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Chinese Journal of Cancer Jan 2013Persistent infection with high-risk types of human papillomavirus(HPV) is known to cause cervical cancer; however, additional genetic and epigenetic alterations are... (Review)
Review
Persistent infection with high-risk types of human papillomavirus(HPV) is known to cause cervical cancer; however, additional genetic and epigenetic alterations are required for progression from precancerous disease to invasive cancer. DNA methylation is an early and frequent molecular alteration in cervical carcinogenesis. In this review, we summarize DNA methylation within the HPV genome and human genome and identify its clinical implications. Methylation of the HPV long control region (LCR) and L1 gene is common during cervical carcinogenesis and increases with the severity of the cervical neoplasm. The L1 gene of HPV16 and HPV18 is consistently hypermethylated in invasive cervical cancers and can potentially be used as a clinical marker of cancer progression. Moreover, promoters of tumor suppressor genes (TSGs) involved in many cellular pathways are methylated in cervical precursors and invasive cancers. Some are associated with squamous cell carcinomas, and others are associated with adenocarcinomas. Identification of methylated TSGs in Pap smear could be an adjuvant test in cervical cancer screening for triage of women with high-risk HPV, atypical squamous cells of undetermined significance, or low grade squamous intraepithelial lesion (LSIL). However, consistent panels must be validated for this approach to be translated to the clinic. Furthermore, reversion of methylated TSGs using demethylating drugs may be an alternative anticancer treatment, but demethylating drugs without toxic carcinogenic and mutagenic properties must be identified and validated.
Topics: Apoptosis; Biomarkers, Tumor; Cell Adhesion; Cell Cycle; CpG Islands; DNA Methylation; Female; Genes, Tumor Suppressor; Genome, Viral; Humans; Papillomaviridae; Promoter Regions, Genetic; Signal Transduction; Uterine Cervical Neoplasms
PubMed: 22943599
DOI: 10.5732/cjc.012.10033 -
Journal of Cachexia, Sarcopenia and... Oct 2023The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron...
BACKGROUND
The functional deterioration and loss of motor neurons are tightly associated with degenerative motor neuron diseases and aging-related muscle wasting. Motor neuron diseases or aging-related muscle wasting in turn contribute to increased risk of adverse health outcomes in the elderly. Cdon (cell adhesion molecule-downregulated oncogene) belongs to the immunoglobulin superfamily of cell adhesion molecule and plays essential roles in multiple signalling pathways, including sonic hedgehog (Shh), netrin, and cadherin-mediated signalling. Cdon as a Shh coreceptor plays a critical role in motor neuron specification during embryonic development. However, its role in adult motor neuron function is unknown.
METHODS
Hb9-Cre recombinase-driven motor neuron-specific Cdon deficient mice (mnKO) and a compound mutant mice (mnKO::SOD1 ) were generated to investigate the role of Cdon in motor neuron degeneration. Motor neuron regeneration was examined by using a sciatic nerve crush injury model. To investigate the phenotype, physical activity, compound muscle action potential, immunostaining, and transmission electron microscopy were carried out. In the mechanism study, RNA sequencing and RNA/protein analyses were employed.
RESULTS
Mice lacking Cdon in motor neurons exhibited middle age onset lethality and aging-related decline in motor function. In the sciatic nerve crush injury model, mnKO mice exhibited an impairment in motor function recovery evident by prolonged compound muscle action potential duration (4.63 ± 0.35 vs. 3.93 ± 0.22 s for f/f, P < 0.01) and physical activity. Consistently, neuromuscular junctions of mnKO muscles were incompletely occupied (49.79 ± 5.74 vs. 79.39 ± 3.77% fully occupied neuromuscular junctions for f/f, P < 0.0001), suggesting an impaired reinnervation. The transmission electron microscopy analysis revealed that mnKO sciatic nerves had smaller axon diameter (0.88 ± 0.13 vs. 1.43 ± 0.48 μm for f/f, P < 0.0001) and myelination defects. RNA sequencing of mnKO lumbar spinal cords showed alteration in genes related to neurogenesis, inflammation and cell death. Among the altered genes, ErbB4 and FgfR expressions were significantly altered in mnKO as well as in Cdon-depleted NSC34 motor neuron cells. Consistently, Cdon-depleted NSC34 cells exhibited elevated levels of cleaved Caspase3 and γH2AX proteins, as well as Bax transcription. Cdon-depleted NSC34 cells also exhibited impaired activation of Akt in response to neuregulin-1 (NRG1) treatment.
CONCLUSIONS
Our current data demonstrate the functional importance of Cdon in motor neuron function and nerve repair. Cdon ablation causes alterations in neurotrophin signalling that leads to motor neuron degeneration.
PubMed: 37559423
DOI: 10.1002/jcsm.13308 -
Clinical Science (London, England :... Mar 2018Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease... (Review)
Review
Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (ME/CFS) is a disabling and debilitating disease of unknown aetiology. It is a heterogeneous disease characterized by various inflammatory, immune, viral, neurological and endocrine symptoms. Several microbiome studies have described alterations in the bacterial component of the microbiome (dysbiosis) consistent with a possible role in disease development. However, in focusing on the bacterial components of the microbiome, these studies have neglected the viral constituent known as the virome. Viruses, particularly those infecting bacteria (bacteriophages), have the potential to alter the function and structure of the microbiome via gene transfer and host lysis. Viral-induced microbiome changes can directly and indirectly influence host health and disease. The contribution of viruses towards disease pathogenesis is therefore an important area for research in ME/CFS. Recent advancements in sequencing technology and bioinformatics now allow more comprehensive and inclusive investigations of human microbiomes. However, as the number of microbiome studies increases, the need for greater consistency in study design and analysis also increases. Comparisons between different ME/CFS microbiome studies are difficult because of differences in patient selection and diagnosis criteria, sample processing, genome sequencing and downstream bioinformatics analysis. It is therefore important that microbiome studies adopt robust, reproducible and consistent study design to enable more reliable and valid comparisons and conclusions to be made between studies. This article provides a comprehensive review of the current evidence supporting microbiome alterations in ME/CFS patients. Additionally, the pitfalls and challenges associated with microbiome studies are discussed.
Topics: Bacteria; Bacteriophages; Dysbiosis; Fatigue Syndrome, Chronic; Gastrointestinal Microbiome; Host Microbial Interactions; Humans; Inflammation; Models, Biological
PubMed: 29523751
DOI: 10.1042/CS20171330 -
BioRxiv : the Preprint Server For... Jun 2023Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations...
UNLABELLED
Protein synthesis is a fundamental cellular process in neurons that is essential for synaptic plasticity and memory consolidation. Here, we describe our investigations of a neuron- and muscle-specific translation factor, e ukaryotic E longation F actor 1a2 (eEF1A2), which when mutated in patients results in autism, epilepsy, and intellectual disability. We characterize three most common patient mutations, G70S, E122K, and D252H, and demonstrate that all three mutations decrease protein synthesis and elongation rates in HEK293 cells. In mouse cortical neurons, the mutations not only decrease protein synthesis, but also alter neuronal morphology, regardless of endogenous levels of eEF1A2, indicating that the mutations act via a toxic gain of function. We also show that eEF1A2 mutant proteins display increased tRNA binding and decreased actin bundling activity, suggesting that these mutations disrupt neuronal function by decreasing tRNA availability and altering the actin cytoskeleton. More broadly, our findings are consistent with the idea that eEF1A2 acts as a bridge between translation and the actin skeleton, which is essential for proper neuron development and function.
SIGNIFICANCE STATEMENT
E ukaryotic E longation F actor 1A2 (eEF1A2) is a muscle- and neuron-specific translation factor responsible for bringing charge tRNAs to the elongating ribosome. Why neurons express this unique translation factor is unclear; however, it is known that mutations in cause severe drug-resistant epilepsy, autism and neurodevelopmental delay. Here, we characterize the impact of three common disease-causing mutations in and demonstrate that they cause decreased protein synthesis via reduced translation elongation, increased tRNA binding, decreased actin bundling activity, as well as altered neuronal morphology. We posit that eEF1A2 serves as a bridge between translation and the actin cytoskeleton, linking these two processes that are essential for neuronal function and plasticity.
PubMed: 37333416
DOI: 10.1101/2023.06.06.543912 -
Aging Pathobiology and Therapeutics Mar 2021Genetic variation does not entirely address the consistent divergence of healthy and unhealthy aging in heterogeneous and homogeneous mammalian populations. The...
Genetic variation does not entirely address the consistent divergence of healthy and unhealthy aging in heterogeneous and homogeneous mammalian populations. The alteration of gene function through modification of histone DNA infrastructure is a logical extending explanation for this divergence. Since epigenetic alterations are reversible, therapeutic interventions that target the right gene or gene products could reverse aging, at the very least in the population of older people with poor health.
PubMed: 35083451
DOI: 10.31491/apt.2021.03.048 -
Frontiers in Neuroscience 2014In this article we present a review of current literature on adaptations to altered head-related auditory localization cues. Localization cues can be altered through ear... (Review)
Review
In this article we present a review of current literature on adaptations to altered head-related auditory localization cues. Localization cues can be altered through ear blocks, ear molds, electronic hearing devices, and altered head-related transfer functions (HRTFs). Three main methods have been used to induce auditory space adaptation: sound exposure, training with feedback, and explicit training. Adaptations induced by training, rather than exposure, are consistently faster. Studies on localization with altered head-related cues have reported poor initial localization, but improved accuracy and discriminability with training. Also, studies that displaced the auditory space by altering cue values reported adaptations in perceived source position to compensate for such displacements. Auditory space adaptations can last for a few months even without further contact with the learned cues. In most studies, localization with the subject's own unaltered cues remained intact despite the adaptation to a second set of cues. Generalization is observed from trained to untrained sound source positions, but there is mixed evidence regarding cross-frequency generalization. Multiple brain areas might be involved in auditory space adaptation processes, but the auditory cortex (AC) may play a critical role. Auditory space plasticity may involve context-dependent cue reweighting.
PubMed: 25120422
DOI: 10.3389/fnins.2014.00219 -
Clinical and Experimental... 2015Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and abnormal bowel patterns. Alteration in gut... (Review)
Review
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by recurrent abdominal pain and abnormal bowel patterns. Alteration in gut flora, visceral hypersensitivity, and abnormal bowel motility are among numerous factors in the complex pathophysiology of IBS. Antibiotics have been used adjunctively to treat IBS for many years but are associated with various systemic side effects. Rifaximin is a nonabsorbable, broad-spectrum antimicrobial that inhibits bacterial RNA synthesis by binding the β-subunit of microbial RNA polymerase. It targets the gastrointestinal tract and works by reducing the quantity of gas-producing bacteria and altering the predominant species of bacteria present. In vivo animal studies suggest additional beneficial mechanisms of rifaximin, including reducing mucosal inflammation and visceral hypersensitivity. Clinical studies have demonstrated that rifaximin improves symptoms associated with IBS, such as bloating, flatulence, stool consistency, and abdominal pain, and has a side-effect profile similar to placebo. Although additional investigation into optimal dosing, treatment duration, and potential resistance is required, rifaximin presents as a safe and beneficial addition to the current management options for IBS.
PubMed: 26089696
DOI: 10.2147/CEG.S67231 -
The Mental Health Clinician Nov 2016Schizophrenia is a severe disorder affecting approximately 1% of the population. Historically, alterations of dopaminergic function were considered the primary cause of...
Schizophrenia is a severe disorder affecting approximately 1% of the population. Historically, alterations of dopaminergic function were considered the primary cause of schizophrenia. However, for many patients, drugs that alter dopaminergic function do not consistently lead to resolution of the symptoms of schizophrenia. Thus, there is an increased interest in pathophysiologic processes that result in altered neurodevelopment and plasticity associated with schizophrenia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis, synaptic plasticity, cognition, and neurotransmission. Genetic polymorphism, expression, and function of BDNF have been implicated in psychiatric diseases, including schizophrenia. This review discusses BDNF, its role in neurologic processes, and the evidence implicating BDNF in schizophrenia.
PubMed: 29955483
DOI: 10.9740/mhc.2016.11.285 -
The Science of the Total Environment Feb 2023Anthropogenic stressors on the environment are increasing at unprecedented rates and include urbanization, nutrient pollution, water management, altered land use and...
Anthropogenic stressors on the environment are increasing at unprecedented rates and include urbanization, nutrient pollution, water management, altered land use and climate change. Their effects on disease vectors are poorly understood. A series of full factorial experiments investigated how key human induced abiotic pressures, and interactions between these, affect population parameters of the cosmopolitan disease vector, Culex pipiens s.l. Selected pressures include eutrophication, salinity, mean temperature, and temperature fluctuation. Data were collected for each individual pressure and for potential interactions between eutrophication, salinization and temperature. All experiments assessed survival, time to pupation, time to emergence, sex-ratio and ovipositioning behavior. The results show that stressors affect vector survival, may speed up development and alter female to male ratio, although large differences between stressors exist to quite different extents. While positive effects of increasing levels of eutrophication on survival were consistent, negative effects of salinity on survival were only apparent at higher temperatures, thus indicating a strong interaction effect between salinization and temperature. Temperature had no independent effect on larval survival. Overall, increasing eutrophication and temperatures, and the fluctuations thereof, lowered development rate, time to pupation and time to emergence while increasing levels of salinity increased development time. Higher levels of eutrophication positively impacted egg-laying behavior; the reverse was found for salinity while no effects of temperature on egg-laying behavior were observed. Results suggest large and positive impacts of anthropogenically induced habitat alterations on mosquito population dynamics. Many of these effects are exacerbated by increasing temperatures and fluctuations therein. In a world where eutrophication and salinization are increasingly abundant, mosquitoes are likely important benefactors. Ultimately, this study illustrates the importance of including multiple and combined stressors in predictive models as well as in prevention and mitigation strategies, particularly because they resonate with possible, but yet underdeveloped action plans.
Topics: Animals; Male; Female; Humans; Culicidae; Mosquito Vectors; Culex; Eutrophication; Larva; Temperature
PubMed: 36302419
DOI: 10.1016/j.scitotenv.2022.159716 -
Ecology and Evolution Dec 2021Trait and functional trait approaches have revolutionized ecology improving our understanding of community assembly, species coexistence, and biodiversity loss. Focusing... (Review)
Review
Trait and functional trait approaches have revolutionized ecology improving our understanding of community assembly, species coexistence, and biodiversity loss. Focusing on traits promotes comparability across spatial and organizational scales, but terms must be used consistently. While several papers have offered definitions, it remains unclear how ecologists operationalize "trait" and "functional trait" terms. Here, we evaluate how researchers and the published literatures use these terms and explore differences among subdisciplines and study systems (taxa and biome). By conducting both a survey and a literature review, we test the hypothesis that ecologists' working definition of "trait" is adapted or altered when confronting the realities of collecting, analyzing and presenting data. From 486 survey responses and 712 reviewed papers, we identified inconsistencies in the understanding and use of terminology among researchers, but also limited inclusion of definitions within the published literature. Discrepancies were not explained by subdiscipline, system of study, or respondent characteristics, suggesting there could be an inconsistent understanding even among those working in related topics. Consistencies among survey responses included the use of morphological, phonological, and physiological traits. Previous studies have called for unification of terminology; yet, our study shows that proposed definitions are not consistently used or accepted. Sources of disagreement include trait heritability, defining and interpreting function, and dealing with organisms in which individuals are not clearly recognizable. We discuss and offer guidelines for overcoming these disagreements. The diversity of life on Earth means traits can represent different features that can be measured and reported in different ways, and thus, narrow definitions that work for one system will fail in others. We recommend ecologists embrace the breadth of biodiversity using a simplified definition of "trait" more consistent with its common use. Trait-based approaches will be most powerful if we accept that traits are at least as diverse as trait ecologists.
PubMed: 34938447
DOI: 10.1002/ece3.8321