Sensitivity to Sunburn Is Associated with Susceptibility to Ultraviolet Radiation–Induced Suppression of Cutaneous Cell–Mediated Immunity

Skin cancer incidence is highest in white-skinned people. Within this group, skin types I/II (sun sensitive/tan poorly) are at greater risk than skin types III/IV (sun tolerant/tan well). Studies in mice demonstrate that ultraviolet radiation (UVR)-induced suppression of cell-mediated immune function plays an important role in the development of skin cancer and induces a susceptibility to infectious disease. A similar role is suspected in humans, but we lack quantitative human data to make risk assessments of ambient solar exposure on human health. This study demonstrates that ambient levels of solar UVR, typically experienced within 1 h of exposure to noonday summer sunlight, can suppress contact hypersensitivity (CHS) responses in healthy white-skinned humans in vivo (n = 93). There was a linear relationship between increase in erythema and suppression of CHS (P < 0.001), and a moderate sunburn (two minimal erythema doses [2 MED]) was sufficient to suppress CHS in all volunteers by 93%. However, a single suberythemal exposure of either 0.25 or 0.5 MED suppressed CHS responses by 50 and 80%, respectively, in skin types I/II, whereas 1 MED only suppressed CHS by 40% in skin types III/IV. The two- to threefold greater sensitivity of skin types I/II for a given level of sunburn may play a role in their greater sensitivity to skin cancer

Insufficient Sun Exposure Has Become a Real Public Health Problem.

This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer's disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5-30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR

[Letter] A distinct genotype of XP complementation group A: surprisingly mild phenotype highly prevalent in Northern India/ Pakistan/ Afghanistan

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Identification of potentially cytotoxic lesions induced by UVA photoactivation of DNA 4-thiothymidine in human cells

Photochemotherapy—in which a photosensitizing drug is combined with ultraviolet or visible radiation—has proven therapeutic effectiveness. Existing approaches have drawbacks, however, and there is a clinical need to develop alternatives offering improved target cell selectivity. DNA substitution by 4-thiothymidine (S4TdR) sensitizes cells to killing by ultraviolet A (UVA) radiation. Here, we demonstrate that UVA photoactivation of DNA S4TdR does not generate reactive oxygen or cause direct DNA breakage and is only minimally mutagenic. In an organotypic human skin model, UVA penetration is sufficiently robust to kill S4TdR-photosensitized epidermal cells. We have investigated the DNA lesions responsible for toxicity. Although thymidine is the predominant UVA photoproduct of S4TdR in dilute solution, more complex lesions are formed when S4TdR-containing oligonucleotides are irradiated. One of these, a thietane/S5-(6-4)T:T, is structurally related to the (6-4) pyrimidine:pyrimidone [(6-4) Py:Py] photoproducts induced by UVB/C radiation. These lesions are detectable in DNA from S4TdR/UVA-treated cells and are excised from DNA more efficiently by keratinocytes than by leukaemia cells. UVA irradiation also induces DNA interstrand crosslinking of S4TdR-containing duplex oligonucleotides. Cells defective in repairing (6-4) Py:Py DNA adducts or processing DNA crosslinks are extremely sensitive to S4TdR/UVA indicating that these lesions contribute significantly to S4TdR/UVA cytotoxicity

Environmental Effects of Stratospheric Ozone Depletion, UV Radiation, and interactions with Climate Change: 2022 Assessment Report

The Montreal Protocol on Substances that Deplete the Ozone Layer was established 35 years ago following the 1985 Vienna Convention for protection of the environment and human health against excessive amounts of harmful ultraviolet-B (UV-B, 280-315 nm) radiation reaching the Earth’s surface due to a reduced UV-B-absorbing ozone layer. The Montreal Protocol, ratified globally by all 198 Parties (countries), controls ca 100 ozone-depleting substances (ODS). These substances have been used in many applications, such as in refrigerants, air conditioners, aerosol propellants, fumigants against pests, fire extinguishers, and foam materials. The Montreal Protocol has phased out nearly 99% of ODS, including ODS with high global warming potentials such as chlorofluorocarbons (CFC), thus serving a dual purpose. However, some of the replacements for ODS also have high global warming potentials, for example, the hydrofluorocarbons (HFCs). Several of these replacements have been added to the substances controlled by the Montreal Protocol. The HFCs are now being phased down under the Kigali Amendment. As of December 2022, 145 countries have signed the Kigali Amendment, exemplifying key additional outcomes of the Montreal Protocol, namely, that of also curbing climate warming and stimulating innovations to increase energy efficiency of cooling equipment used industrially as well as domestically. As the concentrations of ODS decline in the upper atmosphere, the stratospheric ozone layer is projected to recover to pre-1980 levels by the middle of the 21st century, assuming full compliance with the control measures of the Montreal Protocol. However, in the coming decades, the ozone layer will be increasingly influenced by emissions of greenhouse gases and ensuing global warming. These trends are highly likely to modify the amount of UV radiation reaching the Earth\u27s surface with implications for the effects on ecosystems and human health. Against this background, four Panels of experts were established in 1988 to support and advise the Parties to the Montreal Protocol with up-to-date information to facilitate decisions for protecting the stratospheric ozone layer. In 1990 the four Panels were consolidated into three, the Scientific Assessment Panel, the Environmental Effects Assessment Panel, and the Technology and Economic Assessment Panel. Every four years, each of the Panels provides their Quadrennial Assessments as well as a Synthesis Report that summarises the key findings of all the Panels. In the in-between years leading up to the quadrennial, the Panels continue to inform the Parties to the Montreal Protocol of new scientific information

Ozone depletion, ultraviolet radiation, climate change and prospects for a sustainable future

Changes in stratospheric ozone and climate over the past 40-plus years have altered the solar ultraviolet (UV) radiation conditions at the Earth's surface. Ozone depletion has also contributed to climate change across the Southern Hemisphere. These changes are interacting in complex ways to affect human health, food and water security, and ecosystem services. Many adverse effects of high UV exposure have been avoided thanks to the Montreal Protocol with its Amendments and Adjustments, which have effectively controlled the production and use of ozone-depleting substances. This international treaty has also played an important role in mitigating climate change. Climate change is modifying UV exposure and affecting how people and ecosystems respond to UV; these effects will become more pronounced in the future. The interactions between stratospheric ozone, climate and UV radiation will therefore shift over time; however, the Montreal Protocol will continue to have far-reaching benefits for human well-being and environmental sustainability.Peer reviewe

GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.We thank David Wiggins for excellent technical assistance. This work was supported by the Medical Research Council, Diabetes UK (to R. Ramracheya ), Oxford Biomedical Research Centre (to A. Tarasov), the Wellcome Trust (Senior Investigator Awards to A. Galione and P. Rorsman), the Warwick Impact Fund (to C. Weston and G. Ladds), the Biotechnology and Biological Sciences Research Council (to G. Ladds), the Knut and Alice Wallenberg Foundation (to P. Rorsman), and the Swedish Research Council (to P. Rorsman). The initial stages of M. Shigeto’s stay in Oxford were supported by a fellowship from Kawasaki Medical School.This is the final version of the article. It was first available from the American Society for Clinical Investigation via http://dx.doi.org/10.1172/JCI8197

The International Gene Trap Consortium Website: a portal to all publicly available gene trap cell lines in mouse

Gene trapping is a method of generating murine embryonic stem (ES) cell lines containing insertional mutations in known and novel genes. A number of international groups have used this approach to create sizeable public cell line repositories available to the scientific community for the generation of mutant mouse strains. The major gene trapping groups worldwide have recently joined together to centralize access to all publicly available gene trap lines by developing a user-oriented Website for the International Gene Trap Consortium (IGTC). This collaboration provides an impressive public informatics resource comprising ∼45 000 well-characterized ES cell lines which currently represent ∼40% of known mouse genes, all freely available for the creation of knockout mice on a non-collaborative basis. To standardize annotation and provide high confidence data for gene trap lines, a rigorous identification and annotation pipeline has been developed combining genomic localization and transcript alignment of gene trap sequence tags to identify trapped loci. This information is stored in a new bioinformatics database accessible through the IGTC Website interface. The IGTC Website () allows users to browse and search the database for trapped genes, BLAST sequences against gene trap sequence tags, and view trapped genes within biological pathways. In addition, IGTC data have been integrated into major genome browsers and bioinformatics sites to provide users with outside portals for viewing this data. The development of the IGTC Website marks a major advance by providing the research community with the data and tools necessary to effectively use public gene trap resources for the large-scale characterization of mammalian gene function

Protonation-Induced Microphase Separation in Thin Films of a Polyelectrolyte-Hydrophilic Diblock Copolymer

Block copolymers composed of poly(oligo ethylene glycol methyl ether methacrylate) and poly(2-vinylpyridine) are disordered in the neat state but can be induced to order by protonation of the P2VP block, demonstrating a tunable and responsive method for triggering assembly in thin films. Comparison of protonation with the addition of salts shows that microphase separation is due to selective protonation of the P2VP block. Increasing acid incorporation and increasing 2-vinylpyridine content for P2VP minority copolymers both promote increasingly phase-separated morphologies, consistent with protonation increasing the effective strength of segregation between the two blocks. The self-assembled nanostructures formed after casting from acidic solutions may be tuned based on the amount and type of acid incorporation as well as the annealing treatment applied after casting, where both aqueous and polar organic solvents are shown to be effective. Therefore, POEGMA-b-P2VP is a novel ion-containing block copolymer whose morphologies can be facilely tuned during casting and processing by controlling its exposure to acid.United States. Dept. of Energy. Office of Basic Energy Sciences (Award DE-SC0001088)National Science Foundation (U.S.) (Award CMMI-1246740

Effects of acute treatment with a tryptophan-rich protein hydrolysate on plasma amino acids, mood and emotional functioning in older women

RATIONALE: Effective functioning of the neurotransmitter serotonin is important for optimal cognitive and emotional function. Dietary supplements able to increase availability to the brain of the precursor amino acid, tryptophan (TRP), and thereby enhance serotonin synthesis, can have measurable impact on these psychological processes. OBJECTIVES: This study involves a randomised controlled trial of a TRP-rich egg-white protein hydrolysate (DSM Nutritional Products Ltd., Switzerland) on plasma amino acids, cognition, mood and emotional processing in older women. METHODS: Following a baseline test day without treatment, 60 healthy women aged 45–65 years received drinks containing either 2 or 4 g of TRP-rich protein hydrolysate product or 3.11 g casein hydrolysate as a control. One hour later, they undertook a 2-h battery of cognitive and emotional tests. RESULTS: The TRP-rich protein hydrolysate produced the expected dose-dependent increase in the ratio of plasma TRP to competing large neutral amino acids. TRP-rich protein hydrolysate (2 g only) prevented both the decline in wellbeing and increase in fatigue seen over the test session in the control group. This treatment dose resulted in a significant shift in emotional processing towards positive words and reduced negative bias in assessing negative facial expressions. Effects on cognition were small and not statistically reliable and are not reported here. However, there was no evidence for any adverse effects. CONCLUSIONS: Consumption of a low dose of TRP-rich protein hydrolysate may have beneficial effects on emotional function that could promote feelings of wellbeing, possibly conferring resistance to deterioration in mood in healthy subjects or depressive episodes