Microbiota-mediated fine-tuning of the threshold of intestinal inflammasome activation in host-microbial mutualism

The inflammasome is a complex of proteins that controls the activity of caspase-1, pro-IL-1b and pro-IL-18. It acts in inflammatory processes and in pyropoptosis. The lower intestine is densely populated by a community of commensal bacteria that, under healthy conditions, are beneficial to the host. Some evidence suggests that the gut microbiota influences regulation of the inflammasome. Components of inflammasomes have been shown to have a protective function against development of experimental colitis, dependent on IL-18 production. However the precise mechanisms and the role of the inflammasome in maintaining a healthy host-microbial mutualism remains unknown. To address this question, we have performed axenic (GF) and gnotobiotic in vivo experiments to investigate how the inflammasome components mainly at the level of intestinal epithelial cells (IECs) are regulated under different hygiene conditions. We have established that gene expression of the inflammasome components NLRC4, NLRP3, NLRP6, NLRP12, caspase-1, ASC and IL-18 do not differ between germ-free and colonised conditions under steady-state. In contrast, induction in IL-18 was observed following infection with the pathobiont Segmented Filamentous Bacteria or the pathogen C. rodentium. Additional preliminar findings suggest that a more diverse intestinal flora, like specific pathogen-free (SPF) flora, is more efficient in inducing basal activation of the inflammasome and especially production of IL-18 by IECs, shortly after colonisation. We are also in the process of testing if basal activation of the inflammasome upon intestinal colonization with commensal bacteria helps to protect the host from potential pathobiont bacteria, like C. rodentium, SFB, Prevotella and TM7.

Complexity and non-linearity in earth surface processes - concepts, methods and applications

Complexity has long been recognized and is increasingly becoming mainstream in geomorphology. However, the relative novelty of various concepts and techniques associated to it means that ambiguity continues to surround complexity. In this commentary, we present and discuss a variety of recent contributions that have the potential to help clarify issues and advance the use of complexity in geomorphology.

Verbalization of Dependencies Between Concepts Built Through Fuzzy Cognitive Maps

The new computing paradigm known as cognitive computing attempts to imitate the human capabilities of learning, problem solving, and considering things in context. To do so, an application (a cognitive system) must learn from its environment (e.g., by interacting with various interfaces). These interfaces can run the gamut from sensors to humans to databases. Accessing data through such interfaces allows the system to conduct cognitive tasks that can support humans in decision-making or problem-solving processes. Cognitive systems can be integrated into various domains (e.g., medicine or insurance). For example, a cognitive system in cities can collect data, can learn from various data sources and can then attempt to connect these sources to provide real time optimizations of subsystems within the city (e.g., the transportation system). In this study, we provide a methodology for integrating a cognitive system that allows data to be verbalized, making the causalities and hypotheses generated from the cognitive system more understandable to humans. We abstract a city subsystem—passenger flow for a taxi company—by applying fuzzy cognitive maps (FCMs). FCMs can be used as a mathematical tool for modeling complex systems built by directed graphs with concepts (e.g., policies, events, and/or domains) as nodes and causalities as edges. As a verbalization technique we introduce the restriction-centered theory of reasoning (RCT). RCT addresses the imprecision inherent in language by introducing restrictions. Using this underlying combinatorial design, our approach can handle large data sets from complex systems and make the output understandable to humans.

Higgs effects in top anti-top production near threshold in e+e− annihilation

The completion of the third-order QCD corrections to the inclusive top-pair production cross section near threshold demonstrates that the strong dynamics is under control at the few percent level. In this paper we consider the effects of the Higgs boson on the cross section and, for the first time, combine the third-order QCD result with the third-order P-wave, the leading QED and the leading non-resonant contributions. We study the size of the different effects and investigate the sensitivity of the cross section to variations of the top-quark Yukawa coupling due to possible new physics effects.

Next-to-Next-to-Next-to-Leading Order QCD Prediction for the Top Antitop S-Wave Pair Production Cross Section Near Threshold in e + e − Annihilation

We present the third-order QCD prediction for the production of top antitop quark pairs in electron-positron collisions close to the threshold in the dominant S-wave state. We observe a significant reduction of the theoretical uncertainty and discuss the sensitivity to the top quark mass and width.

Migration and population expansion of Abies, Fagus, Picea, and Quercus since 15000 years in and across the Alps, based on pollen-percentage threshold values

Aims: The aim of this study is to explore the migration (colonization of new areas) and subsequent population expansion (within an area) since 15 ka cal BP of Abies, Fagus, Picea, and Quercus into and through the Alps solely on the basis of high-quality pollen data. Methods: Chronologies of 101 pollen sequences are improved or created. Data from the area delimited by 45.5–48.1°N and 6–14°E are summarized in three ways: (1) in a selection of pollen-percentage threshold maps (thresholds 0.5%, 1%, 2%, 4%, 8%, 16%, and 32% of land pollen); (2) in graphic summaries of 250-year time slices and geographic segments (lengthwise and transverse in relation to the main axis of the Alps) as pollen-percentage curves, pollen-percentage difference curves, and pollen-percentage threshold ages cal BP graphed against both the length and the transverse Alpine axes; and (3) in tables showing statistical relationships of either pollen-percentage threshold ages cal BP or pollen expansion durations (=time lapse between different pollen-percentage threshold ages cal BP) with latitude, longitude, and elevation; to establish these relationships we used both simple linear regression and multiple linear regression after stepwise-forward selection. Results: The statistical results indicate that (a) the use of pollen-percentage thresholds between 0.5% and 8% yield mostly similar directions of tree migration, so the method is fairly robust, (b) Abies migrated northward, Fagus southward, Picea westward, and Quercus northward; more detail does not emerge due to an extreme scarcity of high-quality data especially along the southern foothills of the Alps and in the eastern Alps. This scarcity allows the reconstruction of one immigration route only of Abies into the southern Alps. The speed of population expansion (following arrival) of Abies increased and of Picea decreased during the Holocene, of Fagus it decreased especially during the later Holocene, and of Quercus it increased especially at the start of the Holocene.

Acupuncture-induced changes of pressure pain threshold are mediated by segmental inhibition-a randomized controlled trial

Our aim was to distinguish between spinal and supraspinal mechanisms in the intact nervous system by comparing homosegmental and heterosegmental effects of electroacupuncture (EA) and manual acupuncture (MA) on sensory perception in healthy volunteers by means of quantitative sensory testing. Seventy-two healthy volunteers were randomly assigned to receive either MA or EA at SP 6, SP 9, GB 39, and ST 36 at the left leg or relaxed for 30 minutes (control group [CG]). Blinded examiners assessed 13 sensory modalities (thermal and mechanical detection and pain thresholds) at the upper arms and lower legs before and after intervention by means of a standardized quantitative sensory testing battery. Change scores of all 13 sensory thresholds were compared between groups. The main outcome measure was the change score of the pressure pain threshold (PPT). There were no baseline differences between groups. Pressure pain threshold change scores at the lower left leg, in the same segment as the needling site, differed significantly (P = 0.008) between the EA (median: 103.01 kPa) and CG groups (median: 0.00 kPa) but not between the MA (median: 0.00 kPa) and CG groups. No further significant change score differences were found between one of the acupuncture groups and the CG. The PPT can be changed by EA. The PPT increase was confined to the segment of needling, which indicates that it is mainly mediated by segmental inhibition in the spinal cord. This underscores the importance of segmental needling and electrical stimulation in clinical practice.

Immune response in pemphigus and beyond: progresses and emerging concepts

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.

Positron emission mammography in the diagnosis of breast cancer. Is maximum PEM uptake value a valuable threshold for malignant breast cancer detection?

AIM To evaluate the diagnostic value (sensitivity, specificity) of positron emission mammography (PEM) in a single site non-interventional study using the maximum PEM uptake value (PUVmax). PATIENTS, METHODS In a singlesite, non-interventional study, 108 patients (107 women, 1 man) with a total of 151 suspected lesions were scanned with a PEM Flex Solo II (Naviscan) at 90 min p.i. with 3.5 MBq 18F-FDG per kg of body weight. In this ROI(region of interest)-based analysis, maximum PEM uptake value (PUV) was determined in lesions, tumours (PUVmaxtumour), benign lesions (PUVmaxnormal breast) and also in healthy tissues on the contralateral side (PUVmaxcontralateral breast). These values were compared and contrasted. In addition, the ratios of PUVmaxtumour / PUVmaxcontralateral breast and PUVmaxnormal breast / PUVmaxcontralateral breast were compared. The image data were interpreted independently by two experienced nuclear medicine physicians and compared with histology in cases of suspected carcinoma. RESULTS Based on a criteria of PUV>1.9, 31 out of 151 lesions in the patient cohort were found to be malignant (21%). A mean PUVmaxtumour of 3.78 ± 2.47 was identified in malignant tumours, while a mean PUVmaxnormal breast of 1.17 ± 0.37 was reported in the glandular tissue of the healthy breast, with the difference being statistically significant (p < 0.001). Similarly, the mean ratio between tumour and healthy glandular tissue in breast cancer patients (3.15 ± 1.58) was found to be significantly higher than the ratio for benign lesions (1.17 ± 0.41, p < 0.001). CONCLUSION PEM is capable of differentiating breast tumours from benign lesions with 100% sensitivity along with a high specificity of 96%, when a threshold of PUVmax >1.9 is applied.

The use of an electronic von Frey device for evaluation of sensory threshold in neurologically normal dogs and those with acute spinal cord injury

The utility and inter-session repeatability of sensory threshold measurements using an electronic von Frey anesthesiometer (VFA) were assessed in a group of six neurologically normal dogs. Sensory threshold values obtained in neurologically normal dogs were compared to those of dogs with acute spinal cord injury (SCI) caused by intervertebral disc extrusion (n=6) and to a group of neurologically normal dogs with cranial cruciate ligament rupture (CCLR; n=6). Sensory threshold values in neurologically normal dogs were 155.8 ± 37.7 g and 154.7 ± 67.2 g for the left and right pelvic limbs, respectively. The difference in mean sensory threshold values obtained for the group when two distinct testing sessions were compared was not statistically significant (P>0.05). Mean sensory threshold values for the group with SCI were significantly higher than those for neurologically normal dogs at 351.1 ± 116.5 g and 420.3 ± 157.7 g for the left and right pelvic limbs, respectively (P=0.01). A comparison of sensory threshold values for the group with CCLR and neurologically normal dogs was not statistically significant (P>0.05). The modified dorsal technique for VFA described here represents a reliable method to assess sensory threshold in neurologically normal dogs and in those with SCI.

Antithrombotic therapy in TAVI patients: changing concepts.

The clinical and demographic characteristics of patients undergoing TAVI pose unique challenges for developing and implementing optimal antithrombotic therapy. Ischaemic and bleeding events in the periprocedural period and months after TAVI still remain a relevant concern to be faced with optimised antithrombotic therapy. Moreover, the antiplatelet and anticoagulant pharmacopeia has evolved significantly in recent years with new drugs and multiple possible combinations. Dual antiplatelet therapy (DAPT) is currently recommended after TAVI with oral anticoagulation (OAC) restricted for specific indications. However, atrial fibrillation (which is often clinically silent and unrecognised) is common after the procedure and embolic material often thrombin-rich. Recent evidence has therefore questioned this approach, suggesting that DAPT may be futile compared with aspirin alone and that OAC could be a relevant alternative. Future randomised and appropriately powered trials comparing different regimens of antithrombotic therapy, including new antiplatelet and anticoagulant agents, are warranted to increase the available evidence on this topic and create appropriate recommendations for this frail population. Meanwhile, it remains rational to adhere to current guidelines, with routine DAPT and recourse to OAC when specifically indicated, whilst always tailoring therapy on the basis of individual bleeding and thromboembolic risk.

Concepts of Bitemporal Database Theory and the Evolution of Web-Documents

A vast amount of temporal information is provided on the Web. Even though many facts expressed in documents are time-related, the temporal properties of Web presentations have not received much attention. In database research, temporal databases have become a mainstream topic in recent years. In Web documents, temporal data may exist as meta data in the header and as user-directed data in the body of a document. Whereas temporal data can easily be identified in the semi-structured meta data, it is more difficult to determine temporal data and its role in the body. We propose procedures for maintaining temporal integrity of Web pages and outline different approaches of applying bitemporal data concepts for Web documents. In particular, we regard desirable functionalities of Web repositories and other Web-related tools that may support the Webmasters in managing the temporal data of their Web documents. Some properties of a prototype environment are described.

Histopathology of NET: Current concepts and new developments

The diagnosis of neuroendocrine tumors is based on their histopathologic appearance and immunohistochemical profile. With the WHO 2010 classification formal staging and grading was introduced for gastro-entero-pancreatic NET, however, the nomenclature for lung neuroendocrine tumors still relies on the carcinoid term. In this review we also focus on the situation of neuroendocrine carcinoma of unknown primary, tissue biomarkers and actual controversies in the histopathology of NEN.