Transforming growth factor-β and breast cancer: Mammary gland development

Transforming growth factor (TGF)-β(1) is a pluripotent cytokine that profoundly inhibits epithelial proliferation, induces apoptosis, and influences morphogenesis by mediating extracellular matrix deposition and remodeling. The physiologic roles of the action of TGF-β in mammary gland, indeed in most tissues, are poorly understood. In order to understand the actions of TGF-β, we need to take into account the complexity of its effects on different cell types and the influence of context on cellular responses. This task is further compounded by multiple mechanisms for regulating TGF-β transcription, translation, and activity. One of the most significant factors that obscures the action of TGF-β is that it is secreted as a stable latent complex, which consists of the 24-kDa cytokine and the 80-kDa dimer of its prepro region, called latency-associated peptide. Latency imposes a critical restraint on TGF-β activity that is often overlooked.The extracellular process known as activation, in which TGF-β is released from the latent complex, is emphasized in the present discussion of the role of TGF-β in mammary gland development. Definition of the spatial and temporal patterns of latent TGF-β activation in situ is essential for understanding the specific roles that TGF-β plays during mammary gland development, proliferation, and morphogenesis

Potential harm to the skin from unfiltered krypton-chloride “Far-UVC”lamps, even below an occupational exposure limit

Ultraviolet-C (UVC) radiation can effectively inactivate pathogens on surfaces and in the air. Due to the potential for harm to skin and eyes, human exposure to UVC should be limited within the guideline exposure limits produced by the International Commission on Non-Ionising Radiation Protection (ICNIRP) or the American Conference of Governmental Industrial Hygienists (ACGIHs). Both organisations state an effective spectrally weighted limit of 3 mJ cm−2, although the spectral weighting factors of the two organisations diverged following a revision of the ACGIH guidelines in 2022. Using existing published human exposure data, the effective spectrally weighted radiant exposure was calculated for both unfiltered and filtered (to reduce UV emissions above 230 nm) krypton chloride (KrCl*) excimer lamps. The effective radiant exposure of the filtered KrCl* lamp was greater than 3 mJ cm−2 when applying ICNIRP or either of the revised ACGIH spectral weightings. This indicates that both guidelines are appropriately conservative for this specific lamp. However, the effective radiant exposure of the unfiltered KrCl* lamp was as low as 1 mJ cm−2 with the revised ACGIH weighting function that can be applied to the skin if the eyes are protected. Erythema has therefore been directly observed in a clinical study at an exposure within the revised ACGIH guideline limits. Extrapolating this information means that a mild sunburn could be induced in Fitzpatrick skin types I and II if that particular ACGIH weighting function were applied and an individual received an effective exposure of 3 mJ cm−2. Whilst it is improbable that such an effect would be seen in current deployment of KrCl* lamp technology, it does highlight the need for further research into skin sensitivity and irradiance–time reciprocity for UVC wavelengths.Publisher PDFPeer reviewe

Extreme Exposure to Filtered Far-UVC:A Case Study^†

Far-UVC devices are being commercially sold as "safe for humans" for the inactivation of SARS-CoV-2, without supporting human safety data. We felt there was a need for rapid proof-of-concept human self-exposure, to inform future controlled research and promote informed discussion. A Fitzpatrick Skin Type II individual exposed their inner forearms to large radiant exposures from a filtered Krypton-Chloride (KrCl) far-UVC system (SafeZoneUVC, Ushio Inc., Tokyo, Japan) with peak emission at 222 nm. No visible skin changes were observed at 1,500 mJcm-2, whereas skin yellowing that appeared immediately and resolved within 24 hours occurred with a 6,000 mJcm-2 exposure. No erythema was observed at any time point with exposures up to 18,000 mJcm-2. These results combined with Monte Carlo Radiative Transfer computer modelling suggest that filtering longer ultraviolet wavelengths is critical for the human skin safety of far-UVC devices. This work also contributes to growing arguments for the exploration of exposure limit expansion, which would subsequently enable faster inactivation of viruses.Publisher PDFPeer reviewe

Computer Modeling Indicates Dramatically Less DNA Damage from Far-UVC Krypton Chloride Lamps (222 nm) than from Sunlight Exposure

Funding: Dr Paul O’Mahoney is funded by Medi-lase (registered charity SC037390) and the Alfred Stewart Trust. Dr Isla Barnard acknowledges financial support from an UK EPRSC PhD studentship (EP/N509759/1) and Louise Finlayson acknowledges financial support from EPSRC Industrial Doctorate Centre Scheme (2262922) and the Laser Research and Therapy Fund (registered charity SC030850).This study aims to investigate, with computer modeling, the DNA damage (assessed by cyclobutane pyrimidine dimer (CPD) formation) from far-ultraviolet C (far-UVC) in comparison with sunlight exposure in both a temperate (Harwell, England) and Mediterranean (Thessaloniki, Greece) climate. The research utilizes the published results from Barnard et al. [Barnard, I.R.M (2020) Photodermatol. Photoimmunol. Photomed. 36, 476?477] to determine the relative CPD yield of unfiltered and filtered far-UVC and sunlight exposure. Under current American Conference of Governmental Industrial Hygienists (ACGIH) exposure limits, 10 minutes of sunlight at an ultraviolet (UV) Index of 4 ? typical throughout the day in a temperate climate from Spring to Autumn - produces equivalent numbers of CPD as 700 hours of unfiltered far-UVC or more than 30,000 hours of filtered far-UVC at the basal layer. At the top of the epidermis these values are reduced to 30 and 300 hours respectively. In terms of DNA damage induction, as assessed by CPD formation, the risk from sunlight exposure greatly exceeds the risk from far-UVC. However the photochemistry that will occur in the stratum corneum from absorption of the vast majority of the high energy far-UVC photons is unknown, as are the consequences.Publisher PDFPeer reviewe

Observations of Aerosol‐Cloud Interactions During the North Atlantic Aerosol and Marine Ecosystem Study

Clouds and their response to aerosols constitute the largest uncertainty in our understanding of 20th‐century climate change. We present an investigation that determines linkages between remotely sensed marine cloud properties with in situ measurements of cloud condensation nuclei (CCN) and meteorological properties obtained during the North Atlantic Aerosols and Marine Ecosystems Study. The first two deployments of this campaign have geographically similar domains but occur in different seasons allowing the response of clouds to a range of CCN concentrations and meteorological conditions to be investigated. Well‐defined connections between CCN and cloud microphysical properties consistent with the indirect effect are observed, as well as complex, nonlinear secondary effects that are partially supported by previously proposed mechanisms. Using the Research Scanning Polarimeter's remotely sensed effective variance parameter, correlation is found with liquid water path. In general, cloud macrophysical properties are found to better correlate with atmospheric state parameters than changes in CCN concentrations

Cell permeable stapled peptide inhibitor of Wnt signaling that targets β-catenin protein‒protein interactions

The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. Our integrative approach combines peptide stapling to optimize proteolytic stability, with lessons learned from cell-penetrating peptide (CPP) design to maximize cellular uptake resulting in NLS-StAx-h, a selective, cell permeable, stapled peptide inhibitor of oncogenic Wnt signaling that efficiently inhibits β-catenin-transcription factor interactions. We expect that this type of integrative strategy that endows stapled peptides with CPP features will be generally useful for developing inhibitors of intracellular PPIs

Development of a predictive Monte Carlo radiative transfer model for ablative fractional skin lasers

L.M. would like to acknowledge the funding from EPSRC grant code: EP/K503162/1. P.O'M. is funded by Medi‐Lase (registered charity SC 037390) and the Alfred Stewart Trust'.It is possible to enhance topical drug delivery by pretreatment of the skin with ablative fractional lasers (AFLs). However, the parameters to use for a given AFL to achieve the desired depth of ablation or the desired therapeutic or cosmetic outcome are hard to predict. This leaves open the real possibility of overapplication or underapplication of laser energy to the skin. In this study, we developed a numerical model consisting of a Monte Carlo radiative transfer (MCRT) code coupled to a heat transfer and tissue damage algorithm. The simulation is designed to predict the depth effects of AFL on the skin, verified with in vitro experiments in porcine skin via optical coherence tomography (OCT) imaging. Ex vivo porcine skin is irradiated with increasing energies (50–400 mJ/pixel) from a CO2 AFL. The depth of microscopic treatment zones is measured and compared with our numerical model. The data from the OCT images and MCRT model complement each other well. Nonablative thermal effects on surrounding tissue are also discussed. This model, therefore, provides an initial step toward a predictive determination of the effects of AFL on the skin.Publisher PDFPeer reviewe

Air Disinfection with Germicidal Ultraviolet:For this Pandemic and the Next

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A summary of the 2012 JHU CLSP Workshop on Zero Resource Speech Technologies and Models of Early Language Acquisition

We summarize the accomplishments of a multi-disciplinary workshop exploring the computational and scientific issues surrounding zero resource (unsupervised) speech technologies and related models of early language acquisition. Centered around the tasks of phonetic and lexical discovery, we consider unified evaluation metrics, present two new approaches for improving speaker independence in the absence of supervision, and evaluate the application of Bayesian word segmentation algorithms to automatic subword unit tokenizations. Finally, we present two strategies for integrating zero resource techniques into supervised settings, demonstrating the potential of unsupervised methods to improve mainstream technologies.5 page(s