Fear of the unknown as a mechanism of the inverse relation between life meaning and psychological distress

Background and Objectives: Although there is accumulating evidence for an inverse relation between life meaning and psychological distress, little is known about the mechanisms of this relation. Using cross-sectional, observational methods, this research examined fear of uncertainty as one potential mechanism. Design and Methods: Study 1 (N = 141) was completed with a convenience sample, a unidimensional measure of life meaning, and general measures of anxiety and depression. Study 2 (N = 152) was completed with a sample prescreened for anxiety, a multidimensional measure of life meaning, and clinical measures of anxiety and depression. Results: The results from both studies generally showed an inverse relation between life meaning and psychological distress. Study 2 further indicated that these relations were stronger for the meaning subscale of perceiving life as coherent/comprehensible than the subscales assessing whether participants’ lives are perceived as purposeful or significant. Mediation analyses in both studies showed indirect effects of life meaning on psychological distress through fear of uncertainty. Conclusions: These findings support and extend previous research by showing that (i) meaning-as-comprehension may be particularly important in regards to psychological distress, and (ii) fear of uncertainty may mediate the inverse relation between meaning and measures of anxiety and depression

Responding to uncertain threat:A potential mediator for the effect of mindfulness on anxiety

Mindfulness-based interventions have gained extensive support for their application in the treatment of anxiety. However, their mechanisms remain largely unexplored. Excessive reactivity to uncertainty plays a central role in anxiety, and may represent a mechanism for the effect of mindfulness on anxiety, as mindfulness training fosters an open and accepting stance towards all aspects of experience. The present study sought to investigate both (i) self-reported intolerance of uncertainty (IU) as well as (ii) physiological and subjective responding to uncertain threat in a threat-of-shock paradigm, the NPU-threat test, as mediators for the relationship between mindfulness and anxiety in a cross-sectional study of healthy participants (N = 53). The results indicated that IU mediated the effect of mindfulness on some anxiety symptoms. In contrast, scores of physiological as well as subjective responses to uncertain threat from the NPU-threat test were largely unrelated to mindfulness, anxiety, or the IU self-report measure. The results provide initial evidence that reactions to uncertainty may play a role in the mindfulness-anxiety relationship and suggest that studies are needed to address how methodological variations of the NPU-threat test affect perceived levels of uncertainty and uncertainty-related anxiety

Evolution of mitochondrial relationships and biogeography of Palearctic green toads (Bufo viridis subgroup) with insights in their genomic plasticity.

Taxa involving three bisexually reproducing ploidy levels make green toads a unique amphibian system. We put a cytogenetic dataset from Central Asia in a molecular framework and apply phylogenetic and demographic methods to data from the entire Palearctic range. We study the mitochondrial relationships of diploids to infer their phylogeography and the maternal ancestry of polyploids. Control regions (and tRNAs between ND1 and ND2 in representatives) characterize a deeply branched assemblage of twelve haplotype groups, diverged since the Lower Miocene. Polyploidy has evolved several times: Central Asian tetraploids (B. oblongus, B. pewzowi) have at least two maternal origins. Intriguingly, the mitochondrial ancestor of morphologically distinctive, sexually reproducing triploid taxa (B. pseudoraddei) from Karakoram and Hindukush represents a different lineage. We report another potential case of bisexual triploid toads (B. zugmayeri). Identical d-loops in diploids and tetraploids from Iran and Turkmenistan, which differ in morphology, karyotypes and calls, suggest multiple origins and retained polymorphism and/or hybridization. A similar system involves diploids, triploids and tetraploids from Kyrgyzstan and Kazakhstan where green toads exemplify vertebrate genomic plasticity. A new form from Sicily and its African sister species (B. boulengeri) allow internal calibration and divergence time estimates for major clades. The subgroup may have originated in Eurasia rather than Africa since the earliest diverged lineages (B. latastii, B. surdus) and earliest fossils occur in Asia. We delineate ranges, contact and hybrid zones. Phylogeography, including one of the first non-avian datasets from Central Asian high mountains, reflects Quaternary climate and glaciation

Bosonic field equations from an exact uncertainty principle

A Hamiltonian formalism is used to describe ensembles of fields in terms of two canonically conjugate functionals (one being the field probability density). The postulate that a classical ensemble is subject to nonclassical fluctuations of the field momentum density, of a strength determined solely by the field uncertainty, is shown to lead to a unique modification of the ensemble Hamiltonian. The modified equations of motion are equivalent to the quantum equations for a bosonic field, and thus this exact uncertainty principle provides a new approach to deriving and interpreting the properties of quantum ensembles. The examples of electromagnetic and gravitational fields are discussed. In the latter case the exact uncertainty approach specifies a unique operator ordering for the Wheeler-DeWitt and Ashtekar-Wheeler-DeWitt equations.Comment: 24 pages, extended version of part (B) of hep-th/0206235, to appear in J. Phys.

Delivery of sTRAIL variants by MSCs in combination with cytotoxic drug treatment leads to p53-independent enhanced antitumor effects

Mesenchymal stem cells (MSCs) are able to infiltrate tumor tissues and thereby effectively deliver gene therapeutic payloads. Here, we engineered murine MSCs (mMSCs) to express a secreted form of the TNF-related apoptosis-inducing ligand (TRAIL), which is a potent inducer of apoptosis in tumor cells, and tested these MSCs, termed MSC.sTRAIL, in combination with conventional chemotherapeutic drug treatment in colon cancer models. When we pretreated human colorectal cancer HCT116 cells with low doses of 5-fluorouracil (5-FU) and added MSC.sTRAIL, we found significantly increased apoptosis as compared with single-agent treatment. Moreover, HCT116 xenografts, which were cotreated with 5-FU and systemically delivered MSC.sTRAIL, went into remission. Noteworthy, this effect was protein 53 (p53) independent and was mediated by TRAIL-receptor 2 (TRAIL-R2) upregulation, demonstrating the applicability of this approach in p53-defective tumors. Consequently, when we generated MSCs that secreted TRAIL-R2-specific variants of soluble TRAIL (sTRAIL), we found that such engineered MSCs, labeled MSC.sTRAIL DR5, had enhanced antitumor activity in combination with 5-FU when compared with MSC.sTRAIL. In contrast, TRAIL-resistant pancreatic carcinoma PancTu1 cells responded better to MSC.sTRAIL DR4 when the antiapoptotic protein XIAP (X-linked inhibitor of apoptosis protein) was silenced concomitantly. Taken together, our results demonstrate that TRAIL-receptor selective variants can potentially enhance the therapeutic efficacy of MSC-delivered TRAIL as part of individualized and tumor-specific combination treatments. © 2013 Macmillan Publishers Limited All rights reserved

Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity

Genomic characterisation of Eμ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene

The Eμ-Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eμ-Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor. Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nras, Kras and Bcor. These findings challenge the assumed two-hit model of Eμ-Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis.We acknowledge the following funding agencies: Leukaemia Foundation of Australia, Arrow Bone Marrow Transplant Foundation, National Health and Medical Research Council Australia, Cancer Council Victoria, Victorian Cancer Agency, Australian Cancer Research Foundation, Peter MacCallum Cancer Centre Foundation, National Institutes of Health

Influenza Virus-Specific Immunological Memory Is Enhanced by Repeated Social Defeat

Immunological memory (MEM) development is affected by stress-induced neuroendocrine mediators. Current knowledge about how a behavioral interaction, such as social defeat, alters the development of adaptive immunity, and MEM is incomplete. In this study, the experience of social disruption stress (SDR) prior to a primary influenza viral infection enhanced the frequency and function of the T cell memory pool. Socially stressed mice had a significantly enlarged population of CD8+ T cells specific for the immunodominant NP366–74 epitope of A/PR/8/34 virus in lung and spleen tissues at 6–12 wk after primary infection (resting memory). Moreover, during resting memory, SDR-MEM mice responded with an enhanced footpad delayed-type hypersensitivity response, and more IFN-γ–producing CD4+ T cells were detected after ex vivo stimulation. When mice were rechallenged with A/PR/8/34 virus, SDR-MEM mice terminated viral gene expression significantly earlier than MEM mice and generated a greater DbNP366–74CD8+ T cell response in the lung parenchyma and airways. This enhancement was specific to the T cell response. SDR-MEM mice had significantly attenuated anti-influenza IgG titers during resting memory. Similar experiments in which mice were primed with X-31 influenza and challenged with A/PR/8/34 virus elicited similar enhancements in the splenic and lung airway Db NP366–74CD8+ T cell populations in SDR-MEM mice. This study demonstrates that the experience of repeated social defeat prior to a primary viral infection significantly enhances virus-specific memory via augmentation of memory T cell populations and suggests that social stressors should be carefully considered in the design and analysis of future studies on antiviral immunity

Die Ballon-Okklusionsangiographie der Pulmonalarterien bei chronischer pulmonaler Hypertonie

Die chronische pulmonale Hypertonie ist eine seltene Erkrankung, die heute noch als unheilbar gilt. Die therapeutischen Möglichkeiten haben sich in den letzten Jahren rasant weiterentwickelt und orientieren sich an der Pathogenese und an den Befunden aus der bildgebenden Diagnostik. Diese muss in ihren Möglichkeiten der differentialdiagnostischen Eingrenzung zugrundeliegender Ursachen der pulmonalen Hypertonie Schritt halten. Insbesondere die Ergebnisse der intraarteriellen Pulmonalisangiographie als Referenzmethode in der Bildgebung der Lungen-strombahn haben meist unmittelbare therapeutische Konsequenz, z.B. ob ein Patient für eine pulmonale Thrombendarteriektomie gegeignet ist oder nicht. Wir haben überprüft, ob die selektive pulmonale Ballon-Okklusionsangiographie als Erweiterung der standardisierten Übersichtsangiographie die Differentialdiagnose z.B. der embolischen (CTEPH) gegenüber der nichtembolischen (NoCTEPH) Erkrankung verbessert. Zu diesem Zweck wurden Untersuchungen von 50 Patienten bestehend aus jeweils einer konventionellen Übersichtsangiographie und der ergänzenden Ballon-Okklusionsangiographie retrospektiv nach einem standardisierten Studienprotokoll ausgewertet. Zunächst wurde eine digitale Subtraktionsangiographie der Pulmonalarterien angefertigt. Anschließend führten wir einen weichen Latex-Ballonkatheter in Segment- oder Subsegmentarterien ein. Dann entfalteten wir den Ballon, um die sondierte Arterie zu verschließen und injizierten jeweils 10 bis 15 ml Kontrastmittel, um die kleinen peripheren Gefäße sichtbar zu machen. 13 Patienten litten an einer nichtthrombembolischen Form der chronischen pulmonalen Hypertonie. Bei 36 von 37 Patienten mit CTEPH fanden wir organisiertes embolisches Material als irreguläre Stenosen, Verschlüsse oder Strickleitersysteme (Webs und Bands). In der Darstellung dieser pathologischen Befunde war die Ballon-Okklusionsangiographie der Übersichtsangiographie sowohl qualitativ als auch quantitativ überlegen. Nach unseren Daten entdeckt die Ballon-Okklusionsangiographie in etwa bei jedem fünften Patienten mit negativer Übersichtsangiographie wenigstens ein thrombembolisches Residuum, sie steigert somit als Verfeinerung der Methode die Sensitivität der Pulmonalisangiographie. Generell stellte sie 2,7 bis 3,6 Aufteilungsgenerationen der peripheren Gefäße mehr dar als die konventionelle selektive DSA. Außerdem fanden wir bei 17 Patienten Kollateralgefäße zu den peripheren Segmenten von zentral verschlossenen Pulmonal-arterien. Dieses Phänomen war nur in der Ballon-Okklusionsangiographie zu beobachten und erwies sich als spezifisch für Patienten mit thrombembolischer pulmonaler Hypertonie. Der Befund ist insofern erstaunlich, als dass Pulmonalarterien eigentlich als funktionelle Endarterien ohne Anastomosen zu Nachbararterien beschrieben werden. Bei 11 Patienten fanden sich Anastomosen zu subpleuralen Bronchialarterien. Dieses bereits bekannte Phänomen steht nach unseren Daten in keinem Zusammenhang mit einer bestimmten Erkrankung und ist somit als unspezifisches Merkmal der chronischen pulmonalen Hypertonie zu deuten. In drei Fällen konnten histologisch postkapilläre Formen der pulmonalen Hypertonie (zweimal pulmonale veno-okklusive Erkrankung (PVOD), einmal primäre kapilläre Hämangiomatose) gesichert werden. Bei diesen Patienten zeigte die Ballon-Okklusionsangiographie eine Füllung der Lungenvenen ohne angiographisch sichtbare Anfärbung des Kapillarbettes (fehlende Parenchymanfärbung). Die geschilderten Erkenntnisse aus unserer Studie lassen sich für die Praxis wie folgt zusammenfassen: 1. Die Ballon-Okklusionsangiographie verbessert die Visualisierung der peripheren Pulmonalarterien. 2. Sie erleichtert die Detektion und Lokalisation thrombembolischer Residuen 3. Sie hilft bei der Differentialdiagnose zwischen thrombembolischer und nicht-thrombembolischer chronischer pulmonaler Hypertonie. 4. Vorher unsichtbare Anastomosen und Kollateralgefäße werden sichtbar. 5. Venöse Füllung ohne Parenchymanfärbung ist offensichtlich ein Zeichen der Parenchymerkrankung; diese Konstellation ist bei Patienten mit chronischer pulmonaler Hypertonie möglicherweise ein Hinweis auf das Vorliegen der pulmonalen venookklusiven Erkrankung (PVOD) oder der primären kapillären Hämangiomatose (PCH). 6. Die selektive Ballon-Okklusionsangiographie segmentaler Pulmonalarterien verbessert in Zusammenschau mit der Computertomographie die Zuverlässigkeit in der Selektion von Kandidaten für eine pulmonale Thrombendarteriektomie oder eine Prostazyklintherapie.Purpose: Test the ability of selective balloon occlusion angiography of pulmonary segmental arteries in the differential diagnosis of chronic pulmonary hypertension: embolic vs. non-embolic disease, pulmonary capillary hemangiomatosis, and venoocclusive disease. Methods and Materials: In 50 patients with pulmonary hypertension, digital subtraction angiography (DSA) of pulmonary arteries were used to assist in the selection of candidates appropriate for thrombo-endarterectomy. In addition to these standard methods, we introduced a soft latex balloon catheter into segmental arteries, inflated the balloon to occlude the artery, and injected 10 to 15 ml contrast medium to visualize small peripheral vessels as completely as possible. Results: 13 patients suffered from non-embolic pulmonary hypertension. In 36 of 37 patients with embolic pulmonary hypertension organizing embolic material was depicted as irregular narrowing or occlusion of pulmonary arteries, and weblike strictures. In all of these patients occlusion technique revealed more tiny webs or organized micro emboli in small peripheral arteries. According to our data balloon occlusion angiography discovers in every fifth patient showing a negative conventional pulmonary angiography at least one thromboembolic residuum and thus increases as a sophisticated method the sensitivity of the pulmonary angiography. Generally, occlusion technique revealed additional 2,7 to 3,6 ramifications of peripheral vessels in comparison to conventional selective DSA. Unexpectedly, we found in 11 patients anastomoses to bronchial arteries and in 17 patients collateral vessels to the peripheral segments of centrally occluded pulmonary arteries. These findings are astonishing, because pulmonary arteries are believed ramifying dichotomically without anastomoses. Obviously, there are alterations of pulmonary perfusion, which overcome normal anatomy. 3 patients with characteristic CT signs of interstitial disease (poorly defined nodular opacities and septal lines) underwent lung biopsy: 2 cases of venoocclusive disease, 1 case of pulmonary capillary hemangiomatosis. Occlusion angiography in these 3 patients revealed filling of veins without opacification of capillaries (failing parenchymal phase). Conclusion: Balloon occlusion technique improves the visualization of peripheral pulmonary arteries. Differential diagnosis of embolic and non-embolic pulmonary hypertension is facilitated. Previously invisible anastomoses and collateral vessels become visible. Venous filling without capillary opacification is apparently a sign of parenchymal disease; in patients with chronic pulmonary hypertension it might be a hint at venoocclusive disease or pulmonary capillary hemangiomatosi

Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development.

BACKGROUND: We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. RESULTS: The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. CONCLUSIONS: Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution