Relationships and events: towards a general theory of reification and truthmaking.

We propose a novel ontological analysis of relations and relationships based on a re-visitation of a classic problem in the practice of knowledge repre- sentation and conceptual modeling, namely relationship reification. Our idea is that a relation holds in virtue of a relationship's existence. Relationships are therefore truthmakers of relations. In this paper we present a general theory or reification and truthmaking, and discuss the interplay between events and rela- tionships, suggesting that relationships are the focus of events, which emerge from the context (the scene) they occur in

Microbiome and environment explain the absence of correlations between consumers and their diet in Bornean microsnails

Classical ecological theory posits that species partition resources such that each species occupies a unique resource niche. In general, the availability of more resources allows more species to co‐occur. Thus, a strong relationship between communities of consumers and their resources is expected. However, correlations may be influenced by other layers in the food web, or by the environment. Here we show, by studying the relationship between communities of consumers (land snails) and individual diets (from seed plants), that there is in fact no direct, or at most a weak but negative, relationship. However, we found that the diversity of the individual microbiome positively correlates with both consumer community diversity and individual diet diversity in three target species. Moreover, these correlations were affected by various environmental variables, such as anthropogenic activity, habitat island size, and a possibly important nutrient source, guano runoff from nearby caves. Our results suggest that the microbiome and the environment explain the absence of correlations between diet and consumer community diversity. Hence, we advocate that microbiome inventories are routinely added to any community dietary analysis, which our study shows can be done with relatively little extra effort. Our approach presents the tools to quickly obtain an overview of the relationships between consumers and their resources. We anticipate our approach to be useful for ecologists and environmentalist studying different communities in a local food web

Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience

Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue

No increased bleeding events in patients with relapsed chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma treated with idelalisib

The advent of novel B-cell receptor pathway targeting agents like ibrutinib dramatically changed management of B-cell malignancies. However, with concomitant anticoagulation (AC) and antiplatelet (AP) therapy, ibrutinib is associated with increased bleeding. This post hoc analysis aimed to determine the role of AC/AP therapy in patients with idelalisib-treated B-cell malignancies and to establish if it contributes to increased bleeding events. Data from two idelalisib trials (rituximab ± idelalisib in chronic lymphocytic leukemia [CLL] and idelalisib monotherapy in indolent non-Hodgkin lymphoma [iNHL]) were analyzed. Antithrombotic therapy was common (36%–63%), with comparable bleeding incidence across treatment groups (14%–19%; p = 0.56). Bleeding events of grade ≥3 occurred in 0.9% and 3.2% of the idelalisib-treated CLL and iNHL cohorts, respectively. Our findings demonstrate no increase in bleeding events with simultaneous AC/AP treatment and idelalisib use. Hemorrhagic risk is prevalent in these patients and an important consideration when evaluating available treatment options

Role of liraglutide in Alzheimer's disease pathology

Background The described relationship between Alzheimer's disease (AD) and type 2 diabetes (T2D) and the fact that AD has no succesful treatment has led to the study of antidiabetic drugs that may limit or slow down AD pathology. Main body Although T2D treatment has evident limitations, options are increasing including glucagon-like peptide 1 analogs. Among these, liraglutide (LRGT) is commonly used by T2D patients to improve beta cell function and suppress glucagon to restore normoglycaemia. Interestingly, LRGT also counterbalances altered brain metabolism and has anti-inflammatory properties. Previous studies have reported its capacity to reduce AD pathology, including amyloid production and deposition, tau hyperphosphorylation, or neuronal and synaptic loss in animal models of AD, accompanied by cognitive improvement. Given the beneficial effects of LRGT at central level, studies in patients have been carried out, showing modest beneficial effects. At present, the ELAD trial (Evaluating Liraglutide in Alzheimer's Disease NCT01843075) is an ongoing phase IIb study in patients with mild AD. In this minireview, we resume the outcomes of LRGT treatment in preclinical models of AD as well as the available results in patients up to date. Conclusion The effects of LRGT on animal models show significant benefits in AD pathology and cognitive impairment. While studies in patients are limited, ongoing clinical trials will probably provide more definitive conclusions on the role of LRGT in AD patients

Oldest known pantherine skull and evolution of the tiger

The tiger is one of the most iconic extant animals, and its origin and evolution have been intensely debated. Fossils attributable to extant pantherine species-lineages are less than 2 MYA and the earliest tiger fossils are from the Calabrian, Lower Pleistocene. Molecular studies predict a much younger age for the divergence of modern tiger subspecies at <100 KYA, although their cranial morphology is readily distinguishable, indicating that early Pleistocene tigers would likely have differed markedly anatomically from extant tigers. Such inferences are hampered by the fact that well-known fossil tiger material is middle to late Pleistocene in age. Here we describe a new species of pantherine cat from Longdan, Gansu Province, China, Panthera zdanskyi sp. nov. With an estimated age of 2.55–2.16 MYA it represents the oldest complete skull of a pantherine cat hitherto found. Although smaller, it appears morphologically to be surprisingly similar to modern tigers considering its age. Morphological, morphometric, and cladistic analyses are congruent in confirming its very close affinity to the tiger, and it may be regarded as the most primitive species of the tiger lineage, demonstrating the first unequivocal presence of a modern pantherine species-lineage in the basal stage of the Pleistocene (Gelasian; traditionally considered to be Late Pliocene). This find supports a north-central Chinese origin of the tiger lineage, and demonstrates that various parts of the cranium, mandible, and dentition evolved at different rates. An increase in size and a reduction in the relative size of parts of the dentition appear to have been prominent features of tiger evolution, whereas the distinctive cranial morphology of modern tigers was established very early in their evolutionary history. The evolutionary trend of increasing size in the tiger lineage is likely coupled to the evolution of its primary prey species

Single fraction radiosurgery using Rapid Arc for treatment of intracranial targets

<p>Abstract</p> <p>Background</p> <p>Stereotactic-Radio-Surgery (SRS) using Conformal-Arc-Therapy (CAT) is a well established irradiation technique for treatment of intracranial targets. Although small safety margins are required because of very high accuracy of patient positioning and exact online localisation, there are still disadvantages like long treatment time, high number of monitor units (MU) and covering of noncircular targets. This planning study analysed whether Rapid Arc (RA) with stereotactic localisation for single-fraction SRS can solve these problems.</p> <p>Methods</p> <p>Ten consecutive patients were treated with Linac-based SRS. Eight patients had one or more brain metastases. The other patients presented a symptomatic vestibularis schwannoma and an atypic meningeoma. For all patients, two plans (CAT/RA) were calculated and analysed.</p> <p>Results</p> <p>Conformity was higher for RA with additional larger low-dose areas. Furthermore, RA reduced the number of MU and the treatment time for all patients. Dose to organs at risk were equal or slightly higher using RA in comparison to CAT.</p> <p>Conclusions</p> <p>RA provides a new alternative for single-fraction SRS irradiation combining advantages of short treatment time with lower number of MU and better conformity in addition to accuracy of stereotactic localisation in selected cases with uncomplicated clinical realization.</p

Defining the functional traits that drive bacterial decomposer community productivity

Microbial communities are essential to a wide range of ecologically and industrially important processes. To control or predict how these communities function, we require a better understanding of the factors which influence microbial community productivity. Here, we combine functional resource use assays with a biodiversity–ecosystem functioning (BEF) experiment to determine whether the functional traits of constituent species can be used to predict community productivity. We quantified the abilities of 12 bacterial species to metabolise components of lignocellulose and then assembled these species into communities of varying diversity and composition to measure their productivity growing on lignocellulose, a complex natural substrate. A positive relationship between diversity and community productivity was caused by a selection effect whereby more diverse communities were more likely to contain two species that significantly improved community productivity. Analysis of functional traits revealed that the observed selection effect was primarily driven by the abilities of these species to degrade β-glucan. Our results indicate that by identifying the key functional traits underlying microbial community productivity we could improve industrial bioprocessing of complex natural substrates

CD8+ T-Cells Expressing Interferon Gamma or Perforin Play Antagonistic Roles in Heart Injury in Experimental Trypanosoma Cruzi-Elicited Cardiomyopathy

In Chagas disease, CD8+ T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8+ T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8+ T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8+ T-cell capacity to produce interferon-gamma (IFNγ) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8+ T-cells segregated into IFNγ+ perforin (Pfn)neg or IFNγnegPfn+ cell populations. Colonization of the cardiac tissue by anti-T. cruzi CD8+Pfn+ cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8−/− recipients showed that the CD8+ cells from infected ifnγ−/−pfn+/+ donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8+ cells from ifnγ+/+pfn−/− donors. Moreover, the reconstitution of naïve cd8−/− mice with CD8+ cells from naïve ifnγ+/+pfn−/− donors ameliorated T. cruzi-elicited heart injury paralleled IFNγ+ cells accumulation, whereas reconstitution with CD8+ cells from naïve ifnγ−/−pfn+/+ donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn+ cells in the cardiac tissue. Our data support a possible antagonist effect of CD8+Pfn+ and CD8+IFNγ+ cells during CCC. CD8+IFNγ+ cells may exert a beneficial role, whereas CD8+Pfn+ may play a detrimental role in T. cruzi-elicited heart injury