A Frog Skin-Derived Peptide Targeting SCD1 Exerts Radioprotective Effects Against Skin Injury by Inhibiting STING-Mediated Inflammation.

The extensive application of nuclear technology has increased the potential of uncontrolled radiation exposure to the public. Since skin is the largest organ, radiation-induced skin injury remains a serious medical concern. Organisms evolutionally develop distinct strategies to protect against environment insults and the related research may bring novel insights into therapeutics development. Here, 26 increased peptides are identified in skin tissues of frogs (Pelophylax nigromaculatus) exposed to electron beams, among which four promoted the wound healing of irradiated skin in rats. Specifically, radiation-induced frog skin peptide-2 (RIFSP-2), from histone proteolysis exerted membrane permeability property, maintained cellular homeostasis, and reduced pyroptosis of irradiated cells with decreased TBK1 phosphorylation. Subsequently, stearyl-CoA desaturase 1 (SCD1) is identified, a critical enzyme in biogenesis of monounsaturated fatty acids (MUFAs) as a direct target of RIFSP-2 based on streptavidin-biotin system. The lipidomic analysis further assured the restrain of MUFAs biogenesis by RIFSP-2 following radiation. Moreover, the decreased MUFA limited radiation-induced and STING-mediated inflammation response. In addition, genetic depletion or pharmacological inhibition of STING counteracted the decreased pyroptosis by RIFSP-2 and retarded tissue repair process. Altogether, RIFSP-2 restrains radiation-induced activation of SCD1-MUFA-STING axis. Thus, the stress-induced amphibian peptides can be a bountiful source of novel radiation mitigators.

Connexin 43 Prevents Radiation-Induced Intestinal Damage via the Ca2+-Dependent PI3K/Akt Signaling Pathway.

Radiation-induced intestinal damage (RIID) is a common side effect of radiotherapy in patients with abdominopelvic malignancies. Gap junctions are special structures consisting of connexins (Cxs). This study aimed to investigate the expression and role of connexins in RIID and underlying mechanism. In this study, a calcein-AM fluorescence probe was used to detect changes in gap junctional intercellular communication in intestinal epithelial IEC-6 cells. Our results show that gap junctional intercellular communication of IEC-6 cells was reduced at 6, 12, 24, and 48 h after irradiation, with the most pronounced effect at 24 h. Western blotting and immunofluorescence results showed that the expression of Cx43, but not other connexins, was reduced in irradiated intestinal epithelial cells. Silencing of Cx43 reduced gap junctional intercellular communication between irradiated intestinal epithelial cells with increased ROS and intracellular Ca2+ levels. Furthermore, knockdown of Cx43 reduced the number of clonal clusters, decreased cell proliferation with increased cytotoxicity and apoptosis. Western blotting results showed that silencing of Cx43 resulted in changed γ-H2AX and PI3K/AKT pathway proteins in irradiated intestinal epithelial cells. Administration of the PI3K/AKT pathway inhibitor LY294002 inhibited the radioprotective effects in Cx43-overexpressing intestinal epithelial cells. Our study demonstrated that Cx43 expression is decreased by ionizing radiation, which facilitates the radioprotection of intestinal epithelial cells.

Current insights and future perspectives of ultraviolet radiation (UV) exposure: Friends and foes to the skin and beyond the skin.

Ultraviolet (UV) radiation is ubiquitous in the environment, which has been classified as an established human carcinogen. As the largest and outermost organ of the body, direct exposure of skin to sunlight or UV radiation can result in sunburn, inflammation, photo-immunosuppression, photoaging and even skin cancers. To date, there are tactics to protect the skin by preventing UV radiation and reducing the amount of UV radiation to the skin. Nevertheless, deciphering the essential regulatory mechanisms may pave the way for therapeutic interventions against UV-induced skin disorders. Additionally, UV light is considered beneficial for specific skin-related conditions in medical UV therapy. Recent evidence indicates that the biological effects of UV exposure extend beyond the skin and include the treatment of inflammatory diseases, solid tumors and certain abnormal behaviors. This review mainly focuses on the effects of UV on the skin. Moreover, novel findings of the biological effects of UV in other organs and systems are also summarized. Nevertheless, the mechanisms through which UV affects the human organism remain to be fully elucidated to achieve a more comprehensive understanding of its biological effects.

Connexin 43 Prevents Radiation-Induced Intestinal Damage via the Ca2+-Dependent PI3K/Akt Signaling Pathway.

Radiation-induced intestinal damage (RIID) is a common side effect of radiotherapy in patients with abdominopelvic malignancies. Gap junctions are special structures consisting of connexins (Cxs). This study aimed to investigate the expression and role of connexins in RIID and underlying mechanism. In this study, a calcein-AM fluorescence probe was used to detect changes in gap junctional intercellular communication in intestinal epithelial IEC-6 cells. Our results show that gap junctional intercellular communication of IEC-6 cells was reduced at 6, 12, 24, and 48 h after irradiation, with the most pronounced effect at 24 h. Western blotting and immunofluorescence results showed that the expression of Cx43, but not other connexins, was reduced in irradiated intestinal epithelial cells. Silencing of Cx43 reduced gap junctional intercellular communication between irradiated intestinal epithelial cells with increased ROS and intracellular Ca2+ levels. Furthermore, knockdown of Cx43 reduced the number of clonal clusters, decreased cell proliferation with increased cytotoxicity and apoptosis. Western blotting results showed that silencing of Cx43 resulted in changed γ-H2AX and PI3K/AKT pathway proteins in irradiated intestinal epithelial cells. Administration of the PI3K/AKT pathway inhibitor LY294002 inhibited the radioprotective effects in Cx43-overexpressing intestinal epithelial cells. Our study demonstrated that Cx43 expression is decreased by ionizing radiation, which facilitates the radioprotection of intestinal epithelial cells.

Identification of the High Mannose N-Glycan Isomers Undescribed by Conventional Multicellular Eukaryotic Biosynthetic Pathways.

N-linked glycosylation is one of the most important post-translational modifications of proteins. Current knowledge of multicellular eukaryote N-glycan biosynthesis suggests high mannose N-glycans are generated in the endoplasmic reticulum and Golgi apparatus through conserved biosynthetic pathways. According to conventional biosynthetic pathways, four Man7GlcNAc2 isomers, three Man6GlcNAc2 isomers, and one Man5GlcNAc2 isomer are generated during this process. In this study, we applied our latest mass spectrometry method, logically derived sequence tandem mass spectrometry (LODES/MSn), to re-examine high mannose N-glycans extracted from various multicellular eukaryotes which are not glycosylation mutants. LODES/MSn identified many high mannose N-glycan isomers previously unreported in plantae, animalia, cancer cells, and fungi. A database consisting of retention time and CID MSn mass spectra was constructed for all possible MannGlcNAc2 (n = 5, 6, 7) isomers that include the isomers by removing arbitrary numbers and positions of mannose from canonical N-glycan, Man9GlcNAc2. Many N-glycans in this database are not found in current N-glycan mass spectrum libraries. The database is useful for rapid high mannose N-glycan isomeric identification.

Role of affective reactivity induced by cigarette packaging including graphic warning labels: the CASA Study.

OBJECTIVE: To identify whether three types of cigarette pack designs, including three versions of graphic warning label (GWL) plain packs, one GWL absent and branding absent pack (blank) and the smoker's own GWL absent and branding present pack (US), elicit different valence, type and levels of affect. DESIGN: US daily smokers (n=324) were asked to handle each of the five pack types and 'think aloud' their reactions. To avoid a muted familiarity response, exposure to their own US pack followed exposure to at least one GWL plain pack. Reactions were scored on a reactivity scale (-3 to +3) and the text was coded for speech polarity (-1 to +1) and emotive word frequency. RESULTS: Reactivity scores had excellent inter-rater reliability (agreement ≥86%; intraclass correlation coefficient ≥0.89) and were correlated with speech polarity (r=0.21-0.37, p<0.001). When considering their US pack, approximately two-thirds of smokers had a low (31.5%) to medium (34.6%) positive response (reactivity=1.29; polarity=0.14) with expressed feelings of joy and trust. Blank packaging prompted a largely (65.4%) neutral response (reactivity=0.03; polarity=0.00). The gangrenous foot GWL provoked mostly medium (46.9%) to high (48.1%) negative responses (reactivity=-2.44; polarity=-0.20), followed by neonatal baby (reactivity=-1.85; polarity=-0.10) and throat cancer (reactivity=-1.76; polarity=-0.08) warnings. GWLs varied in their elicitation of disgust, anger, fear and sadness. CONCLUSION: Initial reactions to GWL packs, a blank pack, and smokers' current US pack reflected negative, neutral, and positive affect, respectively. Different versions of the GWL pack elicited different levels and types of immediate negative affect.

Machine learning based downscaling of GRACE-estimated groundwater in Central Valley, California.

California's Central Valley, one of the most agriculturally productive regions, is also one of the most stressed aquifers in the world due to anthropogenic groundwater over-extraction primarily for irrigation. Groundwater depletion is further exacerbated by climate-driven droughts. Gravity Recovery and Climate Experiment (GRACE) satellite gravimetry has demonstrated the feasibility of quantifying global groundwater storage changes at uniform monthly sampling, though at a coarse resolution and is thus impractical for effective water resources management. Here, we employ the Random Forest machine learning algorithm to establish empirical relationships between GRACE-derived groundwater storage and in situ groundwater level variations over the Central Valley during 2002-2016 and achieved spatial downscaling of GRACE-observed groundwater storage changes from a few hundred km to 5 km. Validations of our modeled groundwater level with in situ groundwater level indicate excellent Nash-Sutcliffe Efficiency coefficients ranging from 0.94 to 0.97. In addition, the secular components of modeled groundwater show good agreements with those of vertical displacements observed by GPS, and CryoSat-2 radar altimetry measurements and is perfectly consistent with findings from previous studies. Our estimated groundwater loss is about 30 km3 from 2002 to 2016, which also agrees well with previous studies in Central Valley. We find the maximum groundwater storage loss rates of -5.7 ± 1.2 km3 yr-1 and -9.8 ± 1.7 km3 yr-1 occurred during the extended drought periods of January 2007-December 2009, and October 2011-September 2015, respectively while Central Valley also experienced groundwater recharges during prolonged flood episodes. The 5-km resolution Central Valley-wide groundwater storage trends reveal that groundwater depletion occurs mostly in southern San Joaquin Valley collocated with severe land subsidence due to aquifer compaction from excessive groundwater over withdrawal.

Application of Biomineralization Technology to Self-Healing of Fiber-Reinforced Lightweight Concrete after Exposure to High Temperatures.

In the field of civil engineering, concrete self-healing technology plays an important role. Concrete self-healing should be able to effectively heal cracks, not only improving the internal structure, but also improving the mechanical properties and durability of the concrete structure. The biomineralization-repair method is characterized by its potential for long-lasting, rapid, and active crack repair potential. Biomineralization repair has an effective bond ability, is compatible with concrete components, and is also environmentally friendly. This study used biomineralization to explore the self-healing of fiber-reinforced lightweight concrete after its exposure to high temperatures. Concrete specimens of a control group (using lightweight aggregate without bacterial spores and a nutrient source) and an experimental group (using lightweight aggregate containing bacterial spores and a nutrient source) were prepared. The repair effect of the microbial self-healing concrete after the exposure to high temperature was observed by a crack-width gauge, field-emission scanning electron microscopy (FESEM), energy-dispersive spectroscopy (EDS), and X-ray diffraction (XRD). According to the EDS and XRD analyses, the precipitate formed at the crack was calcium carbonate. After 28 days of self-healing, the water absorption rate of the experimental group was lower than that of the control group. This is because the specimens of the penetration test were taken from the middle of the concrete cylinder after high temperature, and their bacterial survival rate was higher, which made the mineralization more significant. However, the mechanical test results of the control and experimental groups after the self-healing in the water were not substantially different, which indicated that the bacterial mineralization in the experimental group was slow in the absence of an adequate source of nutrients.

Fenofibrate Attenuates Radiation-Induced Oxidative Damage to the Skin through Fatty Acid Binding Protein 4 (FABP4).

BACKGROUND: Radiation facilities and radioactive materials have been widely used in military, industry, medicine, science and nuclear facilities, which has significantly increased the potential of large-scale, uncontrolled exposure to radiation. The skin is one of the radiosensitive organ systems and radiation-induced skin injury remains a serious concern after ionizing radiation exposure. Our previous report indicates the involvement of the peroxisome proliferator-activated receptor pathway in the response of skin tissues to ionizing radiation. PPARα is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. However, the protection of fenofibrate against ionizing radiation in skin keratinocytes and fibroblasts has not been described. METHODS: The PPARα mRNA levels in irradiated and nonirradiated skin tissues of rats were determined by real-time assay. The expression of PPARα, and FABP4 were evaluated by western blot and IHC assay. The cell proliferation was detected by colony formation. The γH2AX foci and ROS levels in irradiated WS1 cells with FABP4 overexpression than in control cells were performed by Immunofluorescence assay. RESULTS: We found that PPARα expression was lower in the irradiated skin tissues of mouse, rat, monkey, and human patients than in their nonirradiated counterparts. PPARα fenofibrate significantly decreased radiation-induced ROS and apoptosis in a dose-dependent manner in human keratinocyte HaCaT and skin fibroblast WS1 cells. Moreover, fenofibrate significantly decreased radiation-induced ROS and malondialdehyde (MDA) levels in electron beam irradiated skin tissues of rats. Mechanistically, the proximal promoter of fatty acid binding protein 4 (FABP4) harbored three binding sites of PPARα and fenofibrate stimulated the transcription of FABP4 in skin cells. FABP4 overexpression decreased radiation-induced ROS and γH2AX foci. FABP4 inhibitor BMS309403 abrogated the ROS-eliminating activity as well as the lipid-accumulating role of fenofibrate, indicating that FABP4 mediates the radioprotective role of fenofibrate. In addition, FABP4 overexpression significantly decreased radiation-induced oxidative damage in vivo. CONCLUSIONS: These results confirm that fenofibrate attenuated radiation-induced oxidative damage to the skin by stimulating FABP4.

Proteomic and miRNA profiling of radon-induced skin damage in mice: FASN regulated by miRNAs.

Radon is a naturally occurring radioactive gas and considered as a serious carcinogen to humans. Continuous radioactive decay of this gas emits high-energy alpha particles. Long-term radon exposure induces oxidative stress and inflammatory response, which results in chronic lung diseases. However, biological effects after radon exposure in other organs have been rarely reported. As the outermost organ of the human body, the skin suffers from environmental damage to agents such as air pollution. Epidemiological studies indicated that areas with high level of radon had a high incidence of skin cancer. However, whether radon exposure induces skin damage has not been reported yet. In this study, we established a radon-exposed mouse model and found that radon exposure affected the structure of skin tissues, which was manifested by inflammatory cell infiltration and skin atrophy. Using proteomic approach, we found 45 preferentially expressed proteins in 60 Working Level Months (WLM) group and 314 preferentially expressed proteins in 120 WLM group from radon-exposed skin tissues. Through microRNA (miRNA) sequencing profiling analysis, 57 dysregulated miRNAs were screened between the control and radon-treated mouse skin. By integrating the dysregulated proteins and miRNAs, radon-induced fatty acid synthase (FASN) was investigated in greater detail. Results showed that FASN was regulated by miR-206-3p and miR-378a-3p and involved in the pathogenesis of radon-induced skin damage. Overexpression of FASN inhibited the proliferation, and induced in WS1 cells. Our present findings illustrate the molecular change during radon-induced skin damage and the potential role of FASN during this process.

Development of Diagnosis Model for Early Lung Nodules Based on a Seven Autoantibodies Panel and Imaging Features.

Background: There is increasing incidence of pulmonary nodules due to the promotion and popularization of low-dose computed tomography (LDCT) screening for potential populations with suspected lung cancer. However, a high rate of false-positive and concern of radiation-related cancer risk of repeated CT scanning remains a major obstacle to its wide application. Here, we aimed to investigate the clinical value of a non-invasive and simple test, named the seven autoantibodies (7-AABs) assay (P53, PGP9.5, SOX2, GAGE7, GUB4-5, MAGEA1, and CAGE), in distinguishing malignant pulmonary diseases from benign ones in routine clinical practice, and construct a neural network diagnostic model with the development of machine learning methods. Method: A total of 933 patients with lung diseases and 744 with lung nodules were identified. The serum levels of the 7-AABs were tested by an enzyme-linked Immunosorbent assay (ELISA). The primary goal was to assess the sensitivity and specificity of the 7-AABs panel in the detection of lung cancer. ROC curves were used to estimate the diagnosis potential of the 7-AABs in different groups. Next, we constructed a machine learning model based on the 7-AABs and imaging features to evaluate the diagnostic efficacy in lung nodules. Results: The serum levels of all 7-AABs in the malignant lung diseases group were significantly higher than that in the benign group. The sensitivity and specificity of the 7-AABs panel test were 60.7% and 81.5% in the whole group, and 59.7% and 81.1% in cases with early lung nodules. Comparing to the 7-AABs panel test alone, the neural network model improved the AUC from 0.748 to 0.96 in patients with pulmonary nodules. Conclusion: The 7-AABs panel may be a promising method for early detection of lung cancer, and we constructed a new diagnostic model with better efficiency to distinguish malignant lung nodules from benign nodules which could be used in clinical practice.

U.S. Consumer Demand for Plant-Based Milk Alternative Beverages: Hedonic Metric Augmented Barten's Synthetic Model.

Consumers in the U.S. increasingly prefer plant-based milk alternative beverages (abbreviated "plant milk") to conventional milk. This study is motivated by the need to take into consideration varied nutritional and qualitative attributes in plant milk to examine consumers' purchasing behavior and estimate demand elasticities which are achieved by a new approach combing hedonic pricing model with Barten's synthetic demand system. The method of estimation is enlightened from the common practice of companies differentiating their products in multidimensions in terms of attributes. A research dataset was uniquely created by associating the products' purchase data from Nielsen Homescan dataset with exclusive first-hand nutritional data. Estimations began with creating a multidimensional hedonic attribute space based on the qualitative information of different types of plant milk and conventional milk available to consumers and then calculating the hedonic distances by Euclidean distance measurement to reparametrize Barten's synthetic demand system. Estimation results showed that the highest own-price elasticity pertained to soy milk which was -0.25. Three plant milk types had inelastic demand. Soy milk exerted substituting effects on all types of conventional milk products and vice versa. Soy milk, rice milk and almond milk entertained complementary relationships between each other and four types of conventional milk were strong substitutes within the group.

Consumers preferences on nutritional attributes of dairy-alternative beverages: hedonic pricing models.

Dairy products, especially milk play a crucial role in assuring dietary quality for U.S. households. However, due to taste, nutrition, health and environmental concerns, households increasingly prefer to consume dairy alternative beverages instead of conventional milk in the U.S. This work is motivated by the need to take into consideration of intrinsic characteristics and differences of such characteristics when analyzing the changes of consumers' purchasing behavior of and willingness to pay for dairy alternative beverages and conventional milk products. After aggregating and organizing the purchase data of Nielsen Homescan and first-hand nutrition data, this study estimates both linear and semi-log hedonic pricing models. The results show that consumers exert the highest weights and assign highest evaluation on such qualitative characteristic as nutritional attributes which include calories, protein, fat, vitamin A and vitamin D in which protein is the most valued attribute and other characteristics such as package size, multi pack and brand. The hedonic pricing order and value of these qualitative characteristic are indicative of consumers' purchasing behavior and thus provide essential information for manufacturers to better differentiated their products and develop products catering to consumer's preferred attributes.

A consistent Great Lakes ice cover digital data set for winters 1973-2019.

Ice formation and loss in the Laurentian Great Lakes has a strong impact on regional climate, weather, economy and ecology in North America. To record the ice changes during the winter season, Great Lakes ice cover data has been collected and maintained since 1973 by Canadian Ice Service, U.S. National Ice Center, and National Oceanic and Atmospheric Administration's Great Lakes Environmental Research Laboratory. Throughout this long history, technology has improved and the needs of users have evolved, so Great Lakes ice cover datasets have been upgraded several times in both spatial and temporal resolutions. In order to make those long-term data consistent and accessible, we reprocessed the Great Lakes ice cover database to generate daily gridded data (1.8 km resolution) using a re-project method with Nearest Neighbor Search for spatial interpolation, and linear interpolation with categorization for temporal interpolation. This report elucidates data history, generation procedures, and file structure in order to improve access and usability of Great Lakes ice cover data.

TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleeding.

Excessive vascular remodeling is characteristic of hemophilic arthropathy (HA) and may contribute to joint bleeding and the progression of HA. Mechanisms for pathological vascular remodeling after hemophilic joint bleeding are unknown. In hemophilia, activation of thrombin-activatable fibrinolysis inhibitor (TAFI) is impaired, which contributes to joint bleeding and may also underlie the aberrant vascular remodeling. Here, hemophilia A (factor VIII-deficient; FVIII-deficient) mice or TAFI-deficient mice with transient (antibody-induced) hemophilia A were used to determine the role of FVIII and TAFI in vascular remodeling after joint bleeding. Excessive vascular remodeling and vessel enlargement persisted in FVIII-deficient and TAFI-deficient mice, but not in transient hemophilia WT mice, after similar joint bleeding. TAFI-overexpression in FVIII-deficient mice prevented abnormal vessel enlargement and vascular leakage. Age-related vascular changes were observed with FVIII or TAFI deficiency and correlated positively with bleeding severity after injury, supporting increased vascularity as a major contributor to joint bleeding. Antibody-mediated inhibition of uPA also prevented abnormal vascular remodeling, suggesting that TAFI's protective effects include inhibition of uPA-mediated plasminogen activation. In conclusion, the functional TAFI deficiency in hemophilia drives maladaptive vascular remodeling in the joints after bleeding. These mechanistic insights allow targeted development of potentially new strategies to normalize vascularity and control rebleeding in HA.