Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10-8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10-6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

The emerging role of extracellular vesicle-mediated drug resistance in cancers: Implications in advanced prostate cancer

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

Growth hormone resistance and somatomedins in children with end-stage liver disease awaiting transplantation

Background: The success of orthotopic liver transplantation as treatment for end-stage liver disease has prompted investigation of strategies to maintain or improve nutrition and growth in children awaiting transplantation, because malnutrition is an adverse prognostic factor. The purpose of this study was to evaluate the effect of recombinant human growth hormone therapy on body composition and indices of liver function in patients awaiting transplant. Methods: The study was designed as a placebo- controlled, double-blind, crossover trial. Patients received 0.2 U/kg growth hormone, subcutaneously, or placebo daily for 28 days during two treatment periods, separated by a 2-week washout period. Ten patients (mean age, 3.06 ± 1.15 years; range, 0.51-11.65 years, five men), with extrahepatic biliary atresia (n = 8) or two with Alagille's syndrome (n = 2), with end-stage liver disease, completed the trial while awaiting orthotopic liver transplantation. Height, weight, total body potassium, total body fat, resting energy expenditure, respiratory quotient, hematologic and multiple biochemical profile, number of albumin infusions, insulin-like growth factor-1 and 1, growth hormone binding protein (GHBP), and insulin-like growth factor binding protein-1 (IGFBP-1) and insulin-like growth factor binding protein (IGFBP-3) were measured at the beginning and end of each treatment period. Results: Growth hormone treatment was associated with a significant decline in serum bilirubin (-34.6 ± 16.5 μmol/l vs. 18.2 ± 11.59 μmol/l; p < 0.02) but there was no significant effect on any anthropometric or body composition measurements, or on any biochemical or hematologic parameters. Conclusions: These children with end-stage liver disease displayed growth hormone resistance, particularly in relation to the somatomedin axis. Exogenous growth hormone administration may be of limited value in these patients

Implementation mechanism: Protection against harassment of women at workplace

Pakistan is widely known and appreciated in the world for its history, Islamic culture and norms. Since the creation of Pakistan, it inherited poverty in its roots. There are many reasons for poverty but one lies on the shoulder of women who are 50% of the total population of Pakistan. On the apex of it, women do not take part in the development of Pakistan because when they step out of their homes, they suffer a lot of problems. These problems are a hurdle in their active participation in development .Government has tried to create an environment for those women, who suffer different problems. Harassment of women at work place is one of those problems which discourage women in taking active part in economic and social development of society. Women Activists, from the last decade, were working for the protection of woman’s right at workplace and they succeeded in formulation of Harassment Act 2010. Since law is ineffective without its proper mechanism of implementation, steps should be taken for its proper implementation mechanism. This article aims to provide information about the provisions of law, related to the harassment of women at workplace with an attempt to explore the effectiveness of its implementation. The study was conducted in twin cities of Pakistan, Islamabad and Rawalpindi. Interviews were conducted with the employees and employers of organizations, educational institutions, women activists, NGOs workers, lawyers, judges and some law enforcement officers. Group discussions were also held with teachers, students of Human rights and religious personalities. This report focuses on the implementation mechanism of new legislation in Pakistan. It also highlights some important facts related to its enforcement.

Engineering cellulose nanofibre suspensions to control filtration resistance and sheet permeability

This study examines and quantifies the effect of adding polyelectrolytes to cellulose nanofibre suspensions on the gel point of cellulose nanofibre suspensions, which is the lowest solids concentration at which the suspension forms a continuous network. The lower the gel point, the faster the drainage time to produce a sheet and the higher the porosity of the final sheet formed. Two new techniques were designed to measure the dynamic compressibility and the drainability of nanocellulose–polyelectrolyte suspensions. We developed a master curve which showed that the independent variable controlling the behaviour of nanocellulose suspensions and its composite is the structure of the flocculated suspension which is best quantified as the gel point. This was independent of the type of polyelectrolyte used. At an addition level of 2 mg/g of nanofibre, a reduction in gel point over 50 % was achieved using either a high molecular weight (13 MDa) linear cationic polyacrylamide (CPAM, 40 % charge), a dendrimer polyethylenimine of high molecular weight of 750,000 Da (HPEI) or even a low molecular weight of 2000 Da (LPEI). There was no significant difference in the minimum gel point achieved, despite the difference in polyelectrolyte morphology and molecular weight. In this paper, we show that the gel point controls the flow through the fibre suspension, even when comparing fibre suspensions with solids content above the gel point. A lower gel point makes it easier for water to drain through the fibre network,reducing the pressure required to achieve a given dewatering rate and reducing the filtering time required to form a wet laid sheet. We further show that the lower gel point partially controls the structure of the wet laid sheet after it is dried. Halving the gel point increased the air permeability of the dry sheet by 37, 46 and 25 %, when using CPAM, HPEI and LPEI, respectively. The resistance to liquid flow was reduced by 74 and 90 %, when using CPAM and LPEI. Analysing the paper formed shows that sheet forming process and final sheet properties can be engineered and controlled by adding polyelectrolytes to the nanofibre suspension.

Biophysical response of living cells to boron nitride nanoparticles: Uptake mechanism and bio-mechanical characterization

Boron nitride nanomaterials have attracted significant interest due to their superior chemical and physical properties. Despite these novel properties, investigation on the interaction between boron nitride nanoparticle (BN NP) and living systems has been limited. In this study, BN NP (100–250 nm) is assessed as a promising biomaterial for medical applications. The toxicity of BN NP is evaluated by assessing the cells behaviours both biologically (MTT assay, ROS detection etc.) and physically (atomic force microscopy). The uptake mechanism of BN NP is studied by analysing the alternations in cellular morphology based on cell imaging techniques. The results demonstrate in vitro cytocompatibility of BN NP with immense potential for use as an effective nanoparticle for various bio-medical applications.

Voice, deliberation, resistance and persuasion through participatory journalism business models

The pervasive use of the World Wide Web by the general population has created a cultural shift throughout the world. It has enabled more people to share more information about more events and issues than was possible before its general use. As a consequence, it has transformed traditional news media’s approach to almost every aspect of journalism, with many organisations restructuring their philosophy and practice to include a variety of participatory spaces/forums where people are free to engage in deliberative dialogue about matters of public importance. This paper draws from an international collective case study that showcases various approaches to participatory online news journalism during the period 1997–2011 (Adams, 2013). The research finds differences in the ways in which public service, commercial, and independent news media give voice to the public, and ultimately in their approach to journalism’s role as the Fourth Estate––one of the key institutions of democracy. The work is framed by the notion that journalism in democratic societies has a crucial role in ensuring citizens are informed and engaged with public affairs. An examination of four media models, OhmyNews International, News Corp Australia (formerly News Limited), the Guardian and the British Broadcasting Corporation (BBC), showcases the various approaches to participatory online news journalism and how each provides different avenues for citizen engagement. Semistructured in-depth interviews with some of the key senior journalists and editors provide specific information on comparisons between the distinctive practices in each of their employer organisations.

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377)

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance ((R)) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv(R), ddI(R), and ddC(R) mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp(R) and 3TC(R) mutations were detected frequently at virologic failure, and Nvp(R) mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp(R) and 3TC(R) mutations plus Rtv(R) and Nfv(R) mutations. However, Rtv(R) and Nfv(R) mutations were detected at unexpectedly low rates.

miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma

To identify ‘melanoma-specific’ microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers. To identify miR-514a regulated targets we conducted a miR-514a-mRNA ‘pull-down’ experiment, which revealed hundreds of genes, including: CTNNB1, CDK2, MC1R, and NF1, previously associated with melanoma. NF1 was selected for functional validation because of its recent implication inacquired resistance to BRAFV600E-targeted therapy. Luciferase-reporter assays confirmed NF1 as a direct target of miR-514a and over-expression of miR-514a in melanoma cell lines inhibited NF1 expression, which correlated with increased survival of BRAFV600E cells treated with PLX4032. These data provide another mechanism for the dysregulation of the MAPK pathway which may contribute to the profound resistance associated with current RAF-targeted therapies.

Limitations of the manual supination resistance test

The aim of this study was to asses results obtained from a range of commonly performed lower extremity “open and closed” chain kinetic tests used for predicting foot function and correlate these test findings to data obtained from the Zebris WinFDM-T system®. When performed correctly these tests are thought to be indicators of lower extremity function. Podiatrists frequently perform examinations of joint and muscle structures to understand biomechanical function; however the relationship between these routine tests and forces generated during the gait cycle are not always well understood. This can introduce a degree of variability in clinical interpretation which creates conjecture regarding the value of these tests.

Inter-lamellar shear resistance confers compressive stiffness in the intervertebral disc: An image-based modelling study on the bovine caudal disc

The intervertebral disc withstands large compressive loads (up to nine times bodyweight in humans) while providing flexibility to the spinal column. At a microstructural level, the outer sheath of the disc (the annulus fibrosus) comprises 12–20 annular layers of alternately crisscrossed collagen fibres embedded in a soft ground matrix. The centre of the disc (the nucleus pulposus) consists of a hydrated gel rich in proteoglycans. The disc is the largest avascular structure in the body and is of much interest biomechanically due to the high societal burden of disc degeneration and back pain. Although the disc has been well characterized at the whole joint scale, it is not clear how the disc tissue microstructure confers its overall mechanical properties. In particular, there have been conflicting reports regarding the level of attachment between adjacent lamellae in the annulus, and the importance of these interfaces to the overall integrity of the disc is unknown. We used a polarized light micrograph of the bovine tail disc in transverse cross-section to develop an image-based finite element model incorporating sliding and separation between layers of the annulus, and subjected the model to axial compressive loading. Validation experiments were also performed on four bovine caudal discs. Interlamellar shear resistance had a strong effect on disc compressive stiffness, with a 40% drop in stiffness when the interface shear resistance was changed from fully bonded to freely sliding. By contrast, interlamellar cohesion had no appreciable effect on overall disc mechanics. We conclude that shear resistance between lamellae confers disc mechanical resistance to compression, and degradation of the interlamellar interface structure may be a precursor to macroscopic disc degeneration.

Evaluation of transgenic bananas expressing anti-apoptotic genes for resistance against Fusarium wilt

The banana industry worldwide is under threat from a fungal disease known as Fusarium wilt, a disease for which there is no chemical control. Conventional breeding approaches to generate resistant banana varieties are lengthy and very difficult. As such, genetic engineering for disease resistance is considered the most viable control option. In this PhD thesis, genetically modified banana plants were generated using several different stress tolerance genes. When challenged with Fusarium wilt in glasshouse trials, some lines showed increased resistance to the disease. The promising elite lines generated in this study will now require testing in field trials.

Fire resistance of light gauge steel frame wall systems lined with gypsum plasterboards

Light gauge steel frame (LSF) wall systems are increasingly used in residential and commercial buildings as load bearing and non-load bearing elements. Conventionally, the fire resistance ratings of such building elements are determined using approximate prescriptive methods based on limited standard fire tests. However, recent studies have shown that in some instances real building fire time-temperature curves could be more severe than the standard fire curve, in terms of maximum temperature and rate of temperature rise. This has caused problems for safe evacuation and rescue activities, and in some instances has also lead to the collapse of buildings earlier than the prescribed fire resistance. Therefore a detailed research study into the performance of LSF wall systems under both standard fire and realistic fire conditions was undertaken using full scale fire tests to understand the fire performance of different LSF wall configurations. Both load bearing and non-load bearing full scale fire tests were performed on LSF walls configurations which included single layer, double layer, externally insulated wall panels made up of different steel sections and thicknesses of gypsum plasterboards. The non-load bearing fire test results were utilized to understand the factors affecting the fire resistance of LSF walls, while loading bearing fire test results led to development of simplified methods to predict the fire resistance ratings of load bearing LSF walls exposed to both standard and realistic design fires. This paper presents the results of full scale experimental study and highlights the effects of standard and realistic fire conditions on fire performance of LSF walls.

A case of true hermaphroditism reveals an unusual mechanism of twinning

Traditionally twins are classified as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735-743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysis was performed on peripheral blood cells and skin fibroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin fibroblast samples from the twins and on peripheral blood samples from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin fibroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most significantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin fibroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.

Probing the mechanism of benzaldehyde reduction to chiral hydrobenzoin on the CNT surface under near-UV light irradiation

Metal-free CNTs exhibit high activity (conversion rate 99.6%, 6 h) towards the synthesis of chiral hydrobenzoin from benzaldehyde under near-UV light irradiation (320–400 nm). The CNT structure before and after the reaction, the interaction between the molecule and the CNT surface, the intermediate products, the substitution effect and the influence of light on the reaction were examined using various techniques. A photo-excited conduction electron transfer (PECET) mechanism for the photocatalytic reduction using CNTs has been proposed. This finding provides a green photocatalytic route for the production of hydrobenzoin and highlights a potential photocatalytic application of CNTs.