Telocytes express PDGFRα in the human gastrointestinal tract

Telocytes (TC), a cell population located in the connective tissue of many organs of humans and laboratory mammals, are characterized by a small cell body and extremely long and thin processes. Different TC subpopulations share unique ultrastructural features, but express different markers. In the gastrointestinal (GI) tract, cells with features of TC were seen to be CD34‐positive/c‐kit‐negative and several roles have been proposed for them. Other interstitial cell types with regulatory roles described in the gut are the c‐kit‐positive/CD34‐negative/platelet‐derived growth factor receptor α (PDGFRα)‐negative interstitial cells of Cajal (ICC) and the PDGFRα‐positive/c‐kit‐negative fibroblast‐like cells (FLC). As TC display the same features and locations of the PDGFRα‐positive cells, we investigated whether TC and PDGFRα‐positive cells could be the same cell type. PDGFRα/CD34, PDGFRα/c‐kit and CD34/c‐kit double immunolabelling was performed in full‐thickness specimens from human oesophagus, stomach and small and large intestines. All TC in the mucosa, submucosa and muscle coat were PDGFRα/CD34‐positive. TC formed a three‐dimensional network in the submucosa and in the interstitium between muscle layers, and an almost continuous layer at the submucosal borders of muscularis mucosae and circular muscle layer. Moreover, TC encircled muscle bundles, nerve structures, blood vessels, funds of gastric glands and intestinal crypts. Some TC were located within the muscle bundles, displaying the same location of ICC and running intermingled with them. ICC were c‐kit‐positive and CD34/PDGFRα‐negative. In conclusion, in the human GI tract the TC are PDGFRα‐positive and, therefore, might correspond to the FLC. We also hypothesize that in human gut, there are different TC subpopulations probably playing region‐specific roles.     

Psychiatric Diagnosis Revisited: Towards a System of Staging and Profiling Combining Nomothetic and Idiographic Parameters of Momentary Mental States

Background

Mental disorders may be reducible to sets of symptoms, connected through systems of causal relations. A clinical staging model predicts that in earlier stages of illness, symptom expression is both non-specific and diffuse. With illness progression, more specific syndromes emerge. This paper addressed the hypothesis that connection strength and connection variability between mental states differ in the hypothesized direction across different stages of psychopathology.

Methods

In a general population sample of female siblings (mostly twins), the Experience Sampling Method was used to collect repeated measures of three momentary mental states (positive affect, negative affect and paranoia). Staging was operationalized across four levels of increasing severity of psychopathology, based on the total score of the Symptom Check List. Multilevel random regression was used to calculate inter- and intra-mental state connection strength and connection variability over time by modelling each momentary mental state at t as a function of the three momentary states at t-1, and by examining moderation by SCL-severity.

Results

Mental states impacted dynamically on each other over time, in interaction with SCL-severity groups. Thus, SCL-90 severity groups were characterized by progressively greater inter- and intra-mental state connection strength, and greater inter- and intra-mental state connection variability.

Conclusion

Diagnosis in psychiatry can be described as stages of growing dynamic causal impact of mental states over time. This system achieves a mode of psychiatric diagnosis that combines nomothetic (group-based classification across stages) and idiographic (individual-specific psychopathological profiles) components of psychopathology at the level of momentary mental states impacting on each other over time.     

Improved BM212 MmpL3 Inhibitor Analogue Shows Efficacy in Acute Murine Model of Tuberculosis Infection

1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis. To improve the physical chemical properties and drug-like parameters of this class of compounds, a medicinal chemistry effort was undertaken. By selecting the optimal substitution patterns for the phenyl rings at N1 and C5 and by replacing the thiomorpholine moiety with a morpholine one, a new series of compounds was produced. The replacement of the sulfur with oxygen gave compounds with lower lipophilicity and improved in vitro microsomal stability. Moreover, since the parent compound of this family has been shown to target MmpL3, mycobacterial mutants resistant to two compounds have been isolated and characterized by sequencing the mmpL3 gene; all the mutants showed point mutations in this gene. The best compound identified to date was progressed to dose-response studies in an acute murine TB infection model. The resulting ED₉₉ of 49 mg/Kg is within the range of commonly employed tuberculosis drugs, demonstrating the potential of this chemical series. The in vitro and in vivo target validation evidence presented here adds further weight to MmpL3 as a druggable target of interest for anti-tubercular drug discovery.     

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquin^san/san mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquin^san/san mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquin^gt/gt mice) had small intestinal inflammation that mimicked that of Roquin^san/san mice. MLN cells in Roquin^san/san mice consisted of activated proliferating T cells, and had increased numbers of CD44^hi CD62L^lo KLRG1⁺ short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquin^san/san mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquin^san/san mice consisted of a high proportion of Gr-1⁺ T cells that included IL-17A⁺ cells and CD8⁺ IFN-γ⁺ cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquin^san/san mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn''s disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process.     

Mapping of Alternaria and Pleospora concentrations in Central Italy using meteorological forecast and neural network estimator

Airborne particles (pollens and fungal spores) are recognized as important causes of allergies and many other pathologies whose main symptoms are usually associated with respiratory problems. In addition, these particles seem to be responsible for clinical symptoms of oculorhinitis and bronchial asthma. Many authors showed how pollen and spore concentrations are critically linked to meteorological conditions, while other studies investigated the possibility to estimate these concentrations through meteorological parameters. So, many different approaches have been proposed, and one of the most sophisticated is based on the use of a complex artificial neural network architecture. Once the neural device is calibrated using simultaneous time series of observed meteorological parameters and airborne biological particles, it is straightforward to use the Neural Network to predict spore concentrations using operational Limited Area Meteorological Model. In a previous work, it has been shown that the MM5 meteorological model developed by National Center for Atmospheric Research and Pennsylvania State University can be coupled with the above-cited neural predictor to provide a good prediction of Alternaria and Pleospora spore in the location of L’Aquila (Central Italy). Following the same approach, this work aims to provide the mapping of spore concentration over a wide area covered by high-resolution meteorological prediction in Central Italy. The complex patterns of fungal spore concentrations in selected areas will be described, and the high temporal variability of such fields will be discussed as well. The possibility to infer useful information from the predicted pattern of spore concentrations is discussed, as an example it appears that for people suffering from allergy to fungal spores is more comfortable to spend summertime close to the east coast of Italian Peninsula respect to the west coast. A further step of this work may easily lead to an operational use of the model for supporting the clinical management of allergies and for establishing a preventive strategy in agriculture to avoid unsafe and useless pollution of atmosphere, crops and fields.     

Cryptic introductions and the interpretation of island biodiversity

Species with cryptic origins (i.e. those that cannot be reliably classed as native or non‐native) present a particular challenge to our understanding of the generation and maintenance of biodiversity. Such species may be especially common on islands given that some islands have had a relatively recent history of human settlement. It is likely that select island species considered native might have achieved their current distributions via direct or indirect human actions. As an example, we explore the origins of eastern bluebirds (Sialia sialis bermudensis) on the island of Bermuda. Considered native to the island and a distinct subspecies, this population has diverged in morphology relative to mainland North America. Using microsatellite markers and simulation of island colonization, we show that the Bermuda population of bluebirds is the likely result of a single colonization event that occurred during the 1600s, making this a cryptic invader. To our knowledge, this is one of the youngest examples of a terrestrial vertebrate cryptic invader. We suggest that the eastern bluebird is not an isolated case of cryptic invader on either Bermuda or elsewhere and that caution be exercised when studying present‐day distributions of organisms.     

New structure–activity relationship studies in a series of N,N-bis(cyclohexanol)amine aryl esters as potent reversers of P-glycoprotein-mediated multidrug resistance (MDR)

As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure–activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis).The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I]_0.5) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a–d and 6d, showed excellent efficacy with a α_max close to 1. Selected compounds (2d, 3a, 3b, 5a–d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells.The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site.In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,²⁹ are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs.