Project description:Nicotinamide mononucleotide adenylyl transferases (NMNATs) are a family of highly conserved proteins indispensable for cellular homeostasis. NMNATs are classically known for their enzymatic function of catalyzing NAD+ synthesis, but also have gained a reputation as essential neuronal maintenance factors. NMNAT deficiency has been associated with various human diseases with pronounced consequences on neural tissues, underscoring the importance of the neuronal maintenance and protective roles of these proteins. New mechanistic studies have challenged the role of NMNAT-catalyzed NAD+ production in delaying Wallerian degeneration and have specified new mechanisms of NMNAT's chaperone function critical for neuronal health. Progress in understanding the regulation of NMNAT has uncovered a neuronal stress response with great therapeutic promise for treating various neurodegenerative conditions.
Project description:Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of immunocompromised patients and hence vulnerable hosts increases, which is paralleled by the emergence of a rise in IA cases. Increased frequencies of azole-resistant strains are reported from six continents, presenting a new challenge for the therapeutic management. Treatment options for IA currently consist of three classes of antifungals (azoles, polyenes, echinocandins) with distinctive advantages and shortcomings. Especially in settings of difficult to treat IA, comprising drug tolerance/resistance, limiting drug-drug interactions, and/or severe underlying organ dysfunction, novel approaches are urgently needed. Promising new drugs for the treatment of IA are in late-stage clinical development, including olorofim (a dihydroorotate dehydrogenase inhibitor), fosmanogepix (a Gwt1 enzyme inhibitor), ibrexafungerp (a triterpenoid), opelconazole (an azole optimized for inhalation) and rezafungin (an echinocandin with long half-life time). Further, new insights in the pathophysiology of IA yielding immunotherapy as a potential add-on therapy. Current investigations show encouraging results, so far mostly in preclinical settings. In this review we discuss current treatment strategies, give an outlook on possible new pharmaceutical therapeutic options, and, lastly, provide an overview of the ongoing research in immunotherapy for IA.
Project description:ObjectiveTo compare cognitive testing scores in neurosurgeons and aerospace engineers to help settle the age old argument of which phrase-"It's not brain surgery" or "It's not rocket science"-is most deserved.DesignInternational prospective comparative study.SettingUnited Kingdom, Europe, the United States, and Canada.Participants748 people (600 aerospace engineers and 148 neurosurgeons). After data cleaning, 401 complete datasets were included in the final analysis (329 aerospace engineers and 72 neurosurgeons).Main outcome measuresValidated online test (Cognitron's Great British Intelligence Test) measuring distinct aspects of cognition, spanning planning and reasoning, working memory, attention, and emotion processing abilities.ResultsThe neurosurgeons showed significantly higher scores than the aerospace engineers in semantic problem solving (difference 0.33, 95% confidence interval 0.13 to 0.52). Aerospace engineers showed significantly higher scores in mental manipulation and attention (-0.29, -0.48 to -0.09). No difference was found between groups in domain scores for memory (-0.18, -0.40 to 0.03), spatial problem solving (-0.19, -0.39 to 0.01), problem solving speed (0.03, -0.20 to 0.25), and memory recall speed (0.12, -0.10 to 0.35). When each group's scores for the six domains were compared with those in the general population, only two differences were significant: the neurosurgeons' problem solving speed was quicker (mean z score 0.24, 95% confidence interval 0.07 to 0.41) and their memory recall speed was slower (-0.19, -0.34 to -0.04).ConclusionsIn situations that do not require rapid problem solving, it might be more correct to use the phrase "It's not brain surgery." It is possible that both neurosurgeons and aerospace engineers are unnecessarily placed on a pedestal and that "It's a walk in the park" or another phrase unrelated to careers might be more appropriate. Other specialties might deserve to be on that pedestal, and future work should aim to determine the most deserving profession.
Project description:Interferon-stimulated gene product 15 (ISG15) is a key component of host responses to microbial infection. Despite having been known for four decades, grasping the functions and features of ISG15 has been a slow and elusive process. Substantial work over the past two decades has greatly enhanced this understanding, revealing the complex and variable nature of this protein. This has unveiled multiple mechanisms of action that are only now beginning to be understood. In addition, it has uncovered diversity not only between how ISG15 affects different pathogens but also between the function and structure of ISG15 itself between different host species. Here we review the complexity of ISG15 within the context of viral infection, focusing primarily on its antiviral function and the mechanisms viruses employ to thwart its effects. We highlight what is known regarding the impact of ISG15 sequence and structural diversity on these interactions and discuss the aspects presenting the next frontier toward elucidating a more complete picture of ISG15 function.
Project description:Housekeeping genes are expressed across a wide variety of tissues. Since repetitive sequences have been reported to influence the expression of individual genes, we employed a novel approach to determine whether housekeeping genes can be distinguished from tissue-specific genes by their repetitive sequence context. We show that Alu elements are more highly concentrated around housekeeping genes while various longer (>400-bp) repetitive sequences ("repeats"), including Long Interspersed Nuclear Element-1 (LINE-1) elements, are excluded from these regions. We further show that isochore membership does not distinguish housekeeping genes from tissue-specific genes and that repetitive sequence environment distinguishes housekeeping genes from tissue-specific genes in every isochore. The distinct repetitive sequence environment, in combination with other previously published sequence properties of housekeeping genes, was used to develop a method of predicting housekeeping genes on the basis of DNA sequence alone. Using expression across tissue types as a measure of success, we demonstrate that repetitive sequence environment is by far the most important sequence feature identified to date for distinguishing housekeeping genes.
Project description:Effect of mutagenesis of a sigma 54-dependent transcriptional regulator encoding gene vasH (ECA3425) to global gene expression in P. atrosepticum SCRI1043 in planta mimicking conditions.
Project description:At the beginning of the COVID-19 pandemic, governments around the world employed militaristic metaphors to draw attention to the dangers of the virus. But, do militaristic metaphors truly affect individuals' perceived threat of the COVID-19 virus and increase their support for corresponding restrictive policies? This study assessed the effects of fictitious newspaper articles that described COVID-19 policies using similarly negatively valenced metaphors but with differing militaristic connotations (e.g., "war" vs. "struggle"). Overall, data from three framing experiments (N = 1114) in Germany and the United States indicate limited evidence on the effectiveness of the tested militaristic metaphors. In the U.S. context, the non-militaristic concept of struggle was consistently more strongly associated with the desired outcomes than militaristic metaphors were. In Studies 2 and 3, we also tested whether reporting using a narrative or straightforward facts had additional influence on the framing effect. A congruency effect of the use of a narrative and of warfare metaphors was found in the German sample, but not in that of the United States. Results of post-experimental norming studies (N = 437) in both countries revealed that the metaphor of war is associated with people ascribing greater responsibility to their governments, whereas the concept of struggle triggers a sense of individual responsibility. These results are discussed in terms of the usefulness and appropriateness of militaristic metaphors in the context of a pandemic.
Project description:Emerging data suggest intraventricular hemorrhage (IVH) of the preterm neonate is a complex disorder with contributions from both the environment and the genome. Environmental analyses suggest factors mediating both cerebral blood flow and angiogenesis contribute to IVH, while candidate gene studies report variants in angiogenesis, inflammation, and vascular pathways. Gene-by-environment interactions demonstrate the interaction between the environment and the genome, and a non-replicated genome-wide association study suggests that both environmental and genetic factors contribute to the risk for severe IVH in very low-birth weight preterm neonates.
Project description:The information available about breast cancer risk factors has increased dramatically during the last 10 years. In particular, studies of low-penetrance genes and mammographic density have improved our understanding of breast cancer risk. In addition, initial steps have been taken in investigating interactions between genes and environmental factors. This review concerns with actual data on this topic. Several genome-wide association studies (GWASs) with a case-control design, as well as large-scale validation studies, have identified and validated more than a dozen single nucleotide polymorphisms (SNPs) associated with breast cancer risk. They are located not only in or close to genes known to be involved in cancer pathogenesis, but also in genes not previously associated with breast cancer pathogenesis, or may even not be related to any genes. SNPs have also been identified that alter the lifetime risk in BRCA mutation carriers. With regard to nongenetic risk factors, studies of postmenopausal hormone replacement therapy (HRT) have revealed important information on how to weigh up the risks and benefits of HRT. Mammographic density (MD) has become an accepted and important breast cancer risk factor. Lifestyle and nutritional considerations have become an integral part of most studies of breast cancer risk, and some improvements have been made in this field as well. More than 10 years after the publication of the first breast cancer prevention studies with tamoxifen, other substances such as raloxifene and aromatase inhibitors have been investigated and have also been shown to have preventive potential. Finally, mammographic screening systems have been implemented in most Western countries during the last decade. These may be developed further by including more individualized methods of predicting the patient's breast cancer risk.
Project description:Tobacco use remains the leading cause of preventable death in the US, emphasizing the need to understand which genes and environments are involved in the establishment of cigarette use behaviors. However, to date, no comprehensive review of the influence of genes, the environment, and their interaction on cigarette use exists. This narrative review provides a description of gene variants and environmental factors associated with cigarette use, as well as an overview of studies investigating gene-environment interaction (GxE) in cigarette use. GxE studies of cigarette use have been useful in demonstrating that the influence of genes changes as a function of both the phenotype being measured and the environment. However, it is difficult to determine how the effect of genes contributing to different phenotypes of cigarette use changes as a function of the environment. This suggests the need for more studies of GxE, to parse out the effects of genes and the environment across the development of cigarette use phenotypes, which may help to inform potential prevention and intervention efforts aimed at reducing the prevalence of cigarette use. Key Messages No comprehensive reviews of the influence of genes, the environment, and their interaction on cigarette use exist currently. The influence of genes may change as a function of the environment and the phenotype being measured. It is difficult to determine how the effect of genes contributing to different phenotypes of cigarette use changes according to environmental context, suggesting the need for more studies of gene-environment interaction related to cigarette use to parse out effects.