Neuronal ciliary signaling in homeostasis and disease

Primary cilia are a class of cilia that are typically solitary, immotile appendages present on nearly every mammalian cell type. Primary cilia are believed to perform specialized sensory and signaling functions that are important for normal development and cellular homeostasis. Indeed, primary cilia dysfunction is now linked to numerous human diseases and genetic disorders. Collectively, primary cilia disorders are termed as ciliopathies and present with a wide range of clinical features, including cystic kidney disease, retinal degeneration, obesity, polydactyly, anosmia, intellectual disability, and brain malformations. Although significant progress has been made in elucidating the functions of primary cilia on some cell types, the precise functions of most primary cilia remain unknown. This is particularly true for primary cilia on neurons throughout the mammalian brain. This review will introduce primary cilia and ciliary signaling pathways with a focus on neuronal cilia and their putative functions and roles in human diseases.     

Alzheimer’s disease: the impact of age-related changes in reproductive hormones

Recent findings from the Womens Health Initiative (WHI) have raised considerable concern over prolonged use of opposed and unopposed oral conjugated equine estrogen (CEE), given the increased risk of serious adverse effects, including stroke and venous thromboembolic complications. Furthermore, results from the WHI Memory Study (WHIMS) indicated that over 5 years of therapy with Prempro impaired performance on global cognitive tests and nearly doubled the risk of dementia. These surprising findings were contradictory to cumulative evidence from basic science, epidemiological and some intervention studies suggesting hormone therapy was cardioprotective and could potentially reduce the risk of dementia. This review paper focuses on the neurobiology of estrogen, summarizing the clinical evidence for neuroprotective and cognition-enhancing efficacy of estrogen. Further, the paper briefly discusses variables that may account for the unexpected findings of WHIMS, and offers suggestions for future research.     

The primary cilium as a dual sensor of mechanochemical signals in chondrocytes

The primary cilium is an immotile, solitary, and microtubule-based structure that projects from cell surfaces into the extracellular environment. The primary cilium functions as a dual sensor, as mechanosensors and chemosensors. The primary cilia coordinate several essential cell signaling pathways that are mainly involved in cell division and differentiation. A primary cilium malfunction can result in several human diseases. Mechanical loading is sense by mechanosensitive cells in nearly all tissues and organs. With this sensation, the mechanical signal is further transduced into biochemical signals involving pathways such as Akt, PKA, FAK, ERK, and MAPK. In this review, we focus on the fundamental functional and structural features of primary cilia in chondrocytes and chondrogenic cells.     

Cardiac and circulatory control in decapod Crustacea with comparisons to molluscs

Summary In this review I will attempt to identify the circulatory requirements a decapod is likely to encounter and how the heart is controlled to meet these demands. The decapod heart has been designed as an autonomous system endowed with an intrinsic autorhythmic pacemaker ganglion. Muscle fibers are multiply-innervated and capable of producing regenerative action potentials. This vitally important organ has been designed to be nearly fail-safe. Stroke volume is more important than heart rate in determining cardiac output. Stretch sensitivity of the cardiac ganglion and of the myocardium as well as extrinsic nervous and hormonal modulation of the heart can all contribute to changes in stroke volume. It may be advantageous to an animal to switch the circulation between various vascular beds to meet changing perfusion demands. Neuronal and hormonal mechanisms have been identified which exert differential control of the cardioarterial valves, but it is not known whether switching does occur and if so whether these valves participate in the process. Changes in peripheral resistance can also redirect circulatory flow. The circulatory and ventilatory systems demonstrate coordinated rate changes which suggest that the heart is responding to meet changing ventilatory performance requirements. This coupling is controlled both by the hydrostatic pressure pulses generated within the branchial chambers and by common higher level nervous inputs. Comparisons of the cardiovascular systems of crustaceans and molluscs, based on the papers presented at this symposium, are high-lighted.     

The polycystins: a novel class of membrane-associated proteins involved in renal cystic disease

Polycystin-1, polycystin-2 and polycystin-L are the predicted protein products of the PKD1, PKD2 and PKDL genes, respectively. Mutations in PKD1 and PKD2 are responsible for almost all cases of autosomal dominant polycystic kidney disease (ADPKD). This condition is one of the commonest mendelian disorders of man with a prevalence of 1:800 and is responsible for nearly 10% of cases of end-stage renal failure in adults. The cloning of PKD1 and PKD2 in recent years has provided the initial steps in defining the mechanisms underlying renal cyst formation in this condition, with the aim of defining pharmacological and genetic interventions that may ameliorate the diverse and often serious clinical manifestations of this disease. The PKD genes share regions of sequence similarity, and all predict integral membrane proteins. Whilst the predicted protein domain structure of polycystin-1 suggests it is involved in cell-cell or cell-matrix interactions, the similarity of polycystin-2 and polycystin-L to the pore-forming domains of some cation channels suggests that they all form subunits of a large plasma membrane ion channel. In the few years since the cloning of the PKD genes, a consensus that defines the range of mutations, expression pattern, interactions and functional domains of these genes and their protein products is emerging. This review will therefore attempt to summarise these data and provide an insight in to the key areas in which polycystin research is unravelling the mechanisms involved in renal cyst formation. Received 22 February 1999; received after revision 5 July 1999; accepted 6 July 1999     

Trichomes as models for studying plant cell differentiation

Trichomes, originating from epidermal cells, are present on nearly all terrestrial plants. They exist in diverse forms, are readily accessible, and serve as an excellent model system for analyzing the molecular mechanisms in plant cell differentiation, including cell fate choices, cell cycle control, and cell morphogenesis. In Arabidopsis, two regulatory models have been identified that function in parallel in trichome formation; the activator–inhibitor model and the activator–depletion model. Cotton fiber, a similar unicellular structure, is controlled by some functional homologues of Arabidopsis trichome-patterning genes. Multicellular trichomes, as in tobacco and tomato, may form through a distinct pathway from unicellular trichomes. Recent research has shown that cell cycle control participates in trichome formation. In this review, we summarize the molecular mechanisms involved in the formation of unicellular and multicellular trichomes, and discuss the integration of the cell cycle in its initiation and morphogenesis.     

Physiological mechanism by which acetyl CoA carboxylase is regulated

Summary Compared with rats fed a normal diet, the activity of the protein inhibitor of acetyl CoA carboxylase in rat liver doubled after 48 h of fasting. Conversely, acetyl CoA carboxylase activity was diminished by nearly one half. In animals fasted and then subsequently refed a fat free diet, acetyl CoA carboxylase activity was elevated by nearly 9-fold, with a concomitant decrease in the activity of the protein inhibitor by about 9-fold as compared to fasted rats. Hence it appears that the regulatory protein inhibitor for acetyl CoA carboxylase is of physiological significance for fatty acid biosynthesis.This work supported by grants AM 01383 and AM 21148 from the National Institute of Artheritis, Metabolic and Digestive Disease. We thank Dr J. Porter for his support.     

Developmental control of heat shock and chaperone gene expression Hsp70 genes and heat shock factors during preimplantation phase of mouse development

Heat shock genes are found in all organisms, and synthesis of heat shock proteins is induced by various stressors in nearly all the cells forming these organisms. However, a particular situation is noticed for hsp70 genes in mouse embryos at the beginning of their development. First, spontaneous expression of hsp70 is observed at the onset of zygotic genome activity. Second, inducible expression is delayed until morula or early blastocyst stages. A better understanding of both these points depends on a more careful analysis of hsp70 expression in relation to their major regulators, the heat shock factors. In this review, we will see how the development of the preimplanta tion embryo highlights the complexity of heat shock gene regulation involving trans-cis interactions and the cellular and nuclear environment.     

Endogenous retroviruses

Up to 10% of the mouse genome is comprised of endogenous retrovirus (ERV) sequences, and most represent the remains of ancient germ line infections. Our knowledge of the three distinct classes of ERVs is inversely correlated with their copy number, and their characterization has benefited from the availability of divergent wild mouse species and subspecies, and from ongoing analysis of the Mus genome sequence. In contrast to human ERVs, which are nearly all extinct, active mouse ERVs can still be found in all three ERV classes. The distribution and diversity of ERVs has been shaped by host-virus interactions over the course of evolution, but ERVs have also been pivotal in shaping the mouse genome by altering host genes through insertional mutagenesis, by adding novel regulatory and coding sequences, and by their co-option by host cells as retroviral resistance genes. We review mechanisms by which an adaptive coexistence has evolved. (Part of a Multiauthor Review)     

Efficient forecasting in nearly non‐stationary processes

This paper proposes a procedure to make efficient predictions in a nearly non‐stationary process. The method is based on the adaptation of the theory of optimal combination of forecasts to nearly non‐stationary processes. The proposed combination method is simple to apply and has a better performance than classical combination procedures. It also has better average performance than a differenced predictor, a fractional differenced predictor, or an optimal unit‐root pretest predictor. In the case of a process that has a zero mean, only the non‐differenced predictor is slightly better than the proposed combination method. In the general case of a non‐zero mean, the proposed combination method has a better overall performance than all its competitors. Copyright © 2002 John Wiley & Sons, Ltd.     

Effect of germination on the glycoprotein of mash (Phaseolus mungo) seeds

Summary The soluble carbohydrates and insoluble proteins ofPhaseolus mungo seeds decreased considerably up to 96 h of germination, whereas the soluble proteins remained nearly constant. The carbohydrates content of glycoprotein also remained constant. This suggests that a negligible change took place in the glycoprotein during the initial period of mash seed germination.     

Subcellular localization of noradrenaline and ATP in C1300 mouse neuroblastoma

Summary A density and velocity gradient centrifugation study of C₁₃₀₀ mouse neuroblastoma showed that ATP is nearly absent from noradrenaline-containing granules and is mainly localized in mitochondria, suggesting that in this tissue ATP is not involved in the storage of noradrenaline.This work was supported by a grant from the ASLK Cancer Fund (Belgium).     

Effect of colchicine on polymerization of tubulin from rats,mice, hamsters and guinea-pigs

Summary Colchicine-inhibition of polymerization of tubulin from rats, mice, golden hamsters and guinea-pigs was studied to determine if species differences in tubulin sensitivity to colchicine might parallel species variation in colchicine toxicity. It was found that polymerization of tubulin is nearly equally sensitive to colchicine in all four species.This work was supported by PHS Grant No. CA 16425.     

Molecular mechanisms of CRISPR-mediated microbial immunity

Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems.     

Paralysies révélatrices de la leucémie de Gross chez le rat

Summary Inoculation of Wistar CF rats with Gross virus induces in 86% of the animals a leukaemia which is associated, in nearly 50% of the cases, with a paralysis of the hind legs.This paralysis is due to the compression of the spinal cord by leukaemic cell infiltrates which develop in the lumbar area. No neurotropic virus has been found in these animals.     

Bias‐corrected bootstrap prediction regions for vector autoregression

This paper examines small sample properties of alternative bias‐corrected bootstrap prediction regions for the vector autoregressive (VAR) model. Bias‐corrected bootstrap prediction regions are constructed by combining bias‐correction of VAR parameter estimators with the bootstrap procedure. The backward VAR model is used to bootstrap VAR forecasts conditionally on past observations. Bootstrap prediction regions based on asymptotic bias‐correction are compared with those based on bootstrap bias‐correction. Monte Carlo simulation results indicate that bootstrap prediction regions based on asymptotic bias‐correction show better small sample properties than those based on bootstrap bias‐correction for nearly all cases considered. The former provide accurate coverage properties in most cases, while the latter over‐estimate the future uncertainty. Overall, the percentile‐t bootstrap prediction region based on asymptotic bias‐correction is found to provide highly desirable small sample properties, outperforming its alternatives in nearly all cases. Copyright © 2004 John Wiley & Sons, Ltd.     

Role of peripheral chemoreceptors in response to smoke-induced apnea vs tracheal occlusion

Summary Reflex autonomic changes which occur after cigarette smoke enters the upper airways are partially due to peripheral chemoreceptor stimulation. Chemoreceptor denervation attenuates but does not abolish smoke induced bradycardia. Denervation nearly abolishes bradycardia induced by tracheal occlusion. Hypertension accompanies smoke induced apnea but does not occur during tracheal occlusion.Acknowledgments. This study was supported by Oral Roberts University research funds.     

The plant nuclear envelope

This review summarizes our present knowledge about the composition and function of the plant nuclear envelope. Compared with animals or yeast, our molecular knowledge of the nuclear envelope in higher plants is in its infancy. However, there are fundamental differences between plants and animals in the structure and function of the nuclear envelope. This review will compare and contrast these differences for nuclear pore complexes, nuclear transport, inner nuclear envelope proteins and the role of the nuclear envelope during mitosis. In some cases, seemingly 'novel' aspects of plant nuclear envelope function may provide new insight into the animal cell nucleus.