Monomeric ephrinB2 binding induces allosteric changes in Nipah virus G that precede its full activation.

Nipah virus is an emergent paramyxovirus that causes deadly encephalitis and respiratory infections in humans. Two glycoproteins coordinate the infection of host cells, an attachment protein (G), which binds to cell surface receptors, and a fusion (F) protein, which carries out the process of virus-cell membrane fusion. The G protein binds to ephrin B2/3 receptors, inducing G conformational changes that trigger F protein refolding. Using an optical approach based on second harmonic generation, we show that monomeric and dimeric receptors activate distinct conformational changes in G. The monomeric receptor-induced changes are not detected by conformation-sensitive monoclonal antibodies or through electron microscopy analysis of G:ephrinB2 complexes. However, hydrogen/deuterium exchange experiments confirm the second harmonic generation observations and reveal allosteric changes in the G receptor binding and F-activating stalk domains, providing insights into the pathway of receptor-activated virus entry.Nipah virus causes encephalitis in humans. Here the authors use a multidisciplinary approach to study the binding of the viral attachment protein G to its host receptor ephrinB2 and show that monomeric and dimeric receptors activate distinct conformational changes in G and discuss implications for receptor-activated virus entry

A mixed methods evaluation of medical tattooing for people who have experienced a burn injury

Introduction: There are no existing studies examining the psychological merits of using facial medical tattooing (MT) following burn injury. This study evaluated an MT service supported by The Katie Piper Foundation. It examined accessibility, satisfaction and whether there were improvements in quality of life (QoL). Methods: Thirty-five service-users were invited to participate in a cross-sectional online survey. Twenty-five (71%) responded (24 women; age range = 21–64 years), and of these five (4 women; age range = 26–59 years) also participated in telephone interviews, which were analysed using descriptive thematic analysis. Findings: The service was largely considered easy to access (22/25) and convenient (25/25). Most service-users (22/25) were satisfied with the results of MT. Some areas of dissatisfaction were described, by a minority of service-users, including: the procedure being painful (1/25); the tattoo being below expectation or fading over time (3/25). The majority reported that MT had improved confidence (22/25); mood (19/25); and ability to socialise (19/25). The procedure improved some service-users’ ability to carry out essential activities (14/25) and enjoyable activities (16/25). The qualitative responses provided during interview, indicated that all respondents found the procedure useful to their adjustment, although a minority (3/5) found it painful and also commented on fading (1/5). All described MT as contributing to a sense of increased normality. Conclusions: MT had the largest impact on emotional wellbeing and interpersonal domains of QoL. MT services should now improve awareness of the procedure, lobby for further support to provide wider access to the procedure, and routinely use measures assessing psychosocial outcomes

Dilatation tracheoscopy for laryngeal and tracheal stenosis in patients with Wegener’s granulomatosis

Wegener’s granulomatosis (WG) frequently involves the subglottis and trachea and may compromise the upper airway. The objective of this study is to evaluate retrospectively the effect of treatment of subglottic stenosis (SGS) and tracheal stenosis (TS) by dilatation tracheoscopy (DT) in patients with WG. We performed a cohort study on all patients who underwent DT between February 2001 and September 2005 in our institution. From this cohort we identified a total of nine WG patients. In all patients, clinical, serological and histopathological data had been prospectively collected by a standardized protocol from the time point of diagnosis. In the nine patients that were identified with SGS or TS due to WG (eight women and one man), a total of 22 DT’s were performed. Two patients needed a tracheostoma (one temporarily). The mean follow-up after the first DT was 25.4 ± 14.1 months. Two patients did not experience a recurrence of SGS or TS. Six patients required a second DT without recurrence of local disease. The remaining patient underwent 8 DT's in a 4-year period. DT can offer a simple and repeatable solution to SGS and TS due to WG. Seven of the nine patients required more than one dilatation and some patients experience a functional restriction. One patient has a definitive tracheostoma

Long-term myocardial recovery after mitral valve replacement in noncompaction cardiomyopathy

Isolated noncompaction of the left ventricle is a congenital cardiomyopathy, which has been described recently, with literature limited to case reports and case series. Even though various complications have been reported with noncompaction cardiomyopathy, among them severe mitral regurgitation has been reported recently in a few cases. There is no great evidence in the literature about its management, apart from some cases of mitral valve repair and replacement in young patients. We are reporting a case of an elderly lady with isolated left ventricular noncompaction cardiomyopathy associated with severe mitral regurgitation treated with mitral valve replacement with one and half year of follow up demonstrating significant myocardial recovery

Invasive lobular carcinoma of the breast presenting as retroperitoneal fibrosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Invasive lobular carcinoma of the breast represents approximately 6.3% of mammary malignancies. Distant metastasis of invasive lobular carcinoma to the peritoneum or retroperitoneum has been reported fairly frequently.</p> <p>Case presentation</p> <p>We report the case of a 59-year-old Caucasian-Canadian woman with invasive lobular carcinoma of the breast presenting with retroperitoneal fibrosis and bilateral ureteral obstruction. Intra-operative pathology consultation did not reveal malignancy. The diagnosis, however, was confirmed on permanent sections by histological appearance in addition to immunohistochemistry. To the best of our knowledge, this is the first reported case of invasive lobular carcinoma of the breast presenting with retroperitoneal fibrosis.</p> <p>Conclusion</p> <p>In a case of unexplained ureteric obstruction and retroperitoneal fibrosis, more comprehensive physical examination and additional ancillary studies may be warranted to rule out malignancy as an underlying etiology. This case also emphasizes that intra-operative frozen section consultation cannot always be fully relied upon to exclude a malignancy as the etiology of retroperitoneal fibrosis. Moreover, in permanent histopathology sections, immunohistochemistry testing can be of value to rule out metastatic disease where the morphology is not salient. There is a need for a thorough physical examination of patients with retroperitoneal fibrosis, including the breast and gynecological organs.</p

Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites &lt;i&gt;Trypanosoma brucei&lt;/i&gt; (&lt;i&gt;T.b.&lt;/i&gt;) &lt;i&gt;gambiense&lt;/i&gt; or &lt;i&gt;T.b.rhodesiense&lt;/i&gt; and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage &lt;i&gt;T.b.rhodesiense&lt;/i&gt; infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-&#846;-cyclodextrin and melarsoprol randomly-methylated-&#946;-cyclodextrin. We found that these compounds retain trypanocidal properties &lt;i&gt;in vitro&lt;/i&gt; and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy

Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo

Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids

Integrated information increases with fitness in the evolution of animats

One of the hallmarks of biological organisms is their ability to integrate disparate information sources to optimize their behavior in complex environments. How this capability can be quantified and related to the functional complexity of an organism remains a challenging problem, in particular since organismal functional complexity is not well-defined. We present here several candidate measures that quantify information and integration, and study their dependence on fitness as an artificial agent ("animat") evolves over thousands of generations to solve a navigation task in a simple, simulated environment. We compare the ability of these measures to predict high fitness with more conventional information-theoretic processing measures. As the animat adapts by increasing its "fit" to the world, information integration and processing increase commensurately along the evolutionary line of descent. We suggest that the correlation of fitness with information integration and with processing measures implies that high fitness requires both information processing as well as integration, but that information integration may be a better measure when the task requires memory. A correlation of measures of information integration (but also information processing) and fitness strongly suggests that these measures reflect the functional complexity of the animat, and that such measures can be used to quantify functional complexity even in the absence of fitness data.Comment: 27 pages, 8 figures, one supplementary figure. Three supplementary video files available on request. Version commensurate with published text in PLoS Comput. Bio

A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available. © 2013 Capra et al

Tuning ultrafast electron thermalization pathways in a van der Waals heterostructure

Ultrafast electron thermalization - the process leading to Auger recombination, carrier multiplication via impact ionization and hot carrier luminescence - occurs when optically excited electrons in a material undergo rapid electron-electron scattering to redistribute excess energy and reach electronic thermal equilibrium. Due to extremely short time and length scales, the measurement and manipulation of electron thermalization in nanoscale devices remains challenging even with the most advanced ultrafast laser techniques. Here, we overcome this challenge by leveraging the atomic thinness of two-dimensional van der Waals (vdW) materials in order to introduce a highly tunable electron transfer pathway that directly competes with electron thermalization. We realize this scheme in a graphene-boron nitride-graphene (G-BN-G) vdW heterostructure, through which optically excited carriers are transported from one graphene layer to the other. By applying an interlayer bias voltage or varying the excitation photon energy, interlayer carrier transport can be controlled to occur faster or slower than the intralayer scattering events, thus effectively tuning the electron thermalization pathways in graphene. Our findings, which demonstrate a novel means to probe and directly modulate electron energy transport in nanoscale materials, represent an important step toward designing and implementing novel optoelectronic and energy-harvesting devices with tailored microscopic properties.Comment: Accepted to Nature Physic