Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review

Chronic Granulomatous Disease (CGD), a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans). Deletions and missense, frameshift, or nonsense mutations in the gp91^phox gene (also termed CYBB), located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.     

Computational nature of human adaptive control during learning of reaching movements in force fields

Learning to make reaching movements in force fields was used as a paradigm to explore the system architecture of the biological adaptive controller. We compared the performance of a number of candidate control systems that acted on a model of the neuromuscular system of the human arm and asked how well the dynamics of the candidate system compared with the movement characteristics of 16 subjects. We found that control via a supra-spinal system that utilized an adaptive inverse model resulted in dynamics that were similar to that observed in our subjects, but lacked essential characteristics. These characteristics pointed to a different architecture where descending commands were influenced by an adaptive forward model. However, we found that control via a forward model alone also resulted in dynamics that did not match the behavior of the human arm. We considered a third control architecture where a forward model was used in conjunction with an inverse model and found that the resulting dynamics were remarkably similar to that observed in the experimental data. The essential property of this control architecture was that it predicted a complex pattern of near-discontinuities in hand trajectory in the novel force field. A nearly identical pattern was observed in our subjects, suggesting that generation of descending motor commands was likely through a control system architecture that included both adaptive forward and inverse models. We found that as subjects learned to make reaching movements, adaptation rates for the forward and inverse models could be independently estimated and the resulting changes in performance of subjects from movement to movement could be accurately accounted for. Results suggested that the adaptation of the forward model played a dominant role in the motor learning of subjects. After a period of consolidation, the rates of adaptation in the internal models were significantly larger than those observed before the memory had consolidated. This suggested that consolidation of motor memory coincided with freeing of certain computational resources for subsequent learning. Received: 01 January 1998 / Accepted in revised form: 26 January 1999     

Fluorinated 2′-hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities

Chalcones are involved in the synthesis of flavonoids and are themselves known to exhibit multiple pharmacological properties. However, compared to other structurally similar phytochemicals like garcinol and curcumin, the therapeutic use of chalcones is limited because of their lower bioavailability and rapid metabolic clearance from biological system. In the present work, we have attempted to overcome these limitations in case of 2′-hydroxychalcones through bioisosteric substitution of fluoro groups in place of phenolic hydroxyls. The fluorinated chalcones were found to be more potent antioxidant and anti-proliferative compounds than their hydroxyl counterparts indicating the influence of metabolically stable C–F bonds towards bioavailability. The difluoro derivatives were found to be most effective against human pancreatic BxPC-3 cancer cells which possess up-regulated COX-2 expression and also showed activity against human breast cancer BT-20 cells with triple negative phenotype, suggesting that these compounds will have broader application in the future.     

CesT is a multi-effector chaperone and recruitment factor required for the efficient type III secretion of both LEE- and non-LEE-encoded effectors of enteropathogenic Escherichia coli

Enteropathogenic Escherichia coli (EPEC) is an intestinal attaching and effacing pathogen that utilizes a type III secretion system (T3SS) for the delivery of effectors into host cells. The chaperone CesT has been shown to bind and stabilize the type III translocated effectors Tir and Map in the bacterial cytoplasm prior to their delivery into host cells. In this study we demonstrate a role for CesT in effector recruitment to the membrane embedded T3SS. CesT-mediated effector recruitment was dependent on the presence of the T3SS membrane-associated ATPase EscN. EPEC DeltacesT carrying a C-terminal CesT variant, CesT(E142G), exhibited normal cytoplasmic Tir stability function, but was less efficient in secreting Tir, further implicating CesT in type III secretion. In vivo co-immunoprecipitation studies using CesT-FLAG containing EPEC lysates demonstrated that CesT interacts with Tir and EscN, consistent with the notion of CesT recruiting Tir to the T3SS. CesT was also shown to be required for the efficient secretion of several type III effectors encoded within and outside the locus of enterocyte effacement (LEE) in addition to Tir and Map. Furthermore, a CesT affinity column was shown to specifically retain multiple effector proteins from EPEC culture supernatants. These findings indicate that CesT is centrally involved in recruiting multiple type III effectors to the T3SS via EscN for efficient secretion, and functionally redefine the role of CesT in multiple type III effector interactions.     

Discovery of novel leukotriene A4 hydrolase inhibitors based on piperidine and piperazine scaffolds

Novel piperidine and piperazine derivatives have been designed and tested as inhibitors of LTA₄ hydrolase (LTA₄H). Most potent compounds showed good potency in both enzymatic and functional human whole blood assay. Crystallography studies further confirmed observed structure–activity relationship and LTA₄H binding mode for analogs from the piperidine series.     

Associative learning in biochemical networks

It has been recently suggested that there are likely generic features characterizing the emergence of systems constructed from the self-organization of self-replicating agents acting under one or more selection pressures. Therefore, structures and behaviors at one length scale may be used to infer analogous structures and behaviors at other length scales. Motivated by this suggestion, we seek to characterize various "animate" behaviors in biochemical networks, and the influence that these behaviors have on genomic evolution. Specifically, in this paper, we develop a simple, chemostat-based model illustrating how a process analogous to associative learning can occur in a biochemical network. Associative learning is a form of learning whereby a system "learns" to associate two stimuli with one another. Associative learning, also known as conditioning, is believed to be a powerful learning process at work in the brain (associative learning is essentially "learning by analogy"). In our model, two types of replicating molecules, denoted as A and B, are present in some initial concentration in the chemostat. Molecules A and B are stimulated to replicate by some growth factors, denoted as G(A) and G(B), respectively. It is also assumed that A and B can covalently link, and that the conjugated molecule can be stimulated by either the G(A) or G(B) growth factors (and can be degraded). We show that, if the chemostat is stimulated by both growth factors for a certain time, followed by a time gap during which the chemostat is not stimulated at all, and if the chemostat is then stimulated again by only one of the growth factors, then there will be a transient increase in the number of molecules activated by the other growth factor. Therefore, the chemostat bears the imprint of earlier, simultaneous stimulation with both growth factors, which is indicative of associative learning. It is interesting to note that the dynamics of our model is consistent with certain aspects of Pavlov's original series of conditioning experiments in dogs. We discuss how associative learning can potentially be performed in vitro within RNA, DNA, or peptide networks. We also describe how such a mechanism could be involved in genomic evolution, and suggest relevant bioinformatics studies that could potentially resolve these issues.     

Calyceal Diverticula: A Comprehensive Review

Calyceal diverticula are rare outpouchings of the upper collecting system that likely have a congenital origin. Stones can be found in up to 50% of calyceal diverticula, although, over the combined reported series, 96% of patients presented with stones. Diagnosis is best made by intravenous urography or computed tomography urogram. Shock wave lithotripsy (SWL) is an option for first-line therapy in patients with stone-bearing diverticula that have radiologically patent necks in mid- to upper-pole diverticula and small stone burdens. Stone-free rates are the lowest with SWL, although patients report being asymptomatic following therapy in up to 75% of cases with extended follow-up. Ureteroscopy (URS) is best suited for management of anteriorly located mid- to upperpole diverticular stones. Drawbacks to URS include difficulty in identifying the ostium and low rate of obliteration. Percutaneous management is best used in posteriorly located mid- to lower-pole stones, and offers the ability to directly ablate the diverticulum. Percutaneous nephrolithotomy remains effective in the management of upperpole diverticula, but carries the risk of pulmonary complications unless subcostal access strategies such as triangulation or renal displacement are used. Laparoscopic surgery provides definitive management, but should be reserved for cases with large stones in anteriorly located diverticula with thin overlying parenchyma, and cases that are refractory to other treatment. This article reviews the current theories on the pathogenesis of calyceal diverticula. The current classification is examined in addition to the current diagnostic methods. Here we summarize an extensive review of the literature on the outcomes of the different treatment approaches.Key words: Calyceal diverticula, Percutaneous nephrostolithotomy, Laparoscopic surgery, Shock wave lithotripsy, UreterorenoscopyCalyceal diverticula are eventrations of the upper collecting system lying within the renal parenchyma.¹ These nonsecretory outpouchings are lined by transitional cell epithelium and communicate with the main collecting system via a narrow channel, allowing for passive filling with urine. They were first described in 1841 by Rayer in “Traitements des maladies des reins.”² Thought to be either cysts or localized hydronephrosis, he used the term kyste urinaire to describe his finding of intrarenal urine-containing cavities that communicate with calyces. Other investigators reported similar findings and—depending on location and postulated etiology—described them as pelvic cysts,³ peripelvic cysts,⁴ pyelorenal cysts,⁵ pyelosynaptic cysts,⁶ pyelogenous cysts,⁷ hydrocalicosis,⁸ cystic dilatations of the calyx,⁹ congenital cortical cysts,¹⁰ congenital cystic dysplasia,^4,11 calyceal pseudocysts,¹² juxta-calyceal cysts,¹³ pelvic diverticula, ¹⁴ congenital diverticula of the calyx,¹⁵ and finally, calyceal diverticula.^16–18 Prather is credited with coining the term and the definition of calyceal diverticulum that we use today.