The Human Fungal Pathogen Cryptococcus neoformans Escapes Macrophages by a Phagosome Emptying Mechanism That Is Inhibited by Arp2/3 Complex-Mediated Actin Polymerisation

The lysis of infected cells by disease-causing microorganisms is an efficient but risky strategy for disseminated infection, as it exposes the pathogen to the full repertoire of the host's immune system. Cryptococcus neoformans is a widespread fungal pathogen that causes a fatal meningitis in HIV and other immunocompromised patients. Following intracellular growth, cryptococci are able to escape their host cells by a non-lytic expulsive mechanism that may contribute to the invasion of the central nervous system. Non-lytic escape is also exhibited by some bacterial pathogens and is likely to facilitate long-term avoidance of the host immune system during latency. Here we show that phagosomes containing intracellular cryptococci undergo repeated cycles of actin polymerisation. These actin ‘flashes’ occur in both murine and human macrophages and are dependent on classical WASP-Arp2/3 complex mediated actin filament nucleation. Three dimensional confocal imaging time lapse revealed that such flashes are highly dynamic actin cages that form around the phagosome. Using fluorescent dextran as a phagosome membrane integrity probe, we find that the non-lytic expulsion of Cryptococcus occurs through fusion of the phagosome and plasma membranes and that, prior to expulsion, 95% of phagosomes become permeabilised, an event that is immediately followed by an actin flash. By using pharmacological agents to modulate both actin dynamics and upstream signalling events, we show that flash occurrence is inversely related to cryptococcal expulsion, suggesting that flashes may act to temporarily inhibit expulsion from infected phagocytes. In conclusion, our data reveal the existence of a novel actin-dependent process on phagosomes containing cryptococci that acts as a potential block to expulsion of Cryptococcus and may have significant implications for the dissemination of, and CNS invasion by, this organism.\ud \u

AA--Dependence of ΛΛ\Lambda\Lambda Bond Energies in Double---Λ\Lambda Hypernuclei

The $A$-dependence of the bond energy $\Delta B_{\Lambda\Lambda}$ of the ${\Lambda\Lambda}$ hypernuclear ground states is calculated in a three-body ${\Lambda + \Lambda + {^{A}Z}}$ model and in the Skyrme-Hartree-Fock approach. Various ${\Lambda\Lambda}$ and $\Lambda$-nucleus or ${\Lambda N}$ potentials are used and the sensitivity of $\Delta B_{\Lambda\Lambda}$ to the interactions is discussed. It is shown that in medium and heavy ${\Lambda\Lambda}$ hypernuclei, $\Delta B_{\Lambda\Lambda}$ is a linear function of $r_{\Lambda}^{-3}$, where $r_\Lambda$ is rms radius of the hyperon orbital. It looks unlikely that it will be possible to extract ${\Lambda\Lambda}$ interaction from the double-$\Lambda$ hypernuclear energies only, the additional information about the $\Lambda$-core interaction, in particular, on $r_{\Lambda}$ is needed.Comment: 11 pages, LaTex, 3 figure

Modelling the public health impact of male circumcision for HIV prevention in high prevalence areas in Africa

Background: Recent clinical trials in Africa, in combination with several observational epidemiological studies, have provided evidence that male circumcision can reduce HIV female-to-male transmission risk by 60% or more. However, the public health impact of large-scale male circumcision programs for HIV prevention is unclear. Methods: Two mathematical models were examined to explore this issue: a random mixing model and a compartmental model that distinguishes risk groups associated with sex work. In the compartmental model, two scenarios were developed, one calculating HIV transmission and prevalence in a context similar to the country of Botswana, and one similar to Nyanza Province, in western Kenya. Results: In both models, male circumcision programs resulted in large and sustained declines in HIV prevalence over time among both men and women. Men benefited somewhat more than women, but prevalence among women was also reduced substantially. With 80% male circumcision uptake, the reductions in prevalence ranged from 45% to 67% in the two "countries", and with 50% uptake, from 25% to 41%. It would take over a decade for the intervention to reach its full effect. Conclusion: Large-scale uptake of male circumcision services in African countries with high HIV prevalence, and where male circumcision is not now routinely practised, could lead to substantial reductions in HIV transmission and prevalence over time among both men and women

Effects of a brief mindfulness-based intervention on emotional regulation and levels of mindfulness in senior students

Mindfulness-based interventions have been applied in diverse populations and achieved mental health benefits. This study examined the effects of a brief mindfulness program for emotional regulation and levels of mindfulness on senior students in Brazil. The intervention consisted of six weekly meetings attended by 30 participants. It is a pre-experimental research, with pre- and post-test comparative and correlation measurements. The preliminary results, which relied on parametrical and non-parametrical tests, revealed a reduction in total emotional regulation difficulties (p = 0.0001; r = − 0.55). Also, there was an increase in the levels of mindfulness in the subtests for both dimensions under evaluation: “Awareness” (p = 0.0001; d = 0.77) and “Acceptance” (p = 0.048; d = 0.37). By associating the amount of meditative practices performed by students with the variables, a significant positive correlation was found with the mindfulness dimension “Awareness” (rP = 0.422; p = 0.020), and there was a significant negative correlation with Difficulties in emotion regulation (rS = − 0.478; p = 0.008) and with its respective subscales “Non-acceptance” (rS = − 0.654; p = 0.0001) and “Clarity” (rS = − 0.463; p = 0.010). In conclusion, the application of a brief mindfulness-based intervention is promising in Brazilian university contexts; moreover, it can bring benefits to students, e.g., an increase in emotion regulation as well as in levels of mindfulness. We suggest that further research should use an experimental design and follow-up.info:eu-repo/semantics/publishedVersio

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

INTRODUCTION: Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases. METHOD: This is a retrospective study conducted in the Department of Pathology at Jordan University of Science and Technology. A confirmed 91 cases of BC diagnosed in the period 1995 to 1998 were reviewed and graded. We used immunohistochemistry to evaluate the expression of ER, PR, and Her-2. Immunohistochemical findings were correlated with age, tumor size, grade and axillary lymph node status. RESULTS: Her-2 was overexpressed in 24% of the cases. The mean age of Her-2 positive cases was 42 years as opposed to 53 years among Her-2 negative cases (p = 0.0001). Her-2 expression was inversely related to ER and PR expression. Her-2 positive tumors tended to be larger than Her-2 negative tumors with 35% overexpression among T3 tumors as opposed to 22% among T2 tumors (p = 0.13). Her-2 positive cases tended to have higher rates of axillary metastases, but this did not reach statistical significance. ER and PR positive cases were seen in older patients with smaller tumor sizes. CONCLUSION: Her-2 overexpression was seen in 24% of BC affecting Jordanian females. Her-2 overexpression was associated with young age at presentation, larger tumor size, and was inversely related to ER and PR expression. One-fifth of the carcinomas were Her-2 positive and ER negative. This group appears to represent an aggressive form of BC presenting at a young age with large primary tumors and a high rate of four or more axillary lymph node metastases

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Conserved community structure and simultaneous divergence events in the fig wasps associated with Ficus benjamina in Australia and China

Localised patterns of species diversity can be influenced by many factors, including regional species pools, biogeographic features and interspecific interactions. Despite recognition of these issues, we still know surprisingly little about how invertebrate biodiversity is structured across geographic scales. In particular, there have been few studies of how insect communities vary geographically while using the same plant host. We compared the composition (species, genera) and functional structure (guilds) of the chalcid wasp communities associated with the widespread fig tree, Ficus benjamina, towards the northern (Hainan province, China) and southern (Queensland, Australia) edges of its natural range. Sequence data were generated for nuclear and mtDNA markers and used to delimit species, and Bayesian divergence analyses were used to test patterns of community cohesion through evolutionary time. Both communities host at least 14 fig wasp species, but no species are shared across continents. Community composition is similar at the genus level, with six genera shared although some differ in species diversity between China and Australia; a further three genera occur in only China or Australia. Community functional structure remains very similar in terms of numbers of species in each ecological guild despite community composition differing a little (genera) or a lot (species), depending on taxonomic level. Bayesian clustering analyses favour a single community divergence event across continents over multiple events for different ecological guilds. Molecular dating estimates of lineage splits between nearest inter-continental species pairs are broadly consistent with a scenario of synchronous community divergence from a shared "ancestral community". Fig wasp community structure and genus-level composition are largely conserved in a wide geographic comparison between China and Australia. Moreover, dating analyses suggest that the functional community structure has remained stable for long periods during historic range expansions. This suggests that ecological interactions between species may play a persistent role in shaping these communities, in contrast to findings in some comparable temperate systems

Equal fitness paradigm explained by a trade-off between generation time and energy production rate

Most plant, animal and microbial species of widely varying body size and lifestyle are nearly equally fit as evidenced by their coexistence and persistence through millions of years. All organisms compete for a limited supply of organic chemical energy, derived mostly from photosynthesis, to invest in the two components of fitness: survival and production. All organisms are mortal because molecular and cellular damage accumulates over the lifetime; life persists only because parents produce offspring. We call this the equal fitness paradigm. The equal fitness paradigm occurs because: (1) there is a trade-off between generation time and productive power, which have equal-but-opposite scalings with body size and temperature; smaller and warmer organisms have shorter lifespans but produce biomass at higher rates than larger and colder organisms; (2) the energy content of biomass is essentially constant, ~22.4 kJ g−1 dry body weight; and (3) the fraction of biomass production incorporated into surviving offspring is also roughly constant, ~10–50%. As organisms transmit approximately the same quantity of energy per gram to offspring in the next generation, no species has an inherent lasting advantage in the struggle for existence. The equal fitness paradigm emphasizes the central importance of energy, biological scaling relations and power–time trade-offs in life history, ecology and evolution