Foot-and-mouth disease virus 3C protease: recent structural and functional insights into an antiviral target

The 3C protease from foot-and-mouth disease virus (FMDV 3C(pro)) is critical for viral pathogenesis, having vital roles in both the processing of the polyprotein precursor and RNA replication. Although recent structural and functional studies have revealed new insights into the mechanism and function of the enzyme, key questions remain that must be addressed before the potential of FMDV 3C(pro) as an antiviral drug target can be realised.     

Lymphatic filariasis: new insights into an old disease

Lymphatic filariasis has afflicted people in the tropical areas of the world for thousands of years but even up to comparatively recent times it has been poorly understood and its importance under recognised. In the last 2 decades or so there has been a flurry of activity in filariasis research, which has provided new insights into the global problem of filariasis, the pathogenesis of filarial disease, diagnosis and control.     

New insights into ancient seasonal life timers

Organisms must adapt to seasonal changes in the environment and time their physiology accordingly. In vertebrates, the annual change in photoperiod is often critical for entraining the neuroendocrine pathways, which drive seasonal metabolic and reproductive cycles. These cycles depend on thyroid hormone (TH), reflecting its ancestral role in metabolic control. Recent studies reveal that - in mammals and birds - TH effects are mediated by the hypothalamus. Photoperiodic manipulations alter hypothalamic TH availability by regulating the expression of TH deiodinases (DIO). In non-mammalian vertebrates, light acts through extraretinal, 'deep brain' photoreceptors, and the eyes are not involved in seasonal photoperiodic responses. In mammals, extraretinal photoreceptors have been lost, and the nocturnal melatonin signal generated from the pineal gland has been co-opted to provide the photoperiodic message. Pineal function is phased to the light-dark cycle by retinal input, and photoperiodic changes in melatonin secretion control neuroendocrine pathway function. New evidence indicates that these comparatively divergent photosensensory mechanisms re-converge in the pars tuberalis of the pituitary, lying beneath the hypothalamus. In all vertebrates studied, the pars tuberalis secretes thyrotrophin in a light- or melatonin-sensitive manner, to act on neighbouring hypothalamic DIO expressing cells. Hence, an ancient and fundamentally conserved brain thyroid signalling system governs seasonal biology in vertebrates.     

Triosephosphate isomerase deficiency: New insights into an enigmatic disease

The triosephosphate isomerase (TPI) functions at a metabolic cross-road ensuring the rapid equilibration of the triosephosphates produced by aldolase in glycolysis, which is interconnected to lipid metabolism, to glycerol-3-phosphate shuttle and to the pentose phosphate pathway. The enzyme is a stable homodimer, which is catalytically active only in its dimeric form. TPI deficiency is an autosomal recessive multisystem genetic disease coupled with hemolytic anemia and neurological disorder frequently leading to death in early childhood. Various genetic mutations of this enzyme have been identified; the mutations result in decrease in the catalytic activity and/or the dissociation of the dimers into inactive monomers. The impairment of TPI activity apparently does not affect the energy metabolism at system level; however, it results in accumulation of dihydroxyacetone phosphate followed by its chemical conversion into the toxic methylglyoxal, leading to the formation of advanced glycation end products. By now, the research on this disease seems to enter a progressive stage by adapting new model systems such as Drosophila, yeast strains and TPI-deficient mouse, which have complemented the results obtained by prediction and experiments with recombinant proteins or erythrocytes, and added novel data concerning the complexity of the intracellular behavior of mutant TPIs. This paper reviews the recent studies on the structural and catalytic changes caused by mutation and/or nitrotyrosination of the isomerase leading to the formation of an aggregation-prone protein, a characteristic of conformational disorders.     

Orofacial clefting: recent insights into a complex trait

Orofacial clefts are common birth defects of multifactorial etiology. Several novel approaches have recently been applied to investigate the causes of clefts. These include examining Mendelian forms of clefting to identify genes that might also be implicated in isolated clefting, analyzing chromosomal rearrangements in which clefting is part of the resultant phenotype, studying animal models in which clefts arise either spontaneously or as a result of mutagenesis experiments, exploring how expression patterns correlate with gene function and examining the effects of gene-environment interactions. Together, these complementary strategies are providing researchers with new clues as to what mechanisms underlie orofacial clefting.     

Rift valley fever: recent insights into pathogenesis and prevention

Rift Valley fever virus (RVFV) is a zoonotic pathogen that primarily affects ruminants but can also be lethal in humans. A negative-stranded RNA virus of the family Bunyaviridae, this pathogen is transmitted mainly via mosquito vectors. RVFV has shown the ability to inflict significant damage to livestock and is also a threat to public health. While outbreaks have traditionally occurred in sub-Saharan Africa, recent outbreaks in the Middle East have raised awareness of the potential of this virus to spread to Europe, Asia, and the Americas. Although the virus was initially characterized almost 80 years ago, the only vaccine approved for widespread veterinary use is an attenuated strain that has been associated with significant pathogenic side effects. However, increased understanding of the molecular biology of the virus over the last few years has led to recent advances in vaccine design and has enabled the development of more-potent prophylactic measures to combat infection. In this review, we discuss several aspects of RVFV, with particular emphasis on the molecular components of the virus and their respective roles in pathogenesis and an overview of current vaccine candidates. Progress in understanding the epidemiology of Rift Valley fever has also enabled prediction of potential outbreaks well in advance, thus providing another tool to combat the physical and economic impact of this disease.     

Plant disease resistance genes: recent insights and potential applications

Plant disease resistance genes (R genes) encode proteins that detect pathogens. R genes have been used in resistance breeding programs for decades, with varying degrees of success. Recent molecular research on R proteins and downstream signal transduction networks has provided exciting insights, which will enhance the use of R genes for disease control. Definition of conserved structural motifs in R proteins has facilitated the cloning of useful R genes, including several that are functional in multiple crop species and/or provide resistance to a relatively wide range of pathogens. Numerous signal transduction components in the defense network have been defined, and several are being exploited as switches by which resistance can be activated against diverse pathogens.     

Babesiosis in Italy: an overview

Babesiosis is a tick-transmitted disease caused by hematotropic parasites of the genus Babesia. Tick-borne diseases (TBD) have increasingly been recognized in the world as public health problems. The piroplasms are transmitted by ticks and are able to infect a wide variety of vertebrate hosts which are competent in maintaining the transmission cycle. Babesiosis occurrence is usually linked to seasonal variations that affect the vector, but climatic changes have not been common in the subtropical regions of Italy, especially during the last few years. This paper is aimed at compiling information about babesiosis in Italy both from the available literature and from the records of our Centre. Recent biotechnological approaches have aid to the detection of parasites and the monitoring of tick vectors. Moreover, our research has lately been focused on the investigation of the presence of Babesia parasites in wild animals, yielding very interesting results.     

Actin in striated muscle: recent insights into assembly and maintenance

Striated muscle cells are characterised by a para-crystalline arrangement of their contractile proteins actin and myosin in sarcomeres, the basic unit of the myofibrils. A multitude of proteins is required to build and maintain the structure of this regular arrangement as well as to ensure regulation of contraction and to respond to alterations in demand. This review focuses on the actin filaments (also called thin filaments) of the sarcomere and will discuss how they are assembled during myofibrillogenesis and in hypertrophy and how their integrity is maintained in the working myocardium.     

Opening up the communication channels: recent insights into plasmodesmal function

The past year has seen significant advances in our understanding of the function and regulation of plasmodesmata. Notably, we have learned that plasmodesmata undergo dynamic changes during development and may participate in long-range communication through the transmission of RNA signals. Biochemical studies have enriched our understanding of a putative plasmodesmal receptor and of plant factors involved in viral cell-to-cell movement.     

New insights into an ancient insect nose: the olfactory pathway of Lepismachilis y-signata (Archaeognatha: Machilidae)

Hexapods most likely derived from an aquatic ancestor, which they shared with crustaceans. During the transition from water to land, their sensory systems had to face the new physiological demands that terrestrial conditions impose. This process also concerns the sense of smell and, more specifically, detection of volatile, air-borne chemicals. In insects, olfaction plays an important role in orientation, mating choice, and food and host finding behavior. The first integration center of odor information in the insect brain is the antennal lobe, which is targeted by the afferents from olfactory sensory neurons on the antennae. Within the antennal lobe of most pterygote insects, spherical substructures called olfactory glomeruli are present. In order to gain insights into the evolution of the structure of the central olfactory pathway in insects, we analyzed a representative of the wingless Archaeognatha or jumping bristletails, using immunocytochemistry, antennal backfills and histological section series combined with 3D reconstruction. In the deutocerebrum of Lepismachilis y-signata, we found three different neuropil regions. Two of them show a glomerular organization, but these glomeruli differ in their shape from those in all other insect groups. The connection of the glomerular neuropils to higher brain centers remains unclear and mushroom bodies are absent as reported from other archaeognathan species. We discuss the evolutionary implications of these findings.     

An evolutionarily ancient Oatp: insights into conserved functional domains of these proteins

Cellular uptake of organic solutes is mediated in large part by a gene family of membrane transporters called OATPs (SLC21A). To study the structural determinants and evolutionary development of the SLC21A family, we have cloned and functionally characterized a highly expressed evolutionarily primitive Oatp from the liver of the small skate, Raja erinacea. A full-length cDNA (2.3 kb) was obtained that encodes a protein of 689 amino acids. The characteristics of this novel skate Oatp, including tissue expression, subcellular localization, substrate selectivity, Na(+) dependence, and inhibitor selectivity were generally similar to liver-specific human OATP-C and rat Oatp4. However, sequence comparisons with other OATPs indicate that this skate Oatp shares only approximately 40-50% amino acid identity with the liver-specific OATPs/Oatps and with human OATP-F. Further computer analysis revealed that the highest amino acid identities reside in the first external (78%) and internal loops (75%) and transmembrane domains 2 (76%), 3 (62%), 4 (70%), and 11 (64%). We propose that the conserved regions of the SLC21A transporter family may be critical structural determinants of substrate specificity and function.