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Current Opinion in HIV and AIDS May 2013Recent clinical research suggests that an HIV-infected patient with lymphoma who was transplanted with bone marrow homozygous for a disrupted mutant CCR5 allele has no... (Review)
Review
PURPOSE OF REVIEW
Recent clinical research suggests that an HIV-infected patient with lymphoma who was transplanted with bone marrow homozygous for a disrupted mutant CCR5 allele has no remaining HIV replication and is effectively cured of HIV. Here, we discuss the approaches of disrupting host and viral genes involved in HIV replication and pathogenesis with the aim of curing patients with HIV.
RECENT FINDINGS
Data from the 'Berlin patient' suggest that targeted gene disruption can lead to an HIV cure. This review discusses the recent advances in the field of gene disruption toward the development of an anti-HIV therapy. We will introduce the strategies to disrupt host and viral genes using precise disruptions, imprecise disruptions, or site-specific recombination. Furthermore, the production of engineered rare-cutting endonucleases (zinc finger nucleases, TAL effector nucleases, and homing endonucleases) and recombinases that can recognize specific DNA target sequences and facilitate gene disruption will be discussed.
SUMMARY
The discovery of a gene disruption approach that would cure or efficiently confine HIV infection could have broad implications for the treatment of millions of people infected with HIV. An efficient 'one-shot' curative therapy not only would give infected patients hope of a drug-free or treatment-free future, but also could reduce the huge financial burden faced by many countries because of widespread administration of highly active antiretroviral therapy.
Topics: Endonucleases; Gene Targeting; HIV Infections; Humans
PubMed: 23478911
DOI: 10.1097/COH.0b013e32835f736c -
International Journal of Molecular... Dec 2020Anthropogenic endocrine-disrupting chemicals (EDCs) can contaminate air, soil, and water. Human exposures to EDCs occur through inhalation, absorption, and ingestion.... (Review)
Review
Anthropogenic endocrine-disrupting chemicals (EDCs) can contaminate air, soil, and water. Human exposures to EDCs occur through inhalation, absorption, and ingestion. EDCs act by disrupting various pathways in the endocrine system. When the hypothalamic-pituitary-gonadal (HPG) axis is disrupted by EDCs, there can be effects on fertility in both men and women. Not only can fertility be indirectly affected by EDC disruptions of the HPG axis, but EDCs can also directly affect the menstrual cycle and sperm morphology. In this review, we will discuss the current findings on EDCs that can be inhaled. This review examines effects of exposure to prominent EDCs: brominated and organophosphate flame retardants, diesel exhaust, polycyclic aromatic hydrocarbons, cadmium and lead, TCDD, and polychlorinated biphenyls on fertility through alterations that disrupt the HPG axis and fertility through inhalation. Although the studies included herein include multiple exposure routes, all the studies indicate receptor interactions that can occur from inhalation and the associated effects of all compounds on the HPG axis and subsequent fertility.
Topics: Air Pollutants; Animals; Endocrine Disruptors; Fertility; Gonads; Humans; Hypothalamus; Metals, Heavy; Pituitary Gland; Polycyclic Aromatic Hydrocarbons; Sex Factors; Vehicle Emissions
PubMed: 33276521
DOI: 10.3390/ijms21239191 -
Frontiers in Endocrinology 2023Maternal endocrine homeostasis is vital to a successful pregnancy, regulated by several hormones such as human chorionic gonadotropin, estrogen, leptin, glucocorticoid,... (Review)
Review
Maternal endocrine homeostasis is vital to a successful pregnancy, regulated by several hormones such as human chorionic gonadotropin, estrogen, leptin, glucocorticoid, insulin, prostaglandin, and others. Endocrine stress during pregnancy can modulate nutrient availability from mother to fetus, alter fetoplacental growth and reproductive functions. Endocrine disrupters such as bisphenols (BPs) and phthalates are exposed in our daily life's highest volume. Therefore, they are extensively scrutinized for their effects on metabolism, steroidogenesis, insulin signaling, and inflammation involving obesity, diabetes, and the reproductive system. BPs have their structural similarity to 17-β estradiol and their ability to bind as an agonist or antagonist to estrogen receptors to elicit an adverse response to the function of the endocrine and reproductive system. While adults can negate the adverse effects of these endocrine-disrupting chemicals (EDCs), fetuses do not equip themselves with enzymatic machinery to catabolize their conjugates. Therefore, EDC exposure makes the fetoplacental developmental window vulnerable to programming . On the one hand prenatal BPs and phthalates exposure can impair the structure and function of the ovary and uterus, resulting in placental vascular defects, inappropriate placental expression of angiogenic growth factors due to altered hypothalamic response, expression of nutrient transporters, and epigenetic changes associated with maternal endocrine stress. On the other, their exposure during pregnancy can affect the offspring's metabolic, endocrine and reproductive functions by altering fetoplacental programming. This review highlights the latest development in maternal metabolic and endocrine modulations from exposure to estrogenic mimic chemicals on subcellular and transgenerational changes in placental development and its effects on fetal growth, size, and metabolic & reproductive functions.
Topics: Pregnancy; Female; Humans; Placenta; Endocrine System; Estrogens; Fetal Development; Insulins
PubMed: 37854189
DOI: 10.3389/fendo.2023.1215353 -
Frontiers in Endocrinology 2021Adult and childhood obesity have reached pandemic level proportions. The idea that caloric excess and insufficient levels of physical activity leads to obesity is a... (Review)
Review
Adult and childhood obesity have reached pandemic level proportions. The idea that caloric excess and insufficient levels of physical activity leads to obesity is a commonly accepted answer for unwanted weight gain. This paradigm offers an inconclusive explanation as the world continually moves towards an unhealthier and heavier existence irrespective of energy balance. Endocrine disrupting chemicals (EDCs) are chemicals that resemble natural hormones and disrupt endocrine function by interfering with the body's endogenous hormones. A subset of EDCs called obesogens have been found to cause metabolic disruptions such as increased fat storage, . Obesogens act on the metabolic system through multiple avenues and have been found to affect the homeostasis of a variety of systems such as the gut microbiome and adipose tissue functioning. Obesogenic compounds have been shown to cause metabolic disturbances later in life that can even pass into multiple future generations, post exposure. The rising rates of obesity and related metabolic disease are demanding increasing attention on chemical screening efforts and worldwide preventative strategies to keep the public and future generations safe. This review addresses the most current findings on known obesogens and their effects on the metabolic system, the mechanisms of action through which they act upon, and the screening efforts through which they were identified with. The interplay between obesogens, brown adipose tissue, and the gut microbiome are major topics that will be covered.
Topics: Adipogenesis; Adipose Tissue; Animals; Endocrine Disruptors; Environmental Exposure; Environmental Pollutants; Gastrointestinal Microbiome; Humans; Obesity; Sweetening Agents
PubMed: 34899613
DOI: 10.3389/fendo.2021.780888 -
Information Systems Frontiers : a... 2023The growing availability of data and the emergence of business analytics ecosystems offer possibilities for companies developing innovative business models. However, the...
UNLABELLED
The growing availability of data and the emergence of business analytics ecosystems offer possibilities for companies developing innovative business models. However, the disruptive impact of these business models on society is not always judged favourably. This paper explores the growing tensions in the relationship between disruptive Big Data companies and society through the lens of legitimacy - a judgement about the fit and propriety of an entity, such as a company, to society. The study is based on four instrumental cases where Big Data organisations were faced with challenges to their legitimacy. The findings elaborate how digital transformations require companies to understand and manage how much to disrupt and how much to conform to social norms and values. Big Data businesses face a dynamic and paradoxical tension between the potential costs and benefits of their disruptive business models. The topic of legitimacy management is also addressed, drawing out implications for practice.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s10796-021-10155-3.
PubMed: 34177360
DOI: 10.1007/s10796-021-10155-3 -
British Journal of Pharmacology Oct 2017We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, that is, deficient GABA transmission, within the... (Review)
Review
We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, that is, deficient GABA transmission, within the prefrontal cortex and the hippocampus, for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico-hippocampal neural activity, and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age-related cognitive decline. Regional neural disinhibition, disrupting spatio-temporal control of neural activity and causing aberrant drive of projections, may disrupt processing within the disinhibited region and efferent regions. Recent studies in rats showed that prefrontal and hippocampal neural disinhibition (by local GABA antagonist microinfusion) dysregulates burst firing, which has been associated with important aspects of neural information processing. Using translational tests of clinically relevant cognitive functions, these studies showed that prefrontal and hippocampal neural disinhibition disrupts regional cognitive functions (including prefrontal attention and hippocampal memory function). Moreover, hippocampal neural disinhibition disrupted attentional performance, which does not require the hippocampus but requires prefrontal-striatal circuits modulated by the hippocampus. However, some prefrontal and hippocampal functions (including inhibitory response control) are spared by regional disinhibition. We consider conceptual implications of these findings, regarding the distinct relationships of distinct cognitive functions to prefrontal and hippocampal GABA tone and neural activity. Moreover, the findings support the proposition that prefrontal and hippocampal neural disinhibition contributes to clinically relevant cognitive deficits, and we consider pharmacological strategies for ameliorating cognitive deficits by rebalancing disinhibition-induced aberrant neural activity. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.19/issuetoc.
Topics: Animals; Cognition Disorders; Hippocampus; Humans; Mental Disorders; Neural Inhibition; Neurons; Prefrontal Cortex; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 28477384
DOI: 10.1111/bph.13850 -
Frontiers in Neuroscience 2023Pain behavior and the systems that mediate opioid analgesia and opioid reward processing display circadian rhythms. Moreover, the pain system and opioid processing... (Review)
Review
Pain behavior and the systems that mediate opioid analgesia and opioid reward processing display circadian rhythms. Moreover, the pain system and opioid processing systems, including the mesolimbic reward circuitry, reciprocally interact with the circadian system. Recent work has demonstrated the disruptive relationship among these three systems. Disruption of circadian rhythms can exacerbate pain behavior and modulate opioid processing, and pain and opioids can influence circadian rhythms. This review highlights evidence demonstrating the relationship among the circadian, pain, and opioid systems. Evidence of how disruption of one of these systems can lead to reciprocal disruptions of the other is then reviewed. Finally, we discuss the interconnected nature of these systems to emphasize the importance of their interactions in therapeutic contexts.
PubMed: 36875657
DOI: 10.3389/fnins.2023.1109480 -
Conflict and Health Feb 2023In Syria, disruption to water and sanitation systems, together with poor access to vaccination, forced displacement and overcrowding contribute to increases in...
BACKGROUND
In Syria, disruption to water and sanitation systems, together with poor access to vaccination, forced displacement and overcrowding contribute to increases in waterborne diseases (WBDs). The aim of this study is to perform a spatiotemporal analysis to investigate potential associations between interruptions to water, sanitation, and hygiene (WASH) and WBDs in northeast Syria using data collected by the Early Warning Alert and Response Network (EWARN) from Deir-ez-Zor, Raqqa, Hassakeh and parts of Aleppo governorates.
METHODS
We reviewed the literature databases of MEDLINE and Google Scholar and the updates of ReliefWeb to obtain information on acute disruptions and attacks against water infrastructure in northeast Syria between January 2015 and June 2021. The EWARN weekly trends of five syndromes representing waterborne diseases were plotted and analysed to identify time trends and the influence of these disruptions. To investigate a potential relationship, the Wilcoxon rank sum test was used to compare districts with and without disruptions. Time series analyses were carried out on major disruptions to analyse their effect on WBD incidence.
RESULTS
The literature review found several instances where water infrastructure was attacked or disrupted, suggesting that water has been deliberately targeted by both state and non-state actors in northeast Syria throughout the conflict. Over time, there was an overall upwards trend of other acute diarrhoea (OAD, p < 0.001), but downwards trends for acute jaundice syndrome, suspected typhoid fever and acute bloody diarrhoea. For the major disruption of the Alouk water plant, an interrupted time series analysis did not find a strong correlation between the disruption and changes in disease incidence in the weeks following the incident, but long-term increases in WBD were observed.
CONCLUSIONS
While no strong immediate correlation could be established between disruptions to WASH and WBDs in northeast Syria, further research is essential to explore the impact of conflict-associated damage to civil infrastructure including WASH. This is vital though challenging given confounding factors which affect both WASH and WBDs in contexts like northeast Syria. As such, research which includes exploration of mitigation after damage to WASH is essential to improve understanding of impacts on quantity and quality of WASH. More granular research which explores the origin of cases of WBDs and how such communities are affected by challenges to WASH is needed. One step towards research on this, is the implementation of adequate reporting mechanisms for real time tracking of the WASH attacks, damages, direct effects, and likely impact in conjunction with environmental and public health bodies and surveillance systems.
PubMed: 36739427
DOI: 10.1186/s13031-023-00502-3 -
Journal of Applied Physiology... Apr 2007Null mutation of any one of several members of the dystrophin protein complex can cause progressive, and possibly fatal, muscle wasting. Although these muscular... (Review)
Review
Null mutation of any one of several members of the dystrophin protein complex can cause progressive, and possibly fatal, muscle wasting. Although these muscular dystrophies arise from mutation of a single gene that is expressed primarily in muscle, the resulting pathology is complex and multisystemic, which shows a broader disruption of homeostasis than would be predicted by deletion of a single-gene product. Before the identification of the deficient proteins that underlie muscular dystrophies, such as Duchenne muscular dystrophy (DMD), oxidative stress was proposed as a major cause of the disease. Now, current knowledge supports the likelihood that interactions between the primary genetic defect and disruptions in the normal production of free radicals contribute to the pathophysiology of muscular dystrophies. In this review, we focus on the pathophysiology that results from dystrophin deficiency in humans with DMD and the mdx mouse model of DMD. Current evidence indicates three general routes through which free radical production can be disrupted in dystrophin deficiency to contribute to the ensuing pathology. First, constitutive differences in free radical production can disrupt signaling processes in muscle and other tissues and thereby exacerbate pathology. Second, tissue responses to the presence of pathology can cause a shift in free radical production that can promote cellular injury and dysfunction. Finally, behavioral differences in the affected individual can cause further changes in the production and stoichiometry of free radicals and thereby contribute to disease. Unfortunately, the complexity of the free radical-mediated processes that are perturbed in complex pathologies such as DMD will make it difficult to develop therapeutic approaches founded on systemic administration of antioxidants. More mechanistic knowledge of the specific disruptions of free radicals that underlie major features of muscular dystrophy is needed to develop more targeted and successful therapeutic approaches.
Topics: Animals; Free Radicals; Humans; Models, Biological; Muscle Contraction; Muscle, Skeletal; Muscular Dystrophies; Nitric Oxide; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 17095633
DOI: 10.1152/japplphysiol.01145.2006 -
The Journal of Steroid Biochemistry and... Nov 2011Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development... (Review)
Review
Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products--including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption.
Topics: Animals; Disease Susceptibility; Dose-Response Relationship, Drug; Endocrine Disruptors; Environmental Pollutants; Female; Humans; Male; Metabolic Diseases; Obesity; Pregnancy; Reproduction
PubMed: 21899826
DOI: 10.1016/j.jsbmb.2011.08.007