•We very briefly describe wool processing and how variation in wool fibre characteristics affects it.•We review many publications that present variation in wool fibre characteristics of the body of ...sheep.•We briefly review the development of wool follicles across the body of sheep.•We discuss the variation across the body with respect to other sources of variation and conclude that it has limited impact on processing outcomes.
Variations in wool characteristics due to location on the body of sheep are reviewed and compared with variation from other sources. The biological basis for variation and the relevance of this source of variation to industry are also discussed. For many traits, variation between sites on the body was trivial in comparison with variation between individual fibres within those sites and variation between sheep. To set the context within which wool variation could have an economic impact, fleece skirting and other wool processing steps that are influenced by fibre variation, or might increase or decrease the impact of variation are initially discussed. Processing intimately blends wool from numerous sources and distributes variation from individual fleeces and positions within fleeces among larger processing batches. Variation within fleeces and flocks is thus of limited concern in breeds with a history of selection for wool for industrially manufactured wool products. Variations in dye uptake caused by highly pigmented or medullated fibres are two exceptions that cannot be effectively hidden by blending. The balance of evidence suggests that reducing the variation in most fibre characteristics across the body of wool-producing breeds is not economically justified for conventional manufacture of apparel, interior textiles or lower value products on an industrial scale, though further research may be justified for high value uses or in breeds not selected for uniform wool production.
This paper reports two patients with catastrophic complications after marathon-type running not hitherto documented. The first, who collapsed with acute abdominal pains, was found at surgery to have ...infarction of the omentum and later, after a second laparotomy, acute oedematous pancreatitis. The second patient, who collapsed semi-comatose with hyperthermia, developed disseminated intravascular coagulation, rhabdomyolysis, renal shutdown and progressive hepatic failure. With regular dialysis, his condition stabilised but liver function continued to decline, associated with thrombosis of the portal vein. The spectrum of potentially life threatening disorders includes upper gastrointestinal bleeding, haemorrhagic colitis and rarely infarction of the bowel. The present two cases provide further support for ischaemia being a major contributor to the gastrointestinal catastrophes of marathon-type running.
Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation ...of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 ...(OGG1) binds 8-oxoG and because
-deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-α-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor κB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo.
Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that ...chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.
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•Chronic stress (CS) transiently elevates Klf9 expression in the hippocampus of mice•Klf9 silencing in male and female mice prevents CS-induced spine alterations•Klf9 silencing in male and female mice prevents CS-induced maladaptive fear responses•Hippocampal KLF9 levels are increased in women with CS exposure and MDD
Besnard et al. show that chronic stress induces a transient elevation in hippocampal Klf9 expression in mice and that KLF9 expression is upregulated in hippocampus of women with MDD. Genetic silencing of Klf9 expression prevents chronic stress-induced enlargements of dendritic spines and maladaptive fear responses in male and female mice.
While some studies have previously estimated lives saved by COVID-19 vaccination, we estimate how many deaths could have been averted by vaccination in the US but were not because of a failure to ...vaccinate. We used a simple method based on a nationally representative dataset to estimate the preventable deaths among unvaccinated individuals in the US from May 30, 2021 to September 3, 2022 adjusted for the effects of age and time. We estimated that at least 232,000 deaths could have been prevented among unvaccinated adults during the 15 months had they been vaccinated with at least a primary series. While uncertainties exist regarding the exact number of preventable deaths and more granular data are needed on other factors causing differences in death rates between the vaccinated and unvaccinated groups to inform these estimates, this method is a rapid assessment on vaccine-preventable deaths due to SARS-CoV-2 that has crucial public health implications. The same rapid method can be used for future public health emergencies.
Summary
Background
In developed countries, hepatitis E is a porcine zoonosis caused by hepatitis E virus (HEV) genotype 3. In developing countries, hepatitis E is mainly caused by genotype 1, and ...causes increased mortality in patients with pre‐existing chronic liver disease (CLD).
Aim
To determine the role of HEV in patients with decompensated CLD.
Methods
Prospective HEV testing of 343 patients with decompensated CLD at three UK centres and Toulouse France, with follow‐up for 6 months or death. IgG seroprevalence was compared with 911 controls.
Results
11/343 patients (3.2%) had acute hepatitis E infection, and three died. There were no differences in mortality (27% vs. 26%, OR 1.1, 95% CI 0.28–4.1), age (P = 0.9), bilirubin (P = 0.5), alanine aminotransferase (P = 0.06) albumin (P = 0.5) or international normalised ratio (P = 0.6) in patients with and without hepatitis E infection. Five cases were polymerase chain reaction (PCR) positive (genotype 3). Hepatitis E was more common in Toulouse (7.9%) compared to the UK cohort (1.2%, P = 0.003). HEV IgG seroprevalence was higher in Toulouse (OR 17, 95% CI 9.2–30) and Truro (OR 2.5, 95% CI 1.4–4.6) than in Glasgow, but lower in cases, compared to controls (OR 0.59, 95% CI 0.41–0.86).
Conclusions
Hepatitis E occurs in a minority of patients with decompensated chronic liver disease. The mortality is no different to the mortality in patients without hepatitis E infection. The diagnosis can only be established by a combination of serology and PCR, the yield and utility of which vary by geographical location.
MTH1 Inhibitors for the Treatment of Psoriasis Bivik Eding, Cecilia; Köhler, Ines; Verma, Deepti ...
Journal of investigative dermatology,
08/2021, Letnik:
141, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MTH1 prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 ...small-molecule inhibitors, we found induced apoptosis through 8-oxodeoxyguanosine triphosphate accumulation and DNA double-strand breaks after oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with that in the controls. Using the imiquimod psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in the skin and skin-draining lymph nodes. The inhibition abolished the expression of T helper type 17‒associated cytokines in the skin, which was in line with decreased levels of IL-17–producing γδ T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17‒downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application as a promising therapeutic approach to psoriasis.
•Vapochromic crystals reversibly change colour with adsorption and desorption of water.•Their suitability for measuring gas concentration at a solid-fluid interface has been studied.•The ...colour-change of the crystals was shown to exhibit a pronounced hysteresis.•Temperature and viewing and illumination angles also affects colour-change.•The applicability of the crystals for experimental fluid dynamics research is demonstrated.
This paper demonstrates the potential of vapochromic crystals as a sensing medium for measurements of local species concentration. Vapochromic crystals exhibit a reversible colour change based on the adsorption and desorption of water. As the water content of the crystals changes so too does the wavelength of light that they reflect (i.e. they change colour). In the situation where humid air mixes with a dry gas, the resulting specific humidity of the mixture can be related to the concentration level of the dry gas through a simple mass balance. As far as the authors are aware, this is the first time that vapochromic crystals have been used in this context.
A number of the factors that affect the colour change of the crystal are investigated through simple flat plate experiments in a small wind tunnel. In all experiments, the hue and intensity of the vapochromic crystal was measured as a function of local dry gas concentration; in this case CO2. Green intensity levels exhibited the broadest activity over the widest range of CO2 levels, and was therefore used to quantify concentration.
The crystals demonstrated a pronounced hysteresis, where the adsorption and desorption of water into the crystal structure was shown to occur at different concentration levels. The transition band was also shown to be highly temperature dependent when tested over a range of 22–44 °C. The vapochromic crystals were assessed for repeatability and found to sense the local CO2 concentration to ±1.5% CO2 over a range of green intensity values from 90 to 170. A practical example is presented to show how vapochromic crystals could be applied to the mixing of fluid streams in gas turbine film cooling.
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