Proposing a national ethical framework for animal research in Iran

Background: One of the domains of scientific activities is working on animals. Performing experiments on animals is permissible only with the purpose of obtaining necessary information for saving and improving life of human beings or animals. Principally, all religions believe that human life is more valuable than animal life and humans have a God-given authority over animals, but they should not be cruel to animals and cause their pain or suffering. Based on Islamic view points, although Allah has put the Man as the lord of all creatures, he has not the right to use other creatures for any conditions and does not respect their real statues. Because of the widespread use of experimental animals in our country, special ethical codes should be redefined for living conditions of experimental animals based on the present regulations in Iran and also other countries. Therefore, all our researchers should have enough information about ethical codes of treating experimental animals as well as Islamic principles in this regard.Methods: All Islamic and international sources related to treating animals and also valid international ethical guidelines were collected and classified in order to extract the aimed points. Then all extracted points were reviewed by experts familiar with Islamic and ethical rules of treating animals.Results: Finally the strategies for appropriate and complete implementation of the national ethical guidelines of animal research in Iran were suggested.Conclusion: It is obvious that the suggested principles are applicable only with appropriate planning of training courses based on the facilities and needs of our country

Spatial Regulation of Membrane Fusion Controlled by Modification of Phosphoinositides

Membrane fusion plays a central role in many cell processes from vesicular transport to nuclear envelope reconstitution at mitosis but the mechanisms that underlie fusion of natural membranes are not well understood. Studies with synthetic membranes and theoretical considerations indicate that accumulation of lipids characterised by negative curvature such as diacylglycerol (DAG) facilitate fusion. However, the specific role of lipids in membrane fusion of natural membranes is not well established. Nuclear envelope (NE) assembly was used as a model for membrane fusion. A natural membrane population highly enriched in the enzyme and substrate needed to produce DAG has been isolated and is required for fusions leading to nuclear envelope formation, although it contributes only a small amount of the membrane eventually incorporated into the NE. It was postulated to initiate and regulate membrane fusion. Here we use a multidisciplinary approach including subcellular membrane purification, fluorescence spectroscopy and Förster resonance energy transfer (FRET)/two-photon fluorescence lifetime imaging microscopy (FLIM) to demonstrate that initiation of vesicle fusion arises from two unique sites where these vesicles bind to chromatin. Fusion is subsequently propagated to the endoplasmic reticulum-derived membranes that make up the bulk of the NE to ultimately enclose the chromatin. We show how initiation of multiple vesicle fusions can be controlled by localised production of DAG and propagated bidirectionally. Phospholipase C (PLCγ), GTP hydrolysis and (phosphatidylinsositol-(4,5)-bisphosphate (PtdIns(4,5)P2) are required for the latter process. We discuss the general implications of membrane fusion regulation and spatial control utilising such a mechanism

FRAX-based intervention and assessment thresholds for osteoporosis in Iran

A Summary We compared the utility of the current Iranian guidelines that recommend treatment in women with a T-score <= - 2.5 SD with a FRAX-based intervention threshold equivalent to women of average BMI with a prior fragility fracture. Whereas the FRAX-based intervention threshold identified women at high fracture probability, the T-score threshold was less sensitive, and the associated fracture risk decreased markedly with age. Introduction The fracture risk assessment algorithm FRAX (R) has been recently calibrated for Iran, but guidance is needed on how to apply fracture probabilities to clinical practice. Methods The age-specific ten-year probabilities of a major osteoporotic fracture were calculated in women with average BMI to determine fracture probabilities at two potential intervention thresholds. The first comprised the age-specific fracture probabilities associated with a femoral neck T-score of -2.5 SD, in line with current guidelines in Iran. The second approach determined age-specific fracture probabilities that were equivalent to a woman with a prior fragility fracture, without BMD. The parsimonious use of BMD was additionally explored by the computation of upper and lower assessment thresholds for BMD testing. Results When a BMD T-score <= - 2.5 SD was used as an intervention threshold, FRAX probabilities in women aged 50 years was approximately two-fold higher than in women of the same age but with an average BMD and no risk factors. The relative increase in risk associated with the BMD threshold decreased progressively with age such that, at the age of 80 years or more, a T-score of -2.5 SD was actually protective. The 10-year probability of a major osteoporotic fracture by age, equivalent to women with a previous fracture rose with age from 4.9% at the age of 50 years to 17%, at the age of 80 years, and identified women at increased risk at all ages. Conclusion Intervention thresholds based on BMD alone do not effectively target women at high fracture risk, particularly in the elderly. In contrast, intervention thresholds based on fracture probabilities equivalent to a "fracture threshold" target women at high fracture risk

Key Role of Polyphosphoinositides in Dynamics of Fusogenic Nuclear Membrane Vesicles

The role of phosphoinositides has been thoroughly described in many signalling and membrane trafficking events but their function as modulators of membrane structure and dynamics in membrane fusion has not been investigated. We have reconstructed models that mimic the composition of nuclear envelope precursor membranes with naturally elevated amounts of phosphoinositides. These fusogenic membranes (membrane vesicle 1(MV1) and nuclear envelope remnants (NER) are critical for the assembly of the nuclear envelope. Phospholipids, cholesterol, and polyphosphoinositides, with polyunsaturated fatty acid chains that were identified in the natural nuclear membranes by lipid mass spectrometry, have been used to reconstruct complex model membranes mimicking nuclear envelope precursor membranes. Structural and dynamic events occurring in the membrane core and at the membrane surface were monitored by solid-state deuterium and phosphorus NMR. “MV1-like” (PC∶PI∶PIP∶PIP2, 30∶20∶18∶12, mol%) membranes that exhibited high levels of PtdIns, PtdInsP and PtdInsP2 had an unusually fluid membrane core (up to 20% increase, compared to membranes with low amounts of phosphoinositides to mimic the endoplasmic reticulum). “NER-like” (PC∶CH∶PI∶PIP∶PIP2, 28∶42∶16∶7∶7, mol%) membranes containing high amounts of both cholesterol and phosphoinositides exhibited liquid-ordered phase properties, but with markedly lower rigidity (10–15% decrease). Phosphoinositides are the first lipids reported to counterbalance the ordering effect of cholesterol. At the membrane surface, phosphoinositides control the orientation dynamics of other lipids in the model membranes, while remaining unchanged themselves. This is an important finding as it provides unprecedented mechanistic insight into the role of phosphoinositides in membrane dynamics. Biological implications of our findings and a model describing the roles of fusogenic membrane vesicles are proposed

A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion

Strong evidence suggests that phospholipase Cγ1 (PLCγ1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ1 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCγ1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLCγ1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCγ1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP5 as a leading compound for development of anti-metastatic drugs

A family presenting with multiple endocrine neoplasia type 2B: A case report

<p>Abstract</p> <p>Introduction</p> <p>Multiple endocrine neoplasia 2B, a rare autosomal dominant syndrome, is characterized by early onset of medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus and mucosal neuromas of the tongue, lips, inner cheeks and inner eyelids. Gangliomatosis of the gastrointestinal tract and its complications may also occur in patients with this disease.</p> <p>Case presentation</p> <p>We present the case of a 16-year-old Persian man diagnosed as having a non-invasive form of multiple endocrine neoplasia 2B (medullary thyroid cancer, mucosal neuroma of the tongue, lips and inner eyelids). Our patient, who had a positive family history of medullary thyroid cancer, was of normal height with no signs of marfanoid habitus.</p> <p>Conclusions</p> <p>Ophthalmological and oral manifestations of multiple endocrine neoplasia 2B, as in the case of our patient, are rare presentations of the disease; unfortunately in the case of our patient his condition had not been noted and acted upon until he presented to our department. The diagnosis in our patient's case was made only after his mother presented with the same condition. As a result, we emphasize that physicians should pay more attention to the oral and ocular signs of multiple endocrine neoplasia 2B in order to diagnose this fatal syndrome at an earlier phase.</p

Acute manipulation of diacylglycerol reveals roles in nuclear envelope assembly & endoplasmic reticulum morphology

The functions and morphology of cellular membranes are intimately related and depend not only on their protein content but also on the repertoire of lipids that comprise them. In the absence of in vivo data on lipid asymmetry in endomembranes, it has been argued that motors, scaffolding proteins or integral membrane proteins rather than non-lamellar bilayer lipids such as diacylglycerol (DAG), are responsible for shaping of organelles, local membrane curvature and fusion. The effects of direct alteration of levels of such lipids remain predominantly uninvestigated. Diacylglycerol (DAG) is a well documented second messenger. Here we demonstrate two additional conserved functions of DAG: a structural role in organelle morphology, and a role in localised extreme membrane curvature required for fusion for which proteins alone are insufficient. Acute and inducible DAG depletion results in failure of the nuclear envelope (NE) to reform at mitosis and reorganisation of the ER into multi-lamellar sheets as revealed by correlative light and electron microscopy and 3D reconstructions. Remarkably, depleted cells divide without a complete NE, and unless rescued by 1,2 or 1,3 DAG soon die. Attenuation of DAG levels by enzyme microinjection into echinoderm eggs and embryos also results in alterations of ER morphology and nuclear membrane fusion. Our findings demonstrate that DAG is an in vivo modulator of organelle morphology in mammalian and echinoderm cells, indicating a fundamental role conserved across the deuterostome superphylum

Influence of Different Application of Lubricants on Wear and Pre-existing Rolling Contact Fatigue Cracks of Rail Materials

Rolling contact fatigue (RCF) of rail can be a significant problem affecting safety and maintenance. Rail materials have been optimized to reduce it, but not enough is known about how friction management products applied to the rail affect crack growth. This study presents experimental results carried out to explore the influence of different lubricants and application orders on wear and pre-existing RCF cracks in rail materials. The results indicate that the types or properties of lubricants have a vital role in the wear rate and fatigue crack growth characteristics of rail materials after conditioning with 5000 dry cycles to initiate cracks. Using a different application order of two lubricants has a significant influence on the crack growth angles in the rail rollers