Human aneuploidy: mechanisms and new insights into an age-old problem

Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.     

Fibrocytes: Bringing new insights into mechanisms of inflammation and fibrosis

Regeneration and fibrosis are integral parts of the recovery process following tissue injury, and impaired regulation of these mechanisms is a hallmark of many chronic diseases. A population of bone marrow-derived mesenchymal progenitor cells known as fibrocytes, play an important role in tissue remodeling and fibrosis in both physiologic and pathologic settings. In this review we summarize the key concepts regarding the pathophysiology of wound healing and fibrosis, and present data to support the contention that circulating fibrocytes are important in both normal repair process and aberrant healing and fibrotic damage associated with a diverse set of disease states.     

The flagellated parasite Trichomonas vaginalis: new insights into cytopathogenicity mechanisms

Our knowledge concerning cytopathogenicity of Trichomonas vaginalis has been enriched in the past by numerous findings. In this paper, we review the latest advances in the field and discuss the different mechanisms and molecules responsible for the parasite's virulence.     

New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation

Epidemiological and clinical studies have found that at all ages women are twice as likely as men to form cholesterol gallstones, and this gender difference begins since puberty and continues through the childbearing years, which highlight the importance of female sex hormones. Estrogen is a crucial hormone in human physiology and regulates a multitude of biological processes. The actions of estrogen have traditionally been ascribed to two closely related classical nuclear hormone receptors, estrogen receptor 1 (ESR1) and ESR2. Recent studies have revealed that the increased risk for cholesterol gallstones in women vs. men is related to differences in how the liver metabolizes cholesterol in response to estrogen. A large number of human and animal studies have proposed that estrogen increases the risk of developing cholesterol gallstones by increasing the hepatic secretion of biliary cholesterol, which, in turn, leads to an increase in cholesterol saturation of bile. Furthermore, it has been identified that hepatic ESR1, but not ESR2, plays a major role in cholesterol gallstone formation in mice in response to high doses of 17β-estradiol. The mechanisms mediating estrogen's action have become more complicated with the recent identification of a novel estrogen receptor, G protein-coupled receptor 30 (GPR30), a member of the seven-transmembrane G protein-coupled receptor superfamily. In this review, we provide an overview of the evidence for the lithogenic actions of estrogen through ESR1 and discuss the cellular and physiological actions of GPR30 in estrogen-dependent processes and the relationship between GPR30 and classical ESR1 on gallstone formation.     

Crystal structure of a KSHV-SOX-DNA complex: insights into the molecular mechanisms underlying DNase activity and host shutoff

The early lytic phase of Kaposi's sarcoma herpesvirus infection is characterized by viral replication and the global degradation (shutoff) of host mRNA. Key to both activities is the virally encoded alkaline exonuclease KSHV SOX. While the DNase activity of KSHV SOX is required for the resolution of viral genomic DNA as a precursor to encapsidation, its exact involvement in host shutoff remains to be determined. We present the first crystal structure of a KSHV SOX-DNA complex that has illuminated the catalytic mechanism underpinning both its endo and exonuclease activities. We further illustrate that KSHV SOX, similar to its Epstein-Barr virus homologue, has an intrinsic RNase activity in vitro that although an element of host shutoff, cannot solely account for the phenomenon.     

Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications

Early models for the etiology of schizophrenia focused on dopamine neurotransmission because of the powerful anti-psychotic action of dopamine antagonists. Nevertheless, recent evidence increasingly supports a primarily glutamatergic dysfunction in this condition, where dopaminergic disbalance is a secondary effect. A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which the NMDA receptor (NMDAR) hypofunction leads to a dysregulation of GABA fast- spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing the signal-to-noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of anti-psychotics. Although the modulation of glutamate activity has, in principle, great therapeutic potential, a side effect of NMDAR overactivation is neurotoxicity, which accelerates neuropathological alterations in this illness. We propose that metabotropic glutamate receptors can have a modulatory effect over the NMDAR and regulate excitotoxity mechanisms. Therefore, in our view metabotropic glutamate receptors constitute a highly promising target for future drug treatment in this disease.     

Regulation of receptors and transporters by ubiquitination: new insights into surprisingly similar mechanisms

The function of many receptors and transport proteins that reside at the surface of the cell is regulated by endocytosis and postendocytic trafficking. Modification of receptors and transporters by ubiquitin conjugation has recently emerged as the major regulatory mechanism of internalization and intracellular sorting of these membrane proteins. This review will describe recent advances in elucidating the mechanisms of ubiquitination of mammalian receptors and transporters using two examples: the receptor for epidermal growth factor and the dopamine transporter. How ubiquitination controls the endocytosis and turnover of these proteins will be also discussed.     

Opening a can of centipedes: new insights into mechanisms of body segmentation

The search for a common developmental genetic mechanism of body segmentation appears to become more difficult, and more interesting, as new segmented organisms are added to the roster. Recent work in this journal by Brena and Akam on segmentation of the geophilomorph centipede Strigamia maritima, an arthropod distantly related to the standard insect models, contains developmental and evolutionary surprises that highlight the importance of a wider sampling of phyla.See research article: http://www.biomedcentral.com/1741-7007/11/112     

Redox-sensitive mechanisms underlying vascular dysfunction in heart failure

Abstract

Regardless of the progress in therapeutic drugs and devices to treat heart failure (HF) during the last few years, the clinical outcome of this disease remains deleterious. Impaired left ventricular function leads to neurohumoral activation, altered local shear forces, and hypoxia, which might give rise to inflammatory processes within the vasculature. Among those, the imbalance of the redox equilibrium toward increased concentrations of reactive oxygen species (ROS) is particularly important, as it affects the integrity of vascular function. Apart from injured or dysfunctional cardiomyocytes, vascular dysfunction has been demonstrated to play a crucial role in the development and progression of HF, which makes it an interesting target for new HF therapies. The mechanisms that initiate vascular dysfunction in HF pathogenesis and the processes leading to oxidative stress are not yet fully elucidated. However, oxidative stress promotes a variety of redox-sensitive mechanisms contributing to vascular dysfunction in HF. Here, we will summarize the sources of ROS in the vasculature, elucidate the impact of oxidative stress on functional and structural vascular remodeling, and consider the link to vascular dysfunction. Furthermore, we will point out the importance of vascular dysfunction in HF and discuss therapeutic options.     

Brain injury: New insights into neurotransmitter and receptor mechanisms

The studies reviewed here represent a continuing search for mechanisms which play a role in neurological disturbances resulting from brain injury. Focal cortical freezing lesions in rats were shown to cause a widespread decrease in local cerebral glucose utilization (LCGU) in cortical areas of the lesioned hemisphere and this was interpreted as reflecting a depression of cortical activity. Such an interpretation was supported by the finding that in lesioned brain reduction of cerebral metabolism by pentobarbital and isoflurane was limited by the metabolic depression that has already occurred as a result of injury and by the demonstration that the energy status and substrate (glucose) supply in the cortical areas in the injured brain have not been compromised at the time when LCGU was decreased. Both the serotonergic and the noradrenergic neurotransmitter systems were implicated in functional alterations associated with injury. Cortical serotonin (5-HT) metabolism was increased throughout the lesioned hemisphere and complete inhibition of 5-HT synthesis withp-chlorophenylalanine ameliorated the decrease in cortical LCGU, interpreted as reflecting cortical functional depression. Cortical norepinephrine metabolism was bilaterally increased in focally injured brain, while prazosin, a selective ₁-noradrenergic receptor blocker, normalized cortical LCGU in the lesioned hemisphere. Low-affinity in vivo binding of [¹²⁵I]HEAT, another selective ₁-receptor ligand, was specifically increased in cortical areas of the lesioned hemisphere at the time of the greatest depression in LCGU, suggesting that ₁-adrenoreceptors may be of functional importance in injured brain. The general conclusion from this series of studies on mechanisms underlying functional disturbances in injured brain is that both the serotonergic and the noradrenergic neurotransmitter systems are involved in the widespread cortical depression which develops with time as a consequence of a focal lesion. The data are compatible with the inhibitory effects of NE and 5-HT in the cortex and with the hypothesis that these two transmitter systems affect cortical information processing.     

Phosphoproteomics: new insights into cellular signaling

Developments in the field of phosphoproteomics have been fueled by the need simultaneously to monitor many different phosphoproteins within the signaling networks that coordinate responses to changes in the cellular environment. This article presents a brief review of phosphoproteomics with an emphasis on the biological insights that have been derived so far.     

Biochemical and structural insights into intramembrane metalloprotease mechanisms

Intramembrane metalloproteases are nearly ubiquitous in living organisms and they function in diverse processes ranging from cholesterol homeostasis and the unfolded protein response in humans to sporulation, stress responses, and virulence of bacteria. Understanding how these enzymes function in membranes is a challenge of fundamental interest with potential applications if modulators can be devised. Progress is described toward a mechanistic understanding, based primarily on molecular genetic and biochemical studies of human S2P and bacterial SpoIVFB and RseP, and on the structure of the membrane domain of an archaeal enzyme. Conserved features of the enzymes appear to include transmembrane helices and loops around the active site zinc ion, which may be near the membrane surface. Extramembrane domains such as PDZ (PSD-95, DLG, ZO-1) or CBS (cystathionine-β-synthase) domains govern substrate access to the active site, but several different mechanisms of access and cleavage site selection can be envisioned, which might differ depending on the substrate and the enzyme. More work is needed to distinguish between these mechanisms, both for enzymes that have been relatively well-studied, and for enzymes lacking PDZ and CBS domains, which have not been studied. This article is part of a Special Issue entitled: Intramembrane Proteases.