计及轴向压力的方管节点塑性铰线模型

塑性铰线分析模型已成功用于估计由弦杆表面屈服控制的各种管节点的强度；然而弦杆自身的轴向压力对节点承载力的影响仍然是用一个经验折减系数来考虑的．为了计算在轴向压力作用下沿倾斜塑性铰线的极限弯矩，研究者们提出了各种理论模型．该文对这些模型进行了分析和对比．结果表明，采用简化假设的阶梯形塑性铰线模型用于评价T形方管市点的慢度与试验结果和有限元计算结果符合得最好．

A retrofitting framework for pre-Northridge steel moment-frame buildings

In the 1994 M_w 6.7 Northridge and 1995 M_w 6.9 Kobe earthquakes, steel moment-frame buildings were exposed to an unexpected flaw. The commonly utilized welded unreinforced flange, bolted web connections were observed to experience brittle fractures in a number of buildings, even at low levels of seismic demand. A majority of these buildings have not been retrofitted and may be susceptible to structural collapse in a major earthquake.

This dissertation presents a case study of retrofitting a 20-story pre-Northridge steel moment-frame building. Twelve retrofit schemes are developed that present some range in degree of intervention. Three retrofitting techniques are considered: upgrading the brittle beam-to-column moment resisting connections, and implementing either conventional or buckling-restrained brace elements within the existing moment-frame bays. The retrofit schemes include some that are designed to the basic safety objective of ASCE-41 Seismic Rehabilitation of Existing Buildings.

Detailed finite element models of the base line building and the retrofit schemes are constructed. The models include considerations of brittle beam-to-column moment resisting connection fractures, column splice fractures, column baseplate fractures, accidental contributions from ``simple'' non-moment resisting beam-to-column connections to the lateral force-resisting system, and composite actions of beams with the overlying floor system. In addition, foundation interaction is included through nonlinear translational springs underneath basement columns.

To investigate the effectiveness of the retrofit schemes, the building models are analyzed under ground motions from three large magnitude simulated earthquakes that cause intense shaking in the greater Los Angeles metropolitan area, and under recorded ground motions from actual earthquakes. It is found that retrofit schemes that convert the existing moment-frames into braced-frames by implementing either conventional or buckling-restrained braces are effective in limiting structural damage and mitigating structural collapse. In the three simulated earthquakes, a 20% chance of simulated collapse is realized at PGV of around 0.6 m/s for the base line model, but at PGV of around 1.8 m/s for some of the retrofit schemes. However, conventional braces are observed to deteriorate rapidly. Hence, if a braced-frame that employs conventional braces survives a large earthquake, it is questionable how much service the braces provide in potential aftershocks.

Simplifying mooring analysis for deepwater systems using truncation

Over recent years academia and industry have engaged with the challenge of model testing deepwater structures at conventional scales. One approach to the limited depth problem has been to truncate the lines. This concept will be introduced, highlighting the need to better understand line dynamic processes. The type of line truncation developed here models the upper sections of each line in detail, capturing wave action and all coupling effects with the vessel, terminating to an approximate analytical model that aims to simulate the remainder of the line. A rationale for this is that in deep water transverse elastic waves of a line are likely to decay before they are reflected at the seabed because of nonlinear hydrodynamic drag forces. The first part of this paper is centered on verification of this rationale. A simplified model of a mooring line that describes the transverse dynamics in wave frequency is used, adopting the equation of motion of an inextensible taut string. The line is submerged in still water, one end fixed at the bottom the other assumed to follow the vessel response, which can be harmonic or random. A dimensional analysis, supported by exact benchmark numerical solutions, has shown that it is possible to produce a universal curve for the decay of transverse vibrations along the line, which is suitable for any kind of line with any top motion. This has a significant engineering benefit, allowing for a rapid assessment of line dynamics - it can be useful in deciding whether a truncated line model is appropriate, and if so, at which point truncation might be applied. This is followed by developing a truncation mechanism, formulating an end approximation that can reproduce the correct impedance, had the line been continuous to full depth. It has been found that below a certain length criterion, which is also universal, the transverse vibrational characteristics for each line are inertia driven. As such the truncated model can assume a linear damper whose coefficient depends on the line properties and frequency of vibration. Copyright © 2011 by the International Society of Offshore and Polar Engineers (ISOPE).

树突状细胞与 HIV-1 辅助蛋白相互作用的体外研究——细胞系模型研究价值的验证和新的研究方向的确立

树突状细胞（Dendritic cells，DCs）作为人类免疫缺陷病毒（Human Immunodeficiency Virus，HIV）感染的第一靶细胞和第一道防线， 在HIV-1感染 和传播过程当中发挥重要的功能。DC的免疫功能主要包括抗原的捕获、加工、 递呈并激活T细胞对HIV-1作出免疫反应，这些功能的发挥依赖于其自身接受刺 激有效地分化和成熟。 与其它慢病毒（lentivirus）相同，HIV-1所具有的6种辅助蛋白（Nef，Rev， Tat，Vif，Vpr和Vpu），决定着病毒自身的复制增殖和对机体的感染和致病力。 目前，HIV-1辅助蛋白对CD4+ T细胞影响的研究较为深入，是否影响和调节DC 的分化和成熟尚不够清楚，现有的文献报道很少，且相互不一致甚至矛盾。因此， 建立合适的体外研究体系和细胞模型，有针对性地进行研究DC与HIV-1之间的相 互作用，将有助于加深对HIV/AIDS致病和发病机理的理解，具有重要的生物医 学意义。 本实验选择了可被HIV-1感染的白血病细胞系THP-1为实验模型，首先评价 了THP-1作为DC前体在研究DC分化、成熟中的可用性，特别是判定DC分化成熟 和功能状态的主要细胞表面标记的动态变化和规律。进而在相同条件下分析了6 个辅助蛋白基因对THP-1的凋亡诱导作用，证实了Nef和Tat确可诱导转染细胞自 身凋亡，而Rev和Vpr可在THP-1细胞中持续表达，形成了稳定的细胞系，为进一 步研究和比较Rev、Vpr对DC的分化、成熟的影响奠定了实验基础。更重要的是， 我们发现，Vif和Vpu不能在THP-1中有效表达，其原因可能直接与限制性因子 APOBEC3G的存在有关，提示Vpu与APOBEC3G可能存在着新的相互作用——这 一线索已作为实验室新的研究方向，进一步深入的研究可能为HIV/AIDS致病、 发病机理和机体的抗病机制提供新的科学依据。

Biology and distribution of grouper (Epinephelus coioides) in province waters (Abadan Bhrakan)

This survay has been done from Januray 2000 till May 2002 in Khouzestan costal waters. Four species of grouper were identified from which orange spotted grouper (Epinephelus coioides) was the dominant species. For studing environmental parameters and reproductive biology, age, growth parameters and mortality rate samples were collected by fishing ship. Samples were taken montly in 4 days by fishing traps and trawls. In addition, some samples were obtained from Khozestan fish landing centres. Environmental factors such as PH, 02, salinity, water temperature and depth of traping areas, were measured. To identify species, morphometric characteries of 452 individal fishes were measured. Stomach contents of 394 fish were has survaid, from which stomach of 226 fish, and 168 fish had empty stomachs. Percentage of empty stomachs (cv) in males was more than females. Food items found in 73 percent of stomach were crab (11%), shrimps (8.8%) , squids (3.9%), gastropods (17%) and bivalves (0.4%). Feeding intensity in year classes did not obay logic trends The importance relatively indicator (I.R.I) were 81, 9.9, 4, 1.5 and 0.3 percent for fish, crab, shrimp, squid, gastropod and bivalve respectively. For age determination, sagita otoliths of 450 fish were taken and countable sections were obtained from 425 specimens. Relative frequency distribution of opaque and transparent rings showed that each opaque growth ring generates once a year from November to September. It seemed that generation of opaque rings is affected by temperature and photoperiod changes. Correlation between length and age was calculated using Von Bertalanffy's least square method. Following equasion was obtaind: L(t) : 122.27 (1 e 0.146 (t+0.482)) Growth parameters were determined through by Ford Walford equasion and Response Surface and Shepherd subcommands in Elefan program and L00 and K amounts were have determined. Correlation between length and age of 635 fish was determined by gender . Length and age correlation was calculated by exponential model and between total length and standard length by straghit line model. Correlation between age and weight of sagita was calculated by total length and age. The most Correlation was between sagita weight and fish age (r=0.876). Total mortality rate (z) was estimated by Length Converthed Method , Jones and Vanzaling and Powel Wetherall. Total mortality rate was z=0.39. Natural mortality rate, using Pauly method was calculated M=0.32. Fishing mortality (F) was 0.08. Gonads of 425 fishes were surveid within 18 month, from which 363 were female, 46 were male and 16 were sex reversing individuals .Total length of females varied from 26 to 95.5 centimeters while males length varied from 56.5 to 107 centimeters. Sex reversing individuals had a length of 47.5 centimeters, when two years old and 62.5 centimeters at age of 3 years. From the mentioned 425 fish, 401 individuals were matured, containing 339 females and 62 males, 5.47 females against each male. Montly changes of Gonadosomatic Index (GSI) by total body weight and standard length and total body length showed that this index increases from march to May and maximum increase was in May . This experiment was adapted in spawning season. Potential, relative, and absoulate fecundity was estimated by counting eggs in three samples. Total amount of traped fish using special traps was 16182.18 kg from which Epinephelus coioides provided catching 15353.43 kg of it (91.27 %) and By catch was 141.18 kg (8.24 %). Total average CPUE for whole catch was 123.33 kg/day/vessel. Total amount of catch was estimated 232.04 tons, considering CPUE of total catch and total Khuzestan trap ships effort.

Decay of vibrations along deepwater mooring lines

Model tests for global design verification of deepwater floating structures cannot be made at reasonable scales. An overview of recent research efforts to tackle this challenge is given first, introducing the concept of line truncation techniques. In such a method the upper sections of each line are modelled in detail, capturing the wave action zone and all coupling effects with the vessel. These terminate to an approximate analytical model, that aims to simulate the remainder of the line. The rationale for this is that in deep water the transverse elastic waves of a line are likely to decay before they are reflected at the seabed. The focus of this paper is the verification of this rationale and the ongoing work, which is considering ways to produce a truncation model. Transverse dynamics of a mooring line are modelled using the equations of motion of an inextensible taut string, submerged in still water, one end fixed at the bottom the other assumed to follow the vessel response, which can be harmonic or random. Nonlinear hydrodynamic damping is included; bending and VIV effects are neglected. A dimensional analysis, supported by exact benchmark numerical solutions, has shown that it is possible to produce a universal curve for the decay of transverse vibrations along the line, which is suitable for any kind of line with any top motion. This has a significant engineering benefit, allowing for a rapid assessment of line dynamics - it is very useful in deciding whether a truncated line model is appropriate, and if so, at which point truncation might be applied. Initial efforts in developing a truncated model show that a linearized numerical solution in the frequency domain matches very closely the exact benchmark. Copyright © 2011 by ASME.

Chirp-enhanced direct modulation of a monolithic sub-Terahertz dual laser transmitter

A technique enabling 10 Gbps data to be directly modulated onto a monolithic sub-THz dual laser transmitter is proposed. As a result of the laser chirp, the logical zeros of the resultant sub-THz signal have a different peak frequency from that of the logical ones. The signal extinction ratio is therefore enhanced by suppressing the logical zeros with a filter stage at the receiver. With the aid of the chirp-enhanced filtering, an improved extinction ratio can be achieved at moderate modulation current. Hence, 10 GHz modulation bandwidth of the transmitter is predicted without the need for external modulators. In this paper, we demonstrate the operational principle by generating an error-free (bit error rate less than 10-9) 100 Mbps Manchester encoded signal with a centre frequency of 12 GHz within the bandwidth of an envelope detector, whilst direct modulation of a 100 GHz signal at data rates of up to 10 Gbps is simulated by using a transmission line model. This work could be a key technique for enabling monolithic sub-THz transmitters to be readily used in high speed wireless links. © 2013 IEEE.

Index Trees for Efficient Deformable Shape-based Retrieval

An improved method for deformable shape-based image indexing and retrieval is described. A pre-computed index tree is used to improve the speed of our previously reported on-line model fitting method; simple shape features are used as keys in a pre-generated index tree of model instances. In addition, a coarse to fine indexing scheme is used at different levels of the tree to further improve speed while maintaining matching accuracy. Experimental results show that the speedup is significant, while accuracy of shape-based indexing is maintained. A method for shape population-based retrieval is also described. The method allows query formulation based on the population distributions of shapes in each image. Results of population-based image queries for a database of blood cell micrographs are shown.

Coexpressing shRNA with fluorescence tags for quantification of cell migration studies

Understanding migration of cells has many implications in human physiology; some examples include developmental biology, healing, immune responses and tissue remodeling. On the other hand, invasive migration by tumor cells is pathological and is a major cause of mortality amongst cancer sufferers. Cell migration assays have been widely used to quantify potentially metastatic genes. In recent years, the use of RNAi has significantly increased the tools available in cell migration research due to its specific gene targeting for knockdown. The inability to ensure 100% transfection/transduction efficiency reduces the sensitivity of cell migration assays because cells not successfully transfected/transduced with the RNAi are also included in the calculations. This study introduces a different experimental setup mathematically expressed in our named normalized relative infected cell count (N-RICC) that analyses cell migration assays by co-expressing retrovirally transduced shRNA with fluorescence tags from a single vector. Vectors transduced into cells are visible under fluorescence, thus alleviating the problems involved with transduction efficiency by individually identifying cells with targeted genes. Designed shRNAs were targeted against a list of potentially metastatic genes in a highly migratory breast cancer cell line model, MDA-MB-231. We have successfully applied N-RICC analysis to show greater sensitivity of integrin alpha5 (ITGA5) and Ras homologue A (RhoA) in cell metastasis over conventional methods in scratch-wound assays and migration chambers assays.

Distributed passive intermodulation generation in coplanar waveguide transmission lines

A phenomenology of distributed passive intermodulation generation in coplanar waveguide transmission line is presented. The theoretical analysis is based upon the generalised nonlinear transmission line model, which accounts for the coupling of two propagating modes. The case of weak substrate nonlinearity is considered and the model is given qualitative verification through the mapping of passive intermodulation products generated in coplanar waveguide fabricated on a commercial laminate. Implications for future research are discussed. © 2012 IEEE.

Androgen receptor driven transcription in molecular apocrine breast cancer is mediated by FoxA1

Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER- AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER- AR+ molecular apocrine tumours (termed MDA-MB-453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis-regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers.

The effect of acute alcohol exposure on hepatic oxidative stress and function: prevention by micronutrients

Alcohol binge drinking, especially in teenagers and young adults is a major public health issue in the UK, with the number of alcohol related liver disorders steadily increasing. Understanding the mechanisms behind liver disease arising from binge-drinking and finding ways to prevent such damage are currently important areas of research. In the present investigation the effect of acute ethanol administration on hepatic oxidative damage and apoptosis was examined using both an in vivo and in vitro approach; the effect of micronutrient supplementation prior and during ethanol exposure was also studied. The following studies were performed: (1) ethanol administration (75 mmol/kg body weight) and cyanamide pre-treatment followed by ethanol to study elevated acetaldehyde levels with liver tissue analysed 2.5, 6 and 24 hours post-alcohol; (2). Using juvenile animals, 2% betaine supplementation followed by acute ethanol with tissue analysed 24 hrs post ethanol; and (3). Micronutrient supplementation during concomitant ethanol exposure to hepG2 cells. It was found that a single dose of alcohol caused oxidative damage to the liver of rats at 2.5 hr post-alcohol as evidenced by decreased glutathione levels and increased malondialdehyde levels in both the cytosol and mitochondria. Liver function was also depressed but there were no findings of apoptosis as cytochrome c levels and caspase 3 activity was unchanged. At 6 hours, the effect of ethanol was reduced suggesting some degree of recovery, however, by 24 hours, increased mitochondrial oxidative stress was apparent. The effect of elevated acetaldehyde on hepatic damage was particularly evident at 24 hours, with some oxidative changes at earlier time points. At 24 hours, acetaldehyde caused a profound drop in glutathione levels in the cytosol and hepatic function was still deteriorating. Studies examining ethanol exposure to juvenile livers showed that glutathione levels were increased, suggesting an overtly protective response not seen in with older animals. It also showed that despite cytochrome c release into the cytosol, caspase-3 levels were not increased. This suggests that ATP depletion is preventing apoptosis initiation. Betaine supplementation prevented almost all of the alcohol-mediated changes, suggesting that the main mechanism behind alcohol-mediated liver damage is oxidative stress. Results using the hepG2 cell line model showed that micronutrients involved in glutathione synthesis can protect against hepatocyte damage caused by alcohol metabolism, with reduced reactive oxygen species and increased/maintained glutathione levels. In summary, these results demonstrate that both acute alcohol and acetaldehyde can have damaging effects to the liver, but that dietary intervention may be able to protect against ethanol induced oxidative stress.

Étude de Necdin par un modèle de carcinogénèse lié à l’antigène grand T du Virus du polyome

Les virus sont utilisés depuis longtemps dans la recherche sur le cancer et ont grandement contribué à l’avancement des connaissances de même qu’à l’établissement de préceptes importants encore valables aujourd’hui dans le domaine. L’un des défis actuels est de mieux définir les étapes menant à la transition d’une cellule normale à une cellule transformée et c’est sur cette problématique que nous nous sommes penchés. Pour ce faire, nous avons tiré profit de l’utilisation de l’antigène grand-T du virus de polyome (PyLT), un virus capable d’induire des tumeurs chez les rongeurs. Cet oncogène viral à lui seul possède des propriétés intéressantes qui suggèrent que, en plus de l’immortalisation, il peut également contribuer aux événements précoces de la carcinogénèse. Ceci repose principalement sur la capacité de PyLT à induire des tumeurs en souris transgéniques et ce, avec une certaine latence ce qui suggère que des événements supplémentaires sont nécessaires. Ainsi, l’utilisation de PyLT dans un modèle de culture cellulaire permet de disséquer les changements qui lui sont attribuables. Dans un premier temps, l’établissement du profil d'expression génique associé à l'expression de PyLT dans un modèle murin nous a permis de sélectionner un bon nombre de gènes, parmi lesquels figurait Necdin. Nous avons choisi d’étudier Necdin plus en détail puisque peu d’attention était accordée à cette protéine dans le domaine du cancer, malgré que différentes données de la littérature lui suggèrent à la fois des fonctions suppresseurs de tumeur et oncogéniques. Nous avons démontré que, malgré sa fonction proposée de suppresseur de croissance, l’expression de Necdin n’est pas incompatible avec la prolifération dans la lignée cellulaire de souris NIH 3T3 et les cellules primaires humaines (IMR90), bien que l’inhibition de son expression par shARN confère un avantage prolifératif. Nous avons confirmé que Necdin est un gène cible de p53 induit par différents agents génotoxiques, toutefois son expression peut également être régulée de façon p53-indépendante. De plus, Necdin agit négativement sur l’arrêt du cycle cellulaire en réponse à l’activation de p53. Ceci suggère que Necdin est impliqué dans une boucle de régulation négative de la voie de p53 et que l’augmentation anormale de l’expression de Necdin pourrait contribuer à la perturbation la voie du suppresseur de tumeur p53. L’activation de p53 permet l’arrêt transitoire du cycle cellulaire en condition de stress, mais est aussi impliquée dans l’établissement d’un arrêt permanent nommé sénescence. La sénescence est un mécanisme de protection contre l’accumulation de mutations qui peut contribuer à l’initiation du cancer. Vu l’intéressante implication de Necdin dans la régulation de l’activité de p53, nous avons transposé les connaissances acquises du modèle murin à un modèle humain, plus adapté pour l’étude de la sénescence. La caractérisation de l’expression de Necdin dans des fibroblastes primaires humains à différents passages montre que les jeunes cellules en prolifération active expriment Necdin et que son niveau diminue avec l’établissement de la sénescence réplicative. Le même phénomène est observé lors de la sénescence prématurée provoquée par l’expression d’un oncogène et par l’exposition aux radiations ionisantes. De plus, dans des conditions normales de prolifération, la modulation de Necdin par des essais de gain et de perte de fonction n’affecte pas la durée de vie des cellules primaires. Toutefois, en condition de stress génotoxique dû à l’exposition aux irradiations, les cellules surexprimant Necdin présentent une radiorésistance accrue de la même façon que lorsque p53 est inactivé directement. Ce résultat en cellules humaines vient appuyer l’effet observé dans les cellules de souris sur l’impact qu’aura le niveau de Necdin sur la réponse de p53 en condition de stress. Un bref survol a été fait pour aborder de quelle façon nos résultats en culture cellulaire pouvaient se traduire dans des modèles de cancer chez l’humain. Nous avons caractérisé l’expression de Necdin dans deux types différents de cancer. D’abord, dans le cancer de l’ovaire, le niveau élevé de Necdin dans les tumeurs à faible potentiel de malignité (LMP) en comparaison aux cancers agressifs de l’ovaire de type séreux suggère que l’expression de Necdin se limite aux cellules de cancer LMP, qui présente généralement un p53 de type sauvage. Son expression est aussi retrouvée dans deux lignées cellulaires du cancer de l’ovaire non-tumorigéniques en xénogreffe de souris, dont l’une possède un p53 fonctionnel. De plus, la caractérisation de Necdin dans les lignées cellulaires du cancer de la prostate suggère une relation entre son expression et la présence de p53 fonctionnel. Dans le cancer de la prostate, tout comme pour le cancer de l’ovaire, Necdin semble être présent dans les lignées représentant un stade moins avancé de la maladie. L’utilisation de l’oncoprotéine virale PyLT nous a permis de révéler des propriétés intéressantes de Necdin. Nous proposons que dans certains contextes, l’expression constitutive de Necdin pourrait contribuer au cancer en retardant une réponse par p53 appropriée et possiblement en participant à l’augmentation de l’instabilité génomique. La fonction potentiellement oncogénique de Necdin quant à sa relation avec p53 que nous avons révélée requiert davantage d’investigation et les cancers caractérisés ici pourraient constituer de bons modèles à cette fin.

Semisynthetic aminoglycoside antibiotics : toward biomimetic synthesis, evasion of bacterial resistance and reduced toxicity

Les antibiotiques aminoglycosidiques sont des agents bactéricides de grande valeur et d’efficacité à large spectre contre les pathogènes Gram-positifs et Gram-négatifs, dont plusieurs membres naturels et semisynthétiques sont importants dans l’histoire clinique depuis 1950. Des travaux crystallographiques sur le ribosome, récompensés par le prix Nobel, ont démontré comment leurs diverses structures polyaminées sont adaptées pour cibler une hélice d’ARN dans le centre de codage de la sous-unité 30S du ribosome bactérien. Leur interférence avec l’affinité et la cinétique des étapes de sélection et vérification des tARN induit la synthèse de protéines à basse fidélité, et l’inhibition de la translocation, établissant un cercle vicieux d’accumulation d’antibiotique et de stress sur la membrane. En réponse à ces pressions, les pathogènes bactériens ont évolué et disséminé une panoplie de mécanismes de résistance enzymatiques et d’expulsion : tels que les N acétyltransférases, les O phosphotransférases et les O nucleotidyltransférases qui ciblent les groupements hydroxyle et amino sur le coeur des aminoglycosides; des méthyl-transférases, qui ciblent le site de liaison ribosomale; et des pompes d’expulsion actives pour l’élimination sélective des aminoglycosides, qui sont utilisés par les souches Gram-négatives. Les pathogènes les plus problématiques, qui présentent aujourd’hui une forte résilience envers la majorité des classes d’antibiotiques sur le bord de la pan-résistance ont été nommés des bactéries ESKAPE, une mnémonique pour Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa et Enterobacteriaceae. La distribution globale des souches avec des mécanismes de résistance envers les standards cliniques aminoglycosides, tels que la tobramycine, l’amikacine et la gentamicine, est comprise entre 20 et 60% des isolées cliniques. Ainsi, les aminoglycosides du type 4,6-disubstitués-2-deoxystreptamine sont inadéquats comme thérapies anti-infectieuses à large spectre. Cependant, la famille des aminoglycosides 4,5-disubstitués, incluant la butirosine, la neomycine et la paromomycine, dont la structure plus complexe, pourrait constituter une alternative. Des collègues dans le groupe Hanessian et collaborateurs d’Achaogen Inc. ont démontré que certains analogues de la paraomomycine et neomycine, modifiés par désoxygénation sur les positions 3’ et 4’, et par substitution avec la chaîne N1-α-hydroxy-γ-aminobutyramide (HABA) provenant de la butirosine, pourrait produire des antibiotiques très prometteurs. Le Chapitre 4 de cette dissertation présente la conception et le développement d’une stratégie semi-synthétique pour produire des nouveaux aminoglycosides améliorés du type 4,5 disubstitués, inspiré par des modifications biosynthétiques de la sisomicine, qui frustrent les mécanismes de résistance bactérienne distribuées globalement. Cette voie de synthèse dépend d’une réaction d’hydrogénolyse de type Tsuji catalysée par palladium, d’abord développée sur des modèles monosaccharides puis subséquemment appliquée pour générer un ensemble d’aminoglycosides hybrides entre la neomycine et la sisomicine. Les études structure-activité des divers analogues de cette nouvelle classe ont été évaluées sur une gamme de 26 souches bactériennes exprimant des mécanismes de résistance enzymatique et d’expulsion qui englobe l’ensemble des pathogènes ESKAPE. Deux des antibiotiques hybrides ont une couverture antibacterienne excellente, et cette étude a mis en évidence des candidats prometteurs pour le développement préclinique. La thérapie avec les antibiotiques aminoglycosidiques est toujours associée à une probabilité de complications néphrotoxiques. Le potentiel de toxicité de chaque aminoglycoside peut être largement corrélé avec le nombre de groupements amino et de désoxygénations. Une hypothèse de longue date dans le domaine indique que les interactions principales sont effectuées par des sels des groupements ammonium, donc l’ajustement des paramètres de pKa pourrait provoquer une dissociation plus rapide avec leurs cibles, une clairance plus efficace et globalement des analogues moins néphrotoxiques. Le Chapitre 5 de cette dissertation présente la conception et la synthèse asymétrique de chaînes N1 HABA β substitutées par mono- et bis-fluoration. Des chaînes qui possèdent des γ-N pKa dans l’intervalle entre 10 et 7.5 ont été appliquées sur une neomycine tétra-désoxygénée pour produire des antibiotiques avancés. Malgré la réduction considérable du γ N pKa, le large spectre bactéricide n’a pas été significativement affecté pour les analogues fluorés isosteriques. De plus, des études structure-toxicité évaluées avec une analyse d’apoptose propriétaire d’Achaogen ont démontré que la nouvelle chaîne β,β difluoro-N1-HABA est moins nocive sur un modèle de cellules de rein humain HK2 et elle est prometteuse pour le développement d’antibiotiques du type neomycine avec des propriétés thérapeutiques améliorées. Le chapitre final de cette dissertation présente la proposition et validation d’une synthèse biomimétique par assemblage spontané du aminoglycoside 66-40C, un dimère C2 symétrique bis-imine macrocyclique à 16 membres. La structure proposée du macrocycle a été affinée par spectroscopie nucléaire à un système trans,trans-bis-azadiène anti-parallèle. Des calculs indiquent que l’effet anomérique de la liaison α glycosidique entre les anneaux A et B fournit la pré-organisation pour le monomère 6’ aldéhydo sisomicine et favorise le produit macrocyclique observé. L’assemblage spontané dans l’eau a été étudié par la dimérisation de trois divers analogues et par des expériences d’entre croisement qui ont démontré la généralité et la stabilité du motif macrocyclique de l'aminoglycoside 66-40C.

Broad-Band Gap Coupled Microstrip Antenna

A microstrip antenna with large bandwidth is developed using a parasitic technique . Compared to the available wide-baud antennas,the proposed antenna structure is very compact and gives a lessdistorted radiation pattern with frequency . An impedance bandwidth,eight times that of a conventional patch antenna of the same size, Isachieved. The concept of coupled microstrip line model Is extended fortheoretical interpretation of the impedance loci