Empirically-Informed Modal Rationalism

In this chapter, it is suggested that our epistemic access to metaphysical modality generally involves rationalist, a priori elements. However, these a priori elements are much more subtle than ‘traditional’ modal rationalism assumes. In fact, some might even question the ‘apriority’ of these elements, but I should stress that I consider a priori and a posteriori elements especially in our modal inquiry to be so deeply intertwined that it is not easy to tell them apart. Supposed metaphysically necessary identity statements involving natural kind terms are a good example: the fact that empirical input is crucial in establishing their necessity has clouded the role and content of the a priori input, as I have previously argued (Tahko forthcoming). For instance, the supposed metaphysically necessary identity statement involving water and its microstructure can only be established with the help of a controversial a priori principle concerning the determination of chemical properties by microstructure. The Kripke-Putnam framework of modal epistemology fails precisely because it is unclear whether the required a priori element is present. My positive proposal builds on E. J. Lowe’s work. Lowe holds that our knowledge of metaphysical modality is based on our knowledge of essence. Lowe’s account strives to offer a uniform picture of modal epistemology: essence is the basis of all our modal knowledge. This is the basis of Lowe’s modal rationalism. I believe that Lowe’s proposal is on the right lines in the case of abstract objects, but I doubt that it can be successfully applied to the case of natural kinds. Accordingly, the case of natural kinds will be my main focus and I will suggest that modal rationalism, at least as it is traditionally understood, falls short of explaining modal knowledge concerning natural kinds. Yet, I think that Lowe has identified something of crucial importance for modal epistemology, namely the essentialist, a priori elements present in our modal inquiry. The upshot is that rather than moving all the way from modal rationalism to modal empiricism, a type of hybrid approach, ‘empirically-informed modal rationalism’, can be developed.Peer reviewe

Generation of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

Optimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-α +/- IFN-α) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-α, (iii) association between circulating T regulatory cells (Tregs) and clinical responses

Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis

Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, ‘stabilised’ tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer

The Role of Canine Distemper Virus and Persistent Organic Pollutants in Mortality Patterns of Caspian Seals (Pusa caspica)

Persistent organic pollutants are a concern for species occupying high trophic levels since they can cause immunosuppression and impair reproduction. Mass mortalities due to canine distemper virus (CDV) occurred in Caspian seals (Pusa caspica), in spring of 1997, 2000 and 2001, but the potential role of organochlorine exposure in these epizootics remains undetermined. Here we integrate Caspian seal mortality data spanning 1971-2008, with data on age, body condition, pathology and blubber organochlorine concentration for carcases stranded between 1997 and 2002. We test the hypothesis that summed PCB and DDT concentrations contributed to CDV associated mortality during epizootics. We show that age is the primary factor explaining variation in blubber organochlorine concentrations, and that organochlorine burden, age, sex, and body condition do not account for CDV infection status (positive/negative) of animals dying in epizootics. Most animals (57%, n = 67) had PCB concentrations below proposed thresholds for toxic effects in marine mammals (17 μg/g lipid weight), and only 3 of 67 animals had predicted TEQ values exceeding levels seen to be associated with immune suppression in harbour seals (200 pg/g lipid weight). Mean organonchlorine levels were higher in CDV-negative animals indicating that organochlorines did not contribute significantly to CDV mortality in epizootics. Mortality monitoring in Azerbaijan 1971-2008 revealed bi-annual stranding peaks in late spring, following the annual moult and during autumn migrations northwards. Mortality peaks comparable to epizootic years were also recorded in the 1970s-1980s, consistent with previous undocumented CDV outbreaks. Gompertz growth curves show that Caspian seals achieve an asymptotic standard body length of 126-129 cm (n = 111). Males may continue to grow slowly throughout life. Mortality during epizootics may exceed the potential biological removal level (PBR) for the population, but the low frequency of epizootics suggest they are of secondary importance compared to anthropogenic sources of mortality such as fishing by-catch

The role of open abdomen in non-trauma patient : WSES Consensus Paper

The open abdomen (OA) is defined as intentional decision to leave the fascial edges of the abdomen un-approximated after laparotomy (laparostomy). The abdominal contents are potentially exposed and therefore must be protected with a temporary coverage, which is referred to as temporal abdominal closure (TAC). OA use remains widely debated with many specific details deserving detailed assessment and clarification. To date, in patients with intra-abdominal emergencies, the OA has not been formally endorsed for routine utilization; although, utilization is seemingly increasing. Therefore, the World Society of Emergency Surgery (WSES), Abdominal Compartment Society (WSACS) and the Donegal Research Academy united a worldwide group of experts in an international consensus conference to review and thereafter propose the basis for evidence-directed utilization of OA management in non-trauma emergency surgery and critically ill patients. In addition to utilization recommendations, questions with insufficient evidence urgently requiring future study were identified.Peer reviewe

Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines

This article discusses the definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis. Acute cholangitis and cholecystitis mostly originate from stones in the bile ducts and gallbladder. Acute cholecystitis also has other causes, such as ischemia; chemicals that enter biliary secretions; motility disorders associated with drugs; infections with microorganisms, protozoa, and parasites; collagen disease; and allergic reactions. Acute acalculous cholecystitis is associated with a recent operation, trauma, burns, multisystem organ failure, and parenteral nutrition. Factors associated with the onset of cholelithiasis include obesity, age, and drugs such as oral contraceptives. The reported mortality of less than 10% for acute cholecystitis gives an impression that it is not a fatal disease, except for the elderly and/or patients with acalculous disease. However, there are reports of high mortality for cholangitis, although the mortality differs greatly depending on the year of the report and the severity of the disease. Even reports published in and after the 1980s indicate high mortality, ranging from 10% to 30% in the patients, with multiorgan failure as a major cause of death. Because many of the reports on acute cholecystitis and cholangitis use different standards, comparisons are difficult. Variations in treatment and risk factors influencing the mortality rates indicate the necessity for standardized diagnostic, treatment, and severity assessment criteria

Performance and calibration of quark/gluon-jet taggers using 140 fb⁻¹ of pp collisions at √s=13 TeV with the ATLAS detector

The identification of jets originating from quarks and gluons, often referred to as quark/gluon tagging, plays an important role in various analyses performed at the Large Hadron Collider, as Standard Model measurements and searches for new particles decaying to quarks often rely on suppressing a large gluon-induced background. This paper describes the measurement of the efficiencies of quark/gluon taggers developed within the ATLAS Collaboration, using √s=13 TeV proton–proton collision data with an integrated luminosity of 140 fb-1 collected by the ATLAS experiment. Two taggers with high performances in rejecting jets from gluon over jets from quarks are studied: one tagger is based on requirements on the number of inner-detector tracks associated with the jet, and the other combines several jet substructure observables using a boosted decision tree. A method is established to determine the quark/gluon fraction in data, by using quark/gluon-enriched subsamples defined by the jet pseudorapidity. Differences in tagging efficiency between data and simulation are provided for jets with transverse momentum between 500 GeV and 2 TeV and for multiple tagger working points

Improving topological cluster reconstruction using calorimeter cell timing in ATLAS

Clusters of topologically connected calorimeter cells around cells with large absolute signal-to-noise ratio (topo-clusters) are the basis for calorimeter signal reconstruction in the ATLAS experiment. Topological cell clustering has proven performant in LHC Runs 1 and 2. It is, however, susceptible to out-of-time pile-up of signals from soft collisions outside the 25 ns proton-bunch-crossing window associated with the event’s hard collision. To reduce this effect, a calorimeter-cell timing criterion was added to the signal-to-noise ratio requirement in the clustering algorithm. Multiple versions of this criterion were tested by reconstructing hadronic signals in simulated events and Run 2 ATLAS data. The preferred version is found to reduce the out-of-time pile-up jet multiplicity by ∼50% for jet pT ∼ 20 GeV and by ∼80% for jet pT 50 GeV, while not disrupting the reconstruction of hadronic signals of interest, and improving the jet energy resolution by up to 5% for 20 < pT < 30 GeV. Pile-up is also suppressed for other physics objects based on topo-clusters (electrons, photons, τ -leptons), reducing the overall event size on disk by about 6% in early Run 3 pileup conditions. Offline reconstruction for Run 3 includes the timing requirement

Software Performance of the ATLAS Track Reconstruction for LHC Run 3

Charged particle reconstruction in the presence of many simultaneous proton–proton (pp) collisions in the LHC is a challenging task for the ATLAS experiment’s reconstruction software due to the combinatorial complexity. This paper describes the major changes made to adapt the software to reconstruct high-activity collisions with an average of 50 or more simultaneous pp interactions per bunch crossing (pileup) promptly using the available computing resources. The performance of the key components of the track reconstruction chain and its dependence on pile-up are evaluated, and the improvement achieved compared to the previous software version is quantified. For events with an average of 60 pp collisions per bunch crossing, the updated track reconstruction is twice as fast as the previous version, without significant reduction in reconstruction efficiency and while reducing the rate of combinatorial fake tracks by more than a factor two

Measurement and interpretation of same-sign W boson pair production in association with two jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper presents the measurement of fducial and diferential cross sections for both the inclusive and electroweak production of a same-sign W-boson pair in association with two jets (W±W±jj) using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of √ s = 13 TeV by the ATLAS detector at the Large Hadron Collider. The analysis is performed by selecting two same-charge leptons, electron or muon, and at least two jets with large invariant mass and a large rapidity diference. The measured fducial cross sections for electroweak and inclusive W±W±jj production are 2.92 ± 0.22 (stat.) ± 0.19 (syst.)fb and 3.38±0.22 (stat.)±0.19 (syst.)fb, respectively, in agreement with Standard Model predictions. The measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confdence level intervals on dimension-8 operators. A search for doubly charged Higgs bosons H±± that are produced in vector-boson fusion processes and decay into a same-sign W boson pair is performed. The largest deviation from the Standard Model occurs for an H±± mass near 450 GeV, with a global signifcance of 2.5 standard deviations