Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools in the armoury of clinical ...treatments. FQs target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, where they stabilise a covalent enzyme-DNA complex in which the DNA is cleaved in both strands. This leads to cell death and turns out to be a very effective way of killing bacteria. However, resistance to FQs is increasingly problematic, and alternative compounds are urgently needed. Here, we review the mechanisms of action of FQs and discuss the potential pathways leading to cell death. We also discuss quinolone resistance and how quinolone treatment can lead to resistance to non-quinolone antibiotics.
The coronavirus disease 2019 (COVID-19) pandemic, caused by the SARS-CoV-2 virus, has highlighted the need for antiviral approaches that can target emerging viruses with no effective vaccines or ...pharmaceuticals. Here, we demonstrate a CRISPR-Cas13-based strategy, PAC-MAN (prophylactic antiviral CRISPR in human cells), for viral inhibition that can effectively degrade RNA from SARS-CoV-2 sequences and live influenza A virus (IAV) in human lung epithelial cells. We designed and screened CRISPR RNAs (crRNAs) targeting conserved viral regions and identified functional crRNAs targeting SARS-CoV-2. This approach effectively reduced H1N1 IAV load in respiratory epithelial cells. Our bioinformatic analysis showed that a group of only six crRNAs can target more than 90% of all coronaviruses. With the development of a safe and effective system for respiratory tract delivery, PAC-MAN has the potential to become an important pan-coronavirus inhibition strategy.
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•PAC-MAN is a CRISPR-based strategy for RNA-guided viral RNA inhibition and degradation•Cas13d PAC-MAC is effective at targeting and cleaving SARS-CoV-2 sequences•Cas13d PAC-MAC can reduce H1N1 IAV load in respiratory epithelial cells•A group of six crRNAs can target more than 90% of all coronaviruses
A CRISPR-based strategy is developed to target conserved sequences across coronaviruses and other pathogenic viruses.
We report a robust, versatile approach called CRISPR live-cell fluorescent in situ hybridization (LiveFISH) using fluorescent oligonucleotides for genome tracking in a broad range of cell types, ...including primary cells. An intrinsic stability switch of CRISPR guide RNAs enables LiveFISH to accurately detect chromosomal disorders such as Patau syndrome in prenatal amniotic fluid cells and track multiple loci in human T lymphocytes. In addition, LiveFISH tracks the real-time movement of DNA double-strand breaks induced by CRISPR-Cas9-mediated editing and consequent chromosome translocations. Finally, by combining Cas9 and Cas13 systems, LiveFISH allows for simultaneous visualization of genomic DNA and RNA transcripts in living cells. The LiveFISH approach enables real-time live imaging of DNA and RNA during genome editing, transcription, and rearrangements in single cells.
Environmentally sustainable dermatology Allwright, E.; Abbott, R. A.
Clinical and experimental dermatology,
July 2021, Letnik:
46, Številka:
5
Journal Article
Recenzirano
Summary
In 2017, health and social care organizations contributed 6.3% of carbon emissions in England. Efforts to reduce the environmental footprint of the National Health Service (NHS) have been ...broadly focused on reducing demand, through prevention and patient empowerment, and modifying supply side factors by focusing on lean care systems and low carbon alternatives. This narrative review concentrates on supply side factors to identify sustainable practices with a focus on actions that could be implemented in dermatology departments. For this study, a literature review was conducted In MEDLINE in April 2020. The search terms included ‘environmental sustainability’ and ‘climate change’ with ‘dermatology’, ‘telemedicine’, ‘NHS’, ‘surgery’ and ‘operating theatres’. Out of 95 results, 20 were deemed relevant to the review. Although the review showed that there is clearly growing interest in environmental sustainability, the identified literature lacked examples of comprehensive implementation and evaluation of initiatives. The literature discussed distinct areas including transport, waste management and procurement as part of a lean healthcare system. A number of papers highlighted the potential contribution of carbon‐reducing actions without citing verifiable outcome data. This narrative review highlights the need for detailed environmental impact assessments of treatment options in dermatology, in tandem with economic analysis. In conclusion, we have identified a clear need for evidence‐based guidance setting out implementable actions with identifiable benefits achievable within local clinical teams. This will require engagement between clinicians, patients and healthcare organizations.
Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to ...estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.
Sustainability in skin cancer surgery Jabouri, H.; Abbott, R.A.
British journal of dermatology (1951),
April 2022, 2022-04-00, 20220401, Letnik:
186, Številka:
4
Journal Article
AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding ...that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3–36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.
Repurposed CRISPR-Cas molecules provide a useful tool set for broad applications of genomic editing and regulation of gene expression in prokaryotes and eukaryotes. Recent discovery of phage-derived ...proteins, anti-CRISPRs, which serve to abrogate natural CRISPR anti-phage activity, potentially expands the ability to build synthetic CRISPR-mediated circuits. Here, we characterize a panel of anti-CRISPR molecules for expanded applications to counteract CRISPR-mediated gene activation and repression of reporter and endogenous genes in various cell types. We demonstrate that cells pre-engineered with anti-CRISPR molecules become resistant to gene editing, thus providing a means to generate "write-protected" cells that prevent future gene editing. We further show that anti-CRISPRs can be used to control CRISPR-based gene regulation circuits, including implementation of a pulse generator circuit in mammalian cells. Our work suggests that anti-CRISPR proteins should serve as widely applicable tools for synthetic systems regulating the behavior of eukaryotic cells.
To determine if excessive daytime sleepiness (EDS) can predate future Parkinson disease (PD).
EDS was assessed in 3,078 men aged 71 to 93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All ...were free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurologic assessments from 1994 to 2001.
During the course of follow-up, 43 men developed PD (19.9/10,000 person-years). After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS vs men without EDS (55.3 vs 17.0/10,000 person-years; odds ratio OR = 3.3; 95% CI = 1.4 to 7.0; p = 0.004). Additional adjustment for insomnia, cognitive function, depressed mood, midlife cigarette smoking and coffee drinking, and other factors failed to alter the association between EDS and PD (OR = 2.8; 95% CI = 1.1 to 6.4; p = 0.014). Other sleep related features such as insomnia, daytime napping, early morning grogginess, and frequent nocturnal awakening showed little relation with the risk of PD.
Excessive daytime sleepiness may be associated with an increased risk of developing Parkinson disease.
Chorioamnionitis is strongly linked to preterm birth and neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral, and neurodevelopmental ...outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18- to 22-month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates.
To compare the neonatal and neurodevelopmental outcomes of 3 groups of extremely low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis.
Longitudinal observational study at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Two thousand three hundred ninety extremely preterm infants born at less than 27 weeks' gestational age (GA) between January 1, 2006, and December 31, 2008, with placental histopathology and 18 to 22 months' corrected age follow-up data were eligible.
Chorioamnionitis.
Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant and Toddler Development, Third Edition), and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth.
Neonates exposed to chorioamnionitis had a lower GA and higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of GA in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological plus clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (adjusted odds ratio OR, 2.38 95% CI, 1.32 to 4.28 without GA; adjusted OR, 2.00 95% CI, 1.10 to 3.64 with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological plus clinical chorioamnionitis (adjusted OR, 0.68 95% CI, 0.52 to 0.89 without GA; adjusted OR, 0.66 95% CI, 0.49 to 0.89 with GA as a covariate). Risk of behavioral problems did not differ statistically between groups.
Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.
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