in the period immediately after operation, and herein lies its special importance from the surgical standpoint. The usual experience is that no excessive bleeding is noticed during the operation, and haemostasis is generally secured without difficulty; the bleeding takes place a few days later, and the period of greatest danger lies between the third and the sixth day. Such post- operative bleeding may occur at the sites already mentioned, but more commonly it takes place from the raw surfaces in the operative field. It is very apt to take the form of a slow ooze into the depths of the wound, forming a haematoma there or perhaps leaking to the surface at the incision.Haemorrhage in jaundice is thus a condition of no little surgical importance. In the investigation reported here I have aimed at the solution of three problems related to the subject, the cause of the bleeding tendency, its recognition and its prevention or treatment.The work is based upon a study of 50 cases of jaundice under treatment in the Edinburgh Western Hospital and the Edinburgh Royal Infirmary, including 12 cases in which spontaneous or postoperative haemorrhages developed. It comprises clinical and laboratory investigations, with special reference to the coagulability of the blood and other factors concerned in the arrest of haemorrhage Special attention has been directed to the prothrombin content of the blood, and evidence is presented in support of the view that a prothrombin deficiency is an important factor predisposing to haemorrhage in jaundice. The results of prothrombin estimations on 34 jaundiced cases are given,' and the value of this test as a method of gauging the risk of haemorrhage is discussed. The cause of the prothrombin deficiency is considered, and the evidence attributing it to faulty absorption or faulty utilisation of a vitamin is studied. Finally observations are recorded on the effect of administering preparations containing the vitamin to jaundiced patients

GC Insights: Diversifying the geosciences in higher education: a manifesto for change

There is still a significant lack of diversity and equity in geoscience education, even after decades of work and widespread calls for improvement and action. We join fellow community voices in calls for improved diversity, equity, inclusion, and justice in the geosciences. Here, in this manifesto, we present a list of opportunities for educators to bring about this cultural shift within higher education: (1) advocating for institutional change, (2) incorporating diverse perspectives and authors in curricula, (3) teaching historical and socio-political contexts of geoscience information, (4) connecting geoscience principles to more geographically diverse locations, (5) implementing different communication styles that consider different ways of knowing and learning, and (6) empowering learner transformation and agency

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia

Abstract Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P B 0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (PB0.01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r= 0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day