A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD

Body iron metabolism and pathophysiology of iron overload

Iron is an essential metal for the body, while excess iron accumulation causes organ dysfunction through the production of reactive oxygen species. There is a sophisticated balance of body iron metabolism of storage and transport, which is regulated by several factors including the newly identified peptide hepcidin. As there is no passive excretory mechanism of iron, iron is easily accumulated when exogenous iron is loaded by hereditary factors, repeated transfusions, and other diseased conditions. The free irons, non-transferrin-bound iron, and labile plasma iron in the circulation, and the labile iron pool within the cells, are responsible for iron toxicity. The characteristic features of advanced iron overload are failure of vital organs such as liver and heart in addition to endocrine dysfunctions. For the estimation of body iron, there are direct and indirect methods available. Serum ferritin is the most convenient and widely available modality, even though its specificity is sometimes problematic. Recently, new physical detection methods using magnetic resonance imaging and superconducting quantum interference devices have become available to estimate iron concentration in liver and myocardium. The widely used application of iron chelators with high compliance will resolve the problems of organ dysfunction by excess iron and improve patient outcomes

Rise of the Earliest Tetrapods: An Early Devonian Origin from Marine Environment

Tetrapod fossil tracks are known from the Middle Devonian (Eifelian at ca. 397 million years ago - MYA), and their earliest bony remains from the Upper Devonian (Frasnian at 375–385 MYA). Tetrapods are now generally considered to have colonized land during the Carboniferous (i.e., after 359 MYA), which is considered to be one of the major events in the history of life. Our analysis on tetrapod evolution was performed using molecular data consisting of 13 proteins from 17 species and different paleontological data. The analysis on the molecular data was performed with the program TreeSAAP and the results were analyzed to see if they had implications on the paleontological data collected. The results have shown that tetrapods evolved from marine environments during times of higher oxygen levels. The change in environmental conditions played a major role in their evolution. According to our analysis this evolution occurred at about 397–416 MYA during the Early Devonian unlike previously thought. This idea is supported by various environmental factors such as sea levels and oxygen rate, and biotic factors such as biodiversity of arthropods and coral reefs. The molecular data also strongly supports lungfish as tetrapod's closest living relative

Is drinking water a risk factor for endemic cryptosporidiosis? A case-control study in the immunocompetent general population of the San Francisco Bay Area

BACKGROUND: Cryptosporidiosis, caused by Cryptosporidium, is an enteric illness that has received much attention as an infection of immunocompromised persons as well as in community outbreaks (frequently waterborne). There are, however, no studies of the risk factors for sporadic community-acquired cryptosporidiosis in the immunocompetent US population. We undertook a case-control study in the San Francisco Bay Area as part of a national study sponsored by the Centers for Disease Control and Prevention to ascertain the major routes of transmission for endemic cryptosporidiosis, with an emphasis on evaluating risk from drinking water. METHODS: Cases were recruited from a population-based, active surveillance system and age-matched controls were recruited using sequential random-digit dialing. Cases (n = 26) and controls (n = 62) were interviewed by telephone using a standardized questionnaire that included information about the following exposures: drinking water, recreational water, food items, travel, animal contact, and person-to-person fecal contact, and (for adults) sexual practices. RESULTS: In multivariate conditional logistic regression analyses no significant association with drinking water was detected. The major risk factor for cryptosporidiosis in the San Francisco Bay Area was travel to another country (matched odds ratio [95% confidence interval]: 24.1 [2.6, 220]). CONCLUSION: The results of this study do not support the hypothesis that drinking water is an independent risk factor for cryptosporidiosis among the immunocompetent population. These findings should be used to design larger studies of endemic cryptosporidiosis to elucidate the precise mechanisms of transmission, whether waterborne or other

Immunomodulation Targeting Abnormal Protein Conformation Reduces Pathology in a Mouse Model of Alzheimer's Disease

Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high β-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid β (sAβ) peptide is converted into highly toxic oligomeric Aβ and fibrillar Aβ that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAβ and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Aβ or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Aβ in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Aβ40/42 levels, as well as reduced Aβ oligomer levels. This type of immunomodulation has the potential to be a universal β-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases

Dopamine D4 Receptor Gene Associated with Fairness Preference in Ultimatum Game

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making

The human keratins: biology and pathology

The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family

Global energy governance : a review and research agenda

Over the past few years, global energy governance (GEG) has emerged as a major new field of enquiry in international studies. Scholars engaged in this field seek to understand how the energy sector is governed at the global level, by whom and with what consequences. By focusing on governance, they broaden and enrich the geopolitical and hard-nosed security perspectives that have long been, and still are, the dominant perspectives through which energy is analysed. Though still a nascent field, the literature on GEG is thriving and continues to attract the attention of a growing number of researchers. This article reviews the GEG literature as it has developed over the past 10 years. Our aim is to highlight both the progress and limitations of the field, and to identify some opportunities for future research. The article proceeds as follows. First, it traces the origins of the GEG literature (section “Origins and roots of GEG research”). The subsequent sections deal with the two topics that have received the most attention in the GEG literature: Why does energy need global governance (section “The goals and rationale of global energy governance”)? And, who governs energy (section “Mapping the global energy architecture”)? We then address a third question that has received far less attention: How well or poor is energy governed (section “Evaluating global energy governance”)? In our conclusions (section “Conclusions and outlook”), we reflect on the current state of GEG, review recent trends and innovations, and identify some questions that warrant future consideration by scholars. This article is published as part of a thematic collection on global governance

Studying neuroanatomy using MRI

The study of neuroanatomy using imaging enables key insights into how our brains function, are shaped by genes and environment, and change with development, aging, and disease. Developments in MRI acquisition, image processing, and data modelling have been key to these advances. However, MRI provides an indirect measurement of the biological signals we aim to investigate. Thus, artifacts and key questions of correct interpretation can confound the readouts provided by anatomical MRI. In this review we provide an overview of the methods for measuring macro- and mesoscopic structure and inferring microstructural properties; we also describe key artefacts and confounds that can lead to incorrect conclusions. Ultimately, we believe that, though methods need to improve and caution is required in its interpretation, structural MRI continues to have great promise in furthering our understanding of how the brain works