Search

Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS-MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5-2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting., (© 2024. The Author(s).)

Introduction: Previous investigations have reported that individuals living in greener neighborhoods have better cardiovascular health. It is unclear whether the effects reported at large geographic scales persist when examined at an intra-neighborhood level. The effects of greenness have not been thoroughly examined using high-resolution metrics of greenness exposure, and how they vary with spatial scales of assessment or participant characteristics., Methods: We conducted a cross-sectional assessment of associations between blood pressure and multiple high-resolution measures of residential area greenness in spatially concentrated HEAL Study cohort of the Green Heart Project. We employed generalized linear models, accounting for individual-level covariates, to examine associations between different high-resolution measures of greenness and blood pressure among 667 participants in a 4 sq. mile contiguous neighborhood area in Louisville, KY., Results: In adjusted models, we observed significant inverse associations between residential greenness, measured by leaf area index (LAI), and systolic blood pressure (SBP) within 150-250 m and 500 m of homes, but not for Normalized Difference Vegetation Index (NDVI) or grass cover. Weaker associations were also found with diastolic blood pressure (DBP). Significant positive associations were observed between LAI and SBP among participants who reported being female, White, without obesity, non-exercisers, non-smokers, younger age, of lower income, and who had high nearby roadway traffic. We found few significant associations between grass cover and SBP, but an inverse association in those with obesity, but positive associations for those without obesity., Conclusions: We found that leaf surface area of trees around participants home is strongly associated with lower blood pressure, with little association with grass cover. These effects varied with participant characteristics and spatial scales. More research is needed to test causative links between greenspace types and cardiovascular health and to develop population-, typology-, and place-based evidence to inform greening interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Electronic nicotine delivery systems (ENDS) aerosol exposures can induce endothelial dysfunction (ED) in healthy young humans and animals. Thermal degradation of ENDS solvents, propylene glycol, and vegetable glycerin (PG: VG), generates abundant formaldehyde (FA) and other carbonyls. Because FA can activate the transient receptor potential ankyrin-1 (TRPA1) sensor, we hypothesized that FA in ENDS aerosols provokes TRPA1-mediated changes that include ED and "respiratory braking"-biomarkers of harm. To test this, wild-type (WT) and TRPA1-null mice were exposed by inhalation to either filtered air, PG: VG-derived aerosol, or FA (5 ppm). Short-term exposures to PG: VG and FA-induced ED in female WT but not in female TRPA1-null mice. Moreover, acute exposures to PG: VG and FA stimulated respiratory braking in WT but not in TRPA1-null female mice. Urinary metabolites of FA (ie, N-1,3-thiazolidine-4-carboxylic acid, TCA; N-1,3-thiazolidine-4-carbonyl glycine, TCG) and monoamines were measured by LC-MS/MS. PG: VG and FA exposures significantly increased urinary excretion of both TCA and TCG in both WT and TRPA1-null mice. To confirm that inhaled FA directly contributed to urinary TCA, mice were exposed to isotopic 13C-FA gas (1 ppm, 6 h). 13C-FA exposure significantly increased the urine level of 13C-TCA in the early collection (0 to 3 h) supporting a direct relationship between inhaled FA and TCA. Collectively, these data suggest that ENDS use may increase CVD risk dependent on FA, TRPA1, and catecholamines, yet independently of either nicotine or flavorants. This study supports that levels of FA in ENDS-derived aerosols should be lowered to mitigate CVD risk in people who use ENDS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The endothelial barrier plays an active role in transendothelial tumor cell migration during metastasis, however, the endothelial regulatory elements of this step remain obscure. Here we show that endothelial RhoA activation is a determining factor during this process. Breast tumor cell-induced endothelial RhoA activation is the combined outcome of paracrine IL-8-dependent and cell-to-cell contact β 1 integrin-mediated mechanisms, with elements of this pathway correlating with clinical data. Endothelial-specific RhoA blockade or in vivo deficiency inhibited the transendothelial migration and metastatic potential of human breast tumor and three murine syngeneic tumor cell lines, similar to the pharmacological blockade of the downstream RhoA pathway. These findings highlight endothelial RhoA as a potent, universal target in the tumor microenvironment for anti-metastatic treatment of solid tumors.

In the current study, the Sonogashira coupling reaction of danazol with aryl halides was carried out, yielding new aryl substituted danazol derivatives. The synthetic compounds were examined for anti-cancer potential on the HeLa human cervical cancer cell line, and they showed promising cytotoxic action. Synthesized compounds 2, 4 and 5 inhibited the growth of HeLa cervical cancer cells, potentially making them effective anti-cancer drugs in the future. Furthermore, molecular docking studies were performed to evaluate the inhibitory impact of danazol derivatives on the Human Papillomavirus (HPV) target protein (1F9F). The docking results showed a significant inhibitory action against the cervical cancer protein (1F9F). The binding energy (ΔG) values of 1, 2, 3, 4 and 5 against the protein 1F9F were -8.01, -8.70, -9.43, -9.58 and -9.75 kcal/mol, indicating a high affinity of the synthesized compounds to bind with the HPV target proteins compared to their parent compound danazol (1). ADMET analyses of all derivatives have also been carried out., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12%, and multiple clinical trials testing anti-PD-1 therapies against PDAC have failed, suggesting a need for a novel therapeutic strategy. In this study, we evaluated the potential of milbemycin oxime (MBO), an antiparasitic compound, as an immunomodulatory agent in PDAC. Our results show that MBO inhibited the growth of multiple PDAC cell lines by inducing apoptosis. In vivo studies showed that the oral administration of 5 mg/kg MBO inhibited PDAC tumor growth in both subcutaneous and orthotopic models by 49% and 56%, respectively. Additionally, MBO treatment significantly increased the survival of tumor-bearing mice by 27 days as compared to the control group. Interestingly, tumors from MBO-treated mice had increased infiltration of CD8 + T cells. Notably, depletion of CD8 + T cells significantly reduced the anti-tumor efficacy of MBO in mice. Furthermore, MBO significantly augmented the efficacy of anti-PD-1 therapy, and the combination treatment resulted in a greater proportion of active cytotoxic T cells within the tumor microenvironment. MBO was safe and well tolerated in all our preclinical toxicological studies. Overall, our study provides a new direction for the use of MBO against PDAC and highlights the potential of repurposing MBO for enhancing anti-PD-1 immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Rationale: Low density cholesterol receptor (LDLR) in the liver is critical for the clearance of low-density lipoprotein cholesterol (LDL-C) in the blood. In atherogenic conditions, proprotein convertase subtilisin/kexin 9 (PCSK9) secreted by the liver, in a nonenzymatic fashion, binds to LDLR on the surface of hepatocytes, preventing its recycling and enhancing its degradation in lysosomes, resulting in reduced LDL-C clearance. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution of circulating LDL-C to atherosclerosis, we hypothesize that liver epsins promote atherosclerosis by controlling LDLR endocytosis and degradation., Objective: We will determine the role of liver epsins in promoting PCSK9-mediated LDLR degradation and hindering LDL-C clearance to propel atherosclerosis., Methods and Results: We generated double knockout mice in which both paralogs of epsins, namely, epsin-1 and epsin-2, are specifically deleted in the liver (Liver-DKO) on an ApoE -/- background. We discovered that western diet (WD)-induced atherogenesis was greatly inhibited, along with diminished blood cholesterol and triglyceride levels. Mechanistically, using scRNA-seq analysis on cells isolated from the livers of ApoE -/- and ApoE -/- /Liver-DKO mice on WD, we found lipogenic Alb hi hepatocytes to glycogenic HNF4α hi hepatocytes transition in ApoE -/- /Liver-DKO. Subsequently, gene ontology analysis of hepatocyte-derived data revealed elevated pathways involved in LDL particle clearance and very-low-density lipoprotein (VLDL) particle clearance under WD treatment in ApoE -/- /Liver-DKO, which was coupled with diminished plasma LDL-C levels. Further analysis using the MEBOCOST algorithm revealed enhanced communication score between LDLR and cholesterol, suggesting elevated LDL-C clearance in the ApoE -/- Liver-DKO mice. In addition, we showed that loss of epsins in the liver upregulates of LDLR protein level. We further showed that epsins bind LDLR via the ubiquitin-interacting motif (UIM), and PCSK9-triggered LDLR degradation was abolished by depletion of epsins, preventing atheroma progression. Finally, our therapeutic strategy, which involved targeting liver epsins with nanoparticle-encapsulated siRNAs, was highly efficacious at inhibiting dyslipidemia and impeding atherosclerosis., Conclusions: Liver epsins promote atherogenesis by mediating PCSK9-triggered degradation of LDLR, thus raising the circulating LDL-C levels. Targeting epsins in the liver may serve as a novel therapeutic strategy to treat atherosclerosis by suppression of PCSK9-mediated LDLR degradation.

Striking the right nutrient balance is essential for sustainable farming and ecosystem health. In this regard, field experiments were conducted in three phases viz., fertility gradient experiment, main experiment and validation experiment through a soil test crop response approach to develop and validate fertilizer prescription equations for sweet corn in comparison with general recommended dose and soil fertility rating approach. The soil data, fresh cob yield, and NPK uptake were used for establishing four important basic parameters, viz., nutrient requirement (kg t-1), contribution of nutrients from fertilizers, soil, and organic manure. The results revealed that nutrients required to produce one tonne of fresh cob yield (NR) were 5.85 kg, 0.87 kg and 4.31kg for N, P and K, respectively under the STCR NPK alone approach and 6.07 kg, 0.92 kg and 4.33 kg for N, P and K, respectively under STCR NPK+FYM approach. In the validation experiment, STCR NPK+FYM approach for the targeted yield of 25 t ha-1 recorded higher fresh cob yield (23.38 t ha-1) and dry stover yield (35.07 t ha-1) which were significantly higher compared to general recommended dose and soil fertility rating approach. The developed STCR equations for the aforesaid crop are valid as the percent deviation of cob yield from the targeted yield was within ±10%. Similarly, highest nutrient use efficiency was achieved with the STCR approach, specifically when targeting a lower yield through an NPK+FYM mode. Thus, implementation of the STCR approach of fertilizer prescription, with or without FYM, at targeted yields of 25 and 22 t ha-1, not only surpassed the effects of the other fertilizer recommendation approach in terms of cob yields, but also increased NPK uptake, improved nutrient use efficiency and greater economic returns., Competing Interests: The author reported no potential conflict of interest., (Copyright: © 2024 Rangaiah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Smoking elevates catecholamines that increase the risk for cardiovascular disease. Sparse evidence exists about the effects of e-cigarettes and catecholamines. Higher levels of catecholamines could trigger the increased heart rate, blood pressure, and decreased vascular function reported with the use of e-cigarettes. We investigated the difference in urinary catecholamines and their metabolites before and after the use of an e-cigarette containing nicotine or cigarettes compared to no tobacco use., Methods: In our observational cohort exposure study, healthy adults aged 21-45 years who were currently using e-cigarettes, cigarettes, or had never used tobacco, participated in an acute exposure visit using their most common tobacco product. Urine was collected before, 1, and 2 hours after a 3-second puff every 30 seconds for 10 minutes on an e-cigarette or straw or use of 1 cigarette. Urinary catecholamines and their metabolites were measured by ultra-high-performance liquid chromatography. Participants (n=323) were grouped by the product used at the visit. We compared levels of creatinine normalized log-transformed urinary catecholamines and their metabolites across groups using Dunn's test following a Kruskal-Wallis test in unadjusted and demographically adjusted models., Results: Prior to use, individuals who used cigarettes (n=70) had lower urinary metabolites from epinephrine, serotonin, and norepinephrine. No differences were seen in those who used e-cigarettes (n=171) and those who did not use tobacco (n=82). In fully adjusted models, 1 h after the use of a combustible or e-cigarette, log-transformed urinary metabolites from norepinephrine (β=1.22; 95% CI: 0.39-2.05, p=0.004 and β=1.06; 95% CI: 0.39-1.74, p=0.002), dopamine (β=0.37; 95% CI: 0.24-0.5, p<0.001 and β=0.15; 95% CI: 0.05-0.26, p<0.001), and epinephrine (β=1.89; 95% CI: 0.51-3.27, p=0.008 and β=1.49; 95% CI: 0.38-2.61, p=0.009) were elevated. In fully adjusted models, combustible cigarette use was associated with elevated urinary norepinephrine (β=0.46; 95% CI: 0.13-0.81, p=0.007) and dopamine (β=0.19; 95% CI: 0.06-0.31, p=0.003) 1 h after use., Conclusions: We found that the use of both e-cigarettes and cigarettes was associated with elevated urinary catecholamines or their metabolites. Catecholamines could be useful as a biomarker of harm for tobacco use and considered by tobacco regulatory scientists in future research., Competing Interests: The authors have each completed and submitted an ICMJE form for Disclosure of Potential Conflicts of Interest. The authors declare that they have no competing interests, financial or otherwise, related to the current work. R.M. Robertson reports that since the initial planning of the work, her organization (AHA) received the following grants: U54 HL120163 2018-2023 (NIH/FDA) and P50 HL120163 2012-2017 (NIH/ FDA). She also reports that in the past 36 months she received support for attending meetings and travel from the American Heart Association (AHA) and Robert Wood Johnson Foundation (RWJF), and that she was a Member and then Chair of the National Advisory Committee for the RWJF’s Harold Amos Medical Faculty Development Program (HAMFDP)., (© 2024 Poudel R. et al.)

The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.

Exposure to plants is known to improve physical and mental health and living in areas of high vegetation is associated with better health. The addition of quantitative measures of greenness exposure at individual-level to other objective and subjective study measures will help establish cause-and-effect relationships between greenspaces and human health. Because limonene is one of the most abundant biogenic volatile organic compounds emitted by plants, we hypothesized that urinary metabolites of inhaled limonene can serve as biomarkers of exposure to greenness. To test our hypothesis, we analyzed urine samples collected from eight human volunteers after limonene inhalation or after greenness exposure using liquid chromatography-high resolution mass spectrometry-based profiling. Eighteen isomers of nine metabolites were detected in urine after limonene inhalation, and their kinetic parameters were estimated using nonlinear mixed effect models. Urinary levels of most abundant limonene metabolites were elevated after brief exposure to a forested area, and the ratio of urinary limonene metabolites provided evidence of recent exposure. The identities and structures of these metabolites were validated using stable isotope tracing and tandem mass spectral comparison. Together, these data suggest that urinary metabolites of limonene, especially uroterpenol glucuronide and dihydroperillic acid glucuronide, could be used as individualized biomarkers of greenness exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil's anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations.

Fluorescence-guided surgery has emerged as a vital tool for tumour resection procedures. As well as intraoperative tumour visualisation, 5-ALA-induced PpIX provides an avenue for quantitative tumour identification based on ratiometric fluorescence measurement. To this end, fluorescence imaging and fibre-based probes have enabled more precise demarcation between the cancerous and healthy tissues. These sensing approaches, which rely on collecting the fluorescence light from the tumour resection site and its "remote" spectral sensing, introduce challenges associated with optical losses. In this work, we demonstrate the viability of tumour detection at the resection site using a miniature fluorescence measurement system. Unlike the current bulky systems, which necessitate remote measurement, we have adopted a millimetre-sized spectral sensor chip for quantitative fluorescence measurements. A reliable measurement at the resection site requires a stable optical window between the tissue and the optoelectronic system. This is achieved using an antifouling diamond window, which provides stable optical transparency. The system achieved a sensitivity of 92.3% and specificity of 98.3% in detecting a surrogate tumour at a resolution of 1 × 1 mm 2 . As well as addressing losses associated with collecting and coupling fluorescence light in the current 'remote' sensing approaches, the small size of the system introduced in this work paves the way for its direct integration with the tumour resection tools with the aim of more accurate interoperative tumour identification.

2-aminothiophenes derivative, Ethyl-2-amino-4-methyl thiophene-3-carboxylate (EAMC) has been synthesized, characterized, and investigated quantum chemically. It was experimentally investigated by different spectroscopic methods like- NMR ( 1 H-NMR and 13 C-NMR), FT-IR, and UV-Visible. B3LYP method and 6-311++G(d,p) basis set were employed for optimization of molecular structure and calculation of wave numbers of normal modes of vibrations and various other important parameters. Calculated bond lengths and angles were compared with the experimental bond lengths and Bond Angle Parameters. Optimized bond parameters and experimental bond parameters were found in good agreement. Complete potential energy distribution assignments were done successfully by VEDA. The HOMO/LUMO energy gap emphasizes adequate charge transfer happening within the molecule. A study of donor-acceptor interconnections was done via NBO analysis. MEP surface analysis was done to demonstrate charge distribution and reactive areas qualitatively in the molecule. The degree of relative localization of electrons was analyzed via ELF Diagram. The Fukui function analysis showed possible sites for attacks by different substituents. By using the TD-DFT method and PCM solvent model, the UV-Vis spectrum (gas, methanol, DMSO) and the maximum absorption wavelength was computed and compared with experimental data. 3D and 2D intermolecular interactions in the crystal were analyzed via Hirshfeld surface analysis and fingerprint plots reveal that the EAMC crystal was stabilized by H--H/H--H/C--H bond formation. The molecular docking was done with 7 different protein receptors on the molecule to find the best ligand-protein interactions. Molecular dynamic simulations and MMGBSA calculations were also carried out to find out the best binding of the ligand with the protein.Communicated by Ramaswamy H. Sarma.

Increased adiposity of both visceral and perivascular adipose tissue (PVAT) depots is associated with an increased risk of diabetes and cardiovascular disease (CVD). Under healthy conditions, PVAT modulates vascular tone via the release of PVAT-derived relaxing factors, including adiponectin and leptin. However, when PVAT expands with high-fat diet (HFD) feeding, it appears to contribute to the development of endothelial dysfunction (ED). Yet, the mechanisms by which PVAT alters vascular health are unclear. Aldose reductase (AR) catalyzes glucose reduction in the first step of the polyol pathway and has been long implicated in diabetic complications including neuropathy, retinopathy, nephropathy, and vascular diseases. To better understand the roles of both PVAT and AR in HFD-induced ED, we studied structural and functional changes in aortic PVAT induced by short-term HFD (60% kcal fat) feeding in wild type (WT) and aldose reductase-null (AR-null) mice. Although 4 weeks of HFD feeding significantly increased body fat and PVAT mass in both WT and AR-null mice, HFD feeding induced ED in the aortas of WT mice but not of AR-null mice. Moreover, HFD feeding augmented endothelial-dependent relaxation in aortas with intact PVAT only in WT and not in AR-null mice. These data indicate that AR mediates ED associated with short-term HFD feeding and that ED appears to provoke 'compensatory changes' in PVAT induced by HFD. As these data support that the ED of HFD feeding is AR-dependent, vascular-localized AR remains a potential target of temporally selective intervention.

Established in October 2021, the Cell and Gene Therapy (CGT) Consortium convened with the goal to bring together key CGT stakeholders - manufacturers, treatment centers, regulators, services providers, and ecosystem partners - to gain alignment on process definitions, terminology, challenges, and opportunities for process and data standardization from CGT program start-up and patient enrollment to therapy administration. With the recognition that the number of investigational and commercial cell and gene therapies will scale over the next several years, so will the number of manufacturer-specific processes and solutions (e.g., portals). As a result, this will increase the burden on academic medical centers, community hospitals, standalone clinics, collection facilities, and labs. Healthcare professionals (HCPs) and other industry stakeholders agree that a multiplicity of manufacturer portals with varying data requirements and nomenclature is unsustainable and adds unnecessary complexity - risk, cost, and time - in coordinating patient treatment. Following extensive discussions and multiple stakeholder meetings and interviews, we have developed a manuscript reporting on our activities and conclusions. Through the course of the manuscript, we delineate a framework for defining common principles, terminology, and user experiences for enrolling patients, ordering therapies, and collecting starting material in a standardized way. We also provide substantial background information on opportunities to streamline communications between manufacturing and healthcare organizations from the HCP end-user's perspective., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The divalent (Ca 2+ )-doped Eu:Y 2 O 3 @SiO 2 core-shell luminescent nanophosphors have been synthesised by a cost-effective combustion technique. Various characterizations were carried out to confirm the successful formation of the core-shell structure. The TEM micrograph reveals the thickness of the SiO 2 coating over Ca-Eu:Y 2 O 3 as ∼25 nm. The optimal value of silica coating over the phosphor has been obtained as 10 vol%(TEOS) of SiO 2 , with this value increasing fluorescence intensity by 34 %. Phosphor exhibits CIE coordinates as x = 0.425, y = 0.569 and a CCT value as ∼2115 K with color purity and the respective CRI of 80 % and 98 %, respectively, which make the core-shell nanophosphor suitable for warm LEDs, and other optoelectronic applications. Further, the core-shell nanophosphor has been investigated for the visualisation of latent finger prints and as security ink. The findings point towards the prospective future application of nanophosphor materials for anti-counterfeiting purposes and latent finger prints for forensic purposes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Urinary mercapturic acids (MAs) are often used as biomarkers for monitoring human exposures to occupational and environmental xenobiotics. In this study, we developed an integrated library-guided analysis workflow using ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry. This method includes expanded assignment criteria and a curated library of 220 MAs and addresses the shortcomings of previous untargeted approaches. We employed this workflow to profile MAs in the urine of 70 participants─40 nonsmokers and 30 smokers. We found approximately 500 MA candidates in each urine sample, and 116 MAs from 63 precursors were putatively annotated. These include 25 previously unreported MAs derived mostly from alkenals and hydroxyalkenals. Levels of 68 MAs were comparable in nonsmokers and smokers, 2 MAs were higher in nonsmokers, and 46 MAs were elevated in smokers. These included MAs of polycyclic aromatic hydrocarbons and hydroxyalkenals and those derived from toxicants present in cigarette smoke (e.g., acrolein, 1,3-butadiene, isoprene, acrylamide, benzene, and toluene). Our workflow allowed profiling of known and unreported MAs from endogenous and environmental sources, and the levels of several MAs were increased in smokers. Our method can also be expanded and applied to other exposure-wide association studies.

The development of imaging technology and optical communication demands a photodetector with high responsiveness. As demonstrated by microfabrication and nanofabrication technology advancements, recent progress in plasmonic sensor technologies can address this need. However, these photodetectors have low optical absorption and ineffective charge carrier transport efficiency. Sb 2 Se 3 is light-sensitive material with a high absorption coefficient, making it suitable for photodetector applications. We developed an efficient, scalable, low-cost near-infrared (NIR) photodetector based on a nanostructured Sb 2 Se 3 film deposited on p -type micropyramidal Si (made via the wet chemical etching process), working on photoconductive phenomena. Our results proved that, at the optimized thickness of the Sb 2 Se 3 layer, the proposed Si micropyramidal substrate enhanced the responsivity nearly two times, compared with that of the Sb 2 Se 3 deposited on a flat Si reference sample and a glass/Sb 2 Se 3 sample at 1064 nm (power density = 15 mW/cm 2 ). More interestingly, the micropyramidal silicon-based device worked at 0 V bias, paving a path for self-bias devices. The highest specific detectivity of 2.25 × 10 15 Jones was achieved at 15 mW/cm 2 power density at a bias voltage of 0.5 V. It is demonstrated that the enhanced responsivity was closely linked with field enhancement due to the Kretschmann configuration of Si pyramids, which acts as hot spots for Si/Sb 2 Se 3 junction. A high responsivity of 47.8 A W -1 proved it suitable for scalable and cost-effective plasmonic-based NIR photodetectors.

Background and Aims: Most guidelines recommend protein restriction in adults with chronic kidney disease (CKD), with or without diabetes. However, advising protein restriction for every person with CKD is controversial. We aim to arrive at a consensus on this topic, especially among Indian adults with CKD., Methods: A systematic literature search in the PubMed electronic database was undertaken using specific keywords and MeSH terms until May 1, 2022. All the retrieved literature was circulated and rigorously deliberated upon by the panel members., Results: Seventeen meta-analyses that evaluated the outcomes of protein restriction in adults with CKD, with or without diabetes, met our inclusion criteria and were analyzed. A low-protein diet (LPD) in people with stages 3-5 of CKD (who are not on haemodialysis [HD]) reduces the severity of uremic symptoms and the rate of decline in glomerular filtration rate, leading to a delay in dialysis initiation. However, LPD in patients on maintenance HD may not be desirable because HD-induced protein catabolism may lead to protein-energy malnutrition. Since the average protein intake among Indians is much lower than recommended, this must be taken into consideration before recommending LPD for all Indian adults with CKD, particularly those on maintenance HD., Conclusion: It is essential to assess the nutritional status of people with CKD, particularly in countries like India where average daily protein intake is poor, before recommending guideline-directed protein restriction. The prescribed diet, including the quantity and quality of proteins, should be tailored to the person's habits, tastes, and needs., Competing Interests: Declaration of competing interest We hereby declare that we have no conflict of interest, related to this article titled “Protein Restriction in Adults with Chronic Kidney Disease, with or without Diabetes: Integrated Diabetes and Endocrine Academy (IDEA) Consensus Statement for Indian Patients”., (Copyright © 2023 Research Trust of DiabetesIndia (DiabetesIndia) and National Diabetes Obesity and Cholesterol Foundation (N-DOC). Published by Elsevier Ltd. All rights reserved.)

While occupational exposures to volatile organic compounds (VOCs) have been linked to steatohepatitis and liver cancer in industrial workers, recent findings have also positively correlated low-dose, residential VOC exposures with liver injury markers. VOC sources are numerous; factors including biological make up (sex), socio-cultural constructs (gender, race) and lifestyle (smoking) can influence both VOC exposure levels and disease outcomes. Therefore, the current study's objective is to investigate how sex and race influence associations between residential VOC exposures and liver injury markers particularly in smokers vs. nonsmokers. Subjects (n = 663) were recruited from residential neighborhoods; informed consent was obtained. Exposure biomarkers included 16 urinary VOC metabolites. Serological disease biomarkers included liver enzymes, direct bilirubin, and hepatocyte death markers (cytokeratin K18). Pearson correlations and generalized linear models were conducted. Models were adjusted for common liver-related confounders and interaction terms. The study population constituted approximately 60% females (n = 401) and 40% males (n = 262), and a higher percent of males were smokers and/or frequent drinkers. Both sexes had a higher percent of White (75% females, 82% males) vs. Black individuals. Positive associations were identified for metabolites of acrolein, acrylamide, acrylonitrile, butadiene, crotonaldehyde, and styrene with alkaline phosphatase (ALP), a biomarker for cholestatic injury; and for the benzene metabolite with bilirubin; only in females. These associations were retained in female smokers. Similar associations were also observed between these metabolites and ALP only in White individuals (n = 514). In Black individuals (n = 114), the styrene metabolite was positively associated with aspartate transaminase. Interaction models indicated that positive associations for acrylamide/crotonaldehyde metabolites with ALP in females were dose-dependent. Most VOC associations with K18 markers were negative in this residential population. Overall, the findings demonstrated that biological sex, race, and smoking status influence VOC effects on liver injury and underscored the role of biological-social-lifestyle factor(s) interactions when addressing air pollution-related health disparities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Among the plethora of defense mechanisms which a host elicits after pathogen invasion, type 1 interferons play a central role in regulating the immune system's response. They induce several interferon-stimulated genes (ISGs) which play a diverse role once activated. Over the past few decades, there have been several studies exploring the role of ISGs in cancer and ISG15 is among the most studied for its pro and anti-tumorigenic role. In this review, we aim to provide an update on the recent observations and findings related to ISG15 in cancer. We provide a brief overview about the initial observations and important historical findings which helped scientists understand structure and function of ISG15. We aim to provide an overview of ISG15 in cancer with an emphasis on studies which delve into the molecular mechanism of ISG15 in modulating the tumor microenvironment. Further, the dysregulation of ISG15 in cancer and the molecular mechanisms associated with its pro and anti-tumor roles are discussed in respective cancer types. Finally, we discuss multiple therapeutic applications of ISG15 in current cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Circulating angiogenic cells (CACs) are indicative of vascular health and repair capacity; however, their relationship with chronic e-cigarette use is unclear. This study aims to assess the association between e-cigarette use and CAC levels., Methods: We analyzed CAC levels in 324 healthy participants aged 21-45 years from the cross-sectional Cardiovascular Injury due to Tobacco Use study in four groups: never tobacco users ( n = 65), sole e-cigarette users ( n = 19), sole combustible cigarette users ( n = 212), and dual users ( n = 28). A total of 15 CAC subpopulations with four cell surface markers were measured using flow cytometry: CD146 (endothelial), CD34 (stem), CD45 (leukocyte), and AC133 (early progenitor/stem). Generalized linear models with gamma distribution and log-link were generated to assess association between CACs and smoking status. Benjamini-Hochberg were used to adjust p -values for multiple comparisons., Results: The cohort was 47% female, 51% Black/African American, with a mean (± SD) age of 31 ± 7 years. Sole cigarette use was significantly associated with higher levels of two endothelial marker CACs (Q ⩽ 0.05). Dual users had higher levels of four endothelial marker CACs and one early progenitor/stem marker CAC (Q ⩽ 0.05). Sole e-cigarette users had higher levels of one endothelial and one leukocyte marker CAC (Q ⩽ 0.05)., Conclusion: Dual use of e-cigarettes and combustible cigarettes was associated with higher levels of endothelial origin CACs, indicative of vascular injury. Sole use of e-cigarettes was associated with higher endothelial and inflammatory CACs, suggesting ongoing systemic injury. Distinct patterns of changes in CAC subpopulations suggest that CACs may be informative biomarkers of changes in vascular health due to tobacco product use.

Background: Excess cholesterol accumulation in lesional macrophages elicits complex responses in atherosclerosis. Epsins, a family of endocytic adaptors, fuel the progression of atherosclerosis; however, the underlying mechanism and therapeutic potential of targeting Epsins remains unknown. In this study, we determined the role of Epsins in macrophage-mediated metabolic regulation. We then developed an innovative method to therapeutically target macrophage Epsins with specially designed S2P-conjugated lipid nanoparticles, which encapsulate small-interfering RNAs to suppress Epsins., Methods: We used single-cell RNA sequencing with our newly developed algorithm MEBOCOST (Metabolite-mediated Cell Communication Modeling by Single Cell Transcriptome) to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells. Biomedical, cellular, and molecular approaches were utilized to investigate the role of macrophage Epsins in regulating lipid metabolism and transport. We performed this study using myeloid-specific Epsin double knockout (LysM-DKO) mice and mice with a genetic reduction of ABCG1 (ATP-binding cassette subfamily G member 1; LysM-DKO-ABCG1 fl/+ ). The nanoparticles targeting lesional macrophages were developed to encapsulate interfering RNAs to treat atherosclerosis., Results: We revealed that Epsins regulate lipid metabolism and transport in atherosclerotic macrophages. Inhibiting Epsins by nanotherapy halts inflammation and accelerates atheroma resolution. Harnessing lesional macrophage-specific nanoparticle delivery of Epsin small-interfering RNAs, we showed that silencing of macrophage Epsins diminished atherosclerotic plaque size and promoted plaque regression. Mechanistically, we demonstrated that Epsins bound to CD36 to facilitate lipid uptake by enhancing CD36 endocytosis and recycling. Conversely, Epsins promoted ABCG1 degradation via lysosomes and hampered ABCG1-mediated cholesterol efflux and reverse cholesterol transport. In a LysM-DKO-ABCG1 fl/+ mouse model, enhanced cholesterol efflux and reverse transport due to Epsin deficiency was suppressed by the reduction of ABCG1., Conclusions: Our findings suggest that targeting Epsins in lesional macrophages may offer therapeutic benefits for advanced atherosclerosis by reducing CD36-mediated lipid uptake and increasing ABCG1-mediated cholesterol efflux.

People from different cultural backgrounds vary in how they define, perceive, and react to violations of relational boundaries. Muslim cultures are diverse and include nearly one in four people in the world, yet research on their relational and moral norms is scarce. We contribute to narrowing this gap by studying gheirat , a moral-emotional experience ubiquitous in Muslim Middle Eastern cultures. In four mixed-methods studies, we study how gheirat is experienced, what situations elicit it, and its social functions among Iranian adults ( N = 1,107) using qualitative interviews, scenario- and prototype-based surveys, and an experiment. The prototypical experience of gheirat consisted of diverse appraisals (including sense of responsibility, insecurity, and low self-worth) and emotional components (including hostility, social fears, and low empowerment). We identified three types of relational violations that elicit gheirat: harm or insult to namoos (people and self-relevant entities one is obliged to protect), romantic betrayal by namoos, and intrusions by a third person. Each violation type led to a distinct variant of the prototype. Contrary to folk theories of gheirat, we did not find support for the idea that gheirat is a predominantly male experience. However, an experiment on the signaling effects of gheirat revealed that gheirat expressors are ascribed both positive and negative traits, but positive traits prevail for men and negative traits prevail for women. We discuss how the results contribute to a better understanding of Iranian social life and intercultural contact, as well as the implications for theories of emotion and the cultural logic of honor. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Background Although the effects of psychological health and optimism have been extensively investigated, data from community-based cohorts assessing the association between psychological health and cardiovascular disease risk factors are sparse, and the concurrent relationship between subjective well-being and cardiovascular health has not been studied. Methods and Results The current cross-sectional study examined the association between well-being and cardiovascular risk factors among 719 individuals living in a middle- to low-income neighborhood. After adjusting for age, sex, race, body mass index, education, smoking status, and exercise status, we found that higher levels of well-being were significantly associated with lower odds of dyslipidemia (odds ratio [OR], 0.7 [95% CI, 0.55-0.85]) and hypertension (OR, 0.8 [95% CI, 0.63-0.92]). Greater well-being was also significantly associated with lower triglyceride levels (mean difference [M diff ], 7.6 [-14.31 to -0.78]), very low-density lipoprotein (M diff , 0.9 [-1.71 to -0.16]), total cholesterol to high-density lipoprotein ratio (M diff , 3.9 [-6.07 to -1.73]), higher high-density lipoprotein levels (M diff , 1.6 [0.46-2.75]), and lower Framingham Risk Scores (M diff , -7.1% [-10.84% to -3.16%]). Well-being also moderated the association between age and arterial stiffness. The strongest association between arterial stiffness and age was found for those with the lowest well-being scores; there was no association between age and arterial stiffness at high levels of well-being. Conclusions In a community-based cohort, individuals reporting higher levels of well-being have lower odds of hypertension and dyslipidemia as well as lower rates of age-dependent increase in vascular stiffness. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03670524.

In an attempt to find a potential cure for cancer, scientists have been probing the efficacy of the food we eat and its bioactive components. Over the decades, there has been an exponentially increasing trend of research correlating food and cancer. This review explains the molecular mechanisms by which bioactive food components exhibit anticancer effects in several cancer models. These bioactive compounds are mainly plant based or microbiome based. While plants remain the primary source of these phytochemicals, little is known about probiotics, i.e., microbiome sources, and their relationships with cancer. Thus, the molecular mechanisms underlying the anticancer effect of probiotics are discussed in this review. The principal mode of cell death for most food bioactives is found to be apoptosis. Principal oncogenic signaling axes such as Akt/PI3K, JAK/STAT, and NF-κB seem to be modulated due to these bioactives along with certain novel targets that provide a platform for further oncogenic research. It has been observed that probiotics have an immunomodulatory effect leading to their chemopreventive actions. Various foods exhibit better efficacy as complete extracts than their individual phytochemicals, indicating an orchestrated effect of the food components. Combining bioactive agents with available chemotherapies helps synergize the anticancer action of both to overcome drug resistance. Novel techniques to deliver bioactive agents enhance their therapeutic response. Such combinations and novel approaches are also discussed in this review. Notably, most of the food components that have been studied for cancer have shown their efficacy in vivo. This bolsters the claims of these studies and, thus, provides us with hope of discovering anticancer agents in the food that we eat.

Immune checkpoint proteins (ICP) are currently one of the most novel and promising areas of immune-oncology research. This novel way of targeting tumor cells has shown favorable success over the past few years with some FDA approvals such as Ipilimumab, Nivolumab, Pembrolizumab etc. Currently, more than 3000 clinical trials of immunotherapeutic agents are ongoing with majority being ICPs. However, as the number of trials increase so do the challenges. Some challenges such as adverse side effects, non-specific binding on healthy tissues and absence of response in some subset populations are critical obstacles. For a safe and effective further therapeutic development of molecules targeting ICPs, understanding their mechanism at molecular level is crucial. Since ICPs are mostly membrane bound receptors, a number of downstream signaling pathways divaricate following ligand-receptor binding. Most ICPs are expressed on more than one type of immune cell populations. Further, the expression varies within a cell type. This naturally varied expression pattern adds to the difficulty of targeting specific effector immune cell types against cancer. Hence, understanding the expression pattern and cellular mechanism helps lay out the possible effect of any immunotherapy. In this review, we discuss the signaling mechanism, expression pattern among various immune cells and molecular interactions derived using interaction database analysis (BioGRID)., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Immune check point inhibitors (ICIs) have marked their existence in the field of cancer immunotherapy. Their existence dates to 2011 when the first anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) got its FDA approval for the management of metastatic melanoma. The class of ICIs now also include antibodies against programmed cell death-1 (PD-1) and its ligand (PD-L1) which immediately gained FDA approval for use against multiple cancer types because of their effect on patient survival. These discoveries were followed by a significant rise in the identification of novel ICIs with potential anti-tumor response. Researchers have identified various novel checkpoint inhibitors which are currently under clinical trials. Despite the success of ICIs, only a small subset of patients with specific tumor types achieves a promising response. Not only efficient therapeutic response but also development of resistance, recurrence and other immune-related adverse effects limit the applicability of immune checkpoint inhibitors. These challenges can only be addressed when a directed approach is implemented at both basic and translational level. In this review, we have briefly discussed the history of ICIs, the next generation of inhibitors which are currently under clinical trial and mechanisms of resistance that can lead to treatment failure. Ultimately, by combining these insights researchers might be able to achieve a more durable and effective response in cancer patients., Competing Interests: Conflict of interest Authors disclose no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Workplace culture has been studied for impact on health risk; however, connections with robust biologic markers of health remain to be established. We examined associations between the work environment and urinary levels of catecholamines and their metabolites as biomarkers of sympathetic nervous system activity, indicative of stress. We recruited participants (n = 219; 2018-2019) from a cardiovascular risk cohort to investigate workplace culture, well-being, and stress. Participants completed seven questionnaires. Urine samples were used to measure catecholamines and their metabolites by LC/MS/MS. Pearson correlation and linear regression models were used after adjusting for demographics and creatinine. Participants reporting higher well-being had lower urinary levels of dopamine, serotonin, and 3-methoxytyramine. Participants reporting a more engaged and more positive workplace had lower levels of dopamine and 3-methoxytyramine. Reported workplace isolation was correlated with higher levels of dopamine and 3-methoxytyramine. Given correlations between catecholamines, we used 3-methoxytyramine for linear regression. In fully adjusted models, in environments with a more positive culture, levels of 3-methoxytyramine remained lower (β = -0.065 ± 0.025, p = 0.01) and indicated a positive association between workplace isolation and 3-methoxytyramine (β = 0.064 ± 0.030, p = 0.04). These findings are consistent with an important relationship between workplace environment and sympathetic nervous system activity.

The Sonic hedgehog-activated subgroup of medulloblastoma (SHH-MB) is one of the most common malignant pediatric brain tumors. Recent clinical studies and genomic databases indicate that GABA A receptor holds significant clinical relevance as a therapeutic target for pediatric MB. Herein, we report that "moxidectin," a GABA A receptor agonist, inhibits the proliferation of Daoy, UW426, UW228, ONS76, and PFSK1 SHH-MB cells by inducing apoptosis. Immunoblotting and immunofluorescence microscopy demonstrated that moxidectin significantly induced GABA A receptor expression and inhibited cyclic AMP (cAMP)-mediated protein kinase A (PKA)-cAMP response element-binding protein (CREB)-Gli1 signaling in SHH-MB. Gli1 and the downstream effector cancer stem cell (CSC) molecules such as Pax6, Oct4, Sox2, and Nanog were also inhibited by moxidectin treatment. Interestingly, moxidectin also inhibited the expression of MDR1. Mechanistic studies using pharmacological or genetic inhibitors/activators of PKA and Gli1 confirmed that the anti-proliferative and apoptotic effects of moxidectin were mediated through inhibition of PKA-Gli1 signaling. Oral administration of 2.5 mg/kg moxidectin suppressed the growth of SHH-MB tumors by 55%-80% in subcutaneous and intracranial tumor models in mice. Ex vivo analysis of excised tumors confirmed the observations made in the in vitro studies. Moxidectin is an FDA-approved drug with an established safety record, therefore any positive findings from our studies will prompt its further clinical investigation for the treatment of MB patients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Psychological science is at an inflection point: The COVID-19 pandemic has exacerbated inequalities that stem from our historically closed and exclusive culture. Meanwhile, reform efforts to change the future of our science are too narrow in focus to fully succeed. In this article, we call on psychological scientists-focusing specifically on those who use quantitative methods in the United States as one context for such conversations-to begin reimagining our discipline as fundamentally open and inclusive. First, we discuss whom our discipline was designed to serve and how this history produced the inequitable reward and support systems we see today. Second, we highlight how current institutional responses to address worsening inequalities are inadequate, as well as how our disciplinary perspective may both help and hinder our ability to craft effective solutions. Third, we take a hard look in the mirror at the disconnect between what we ostensibly value as a field and what we actually practice. Fourth and finally, we lead readers through a roadmap for reimagining psychological science in whatever roles and spaces they occupy, from an informal discussion group in a department to a formal strategic planning retreat at a scientific society.

Because little is known about the effects of individual flavorants in electronic cigarette (e-cig) fluids on human platelet aggregation, we tested for the direct effects of 15 common e-cig flavorants on adenosine diphosphate (ADP)-induced human platelet aggregation ex vivo . To better understand a potential mechanism of action of flavorants, we quantified 2 phases of aggregation. Human platelet-rich plasma (PRP) was obtained from whole blood of healthy volunteers and used in a platelet aggregometry assay. PRP was incubated with 1 of 15 different flavorant compounds (e.g., benzyl alcohol, eugenol, citronellol, menthol, menthone, diacetyl, maltol, limonene, methylbutyric acid, isoamyl acetate, acetylpyridine, eucalyptol, 2,5-dimethylpyrazine, cinnamaldehyde, and vanillin) at 100 µM for 5 min at 37 °C prior to addition of ADP (10 µM). Subsequent ADP-induced platelet aggregation was tracked for 5 min using an aggregometer. Aggregation curves were analyzed for flavorant-induced effects on total (%) aggregation, Phase 1 and Phase 2 components, and compared with their ADP-only control via One-Way ANOVA. Notably, eugenol significantly inhibited total aggregation; an effect due solely to inhibition of Phase 2. No other flavor tested had any effect on total or phase-specific ADP-induced platelet aggregation. These results indicate that parent flavorant compounds commonly found in e-cig liquids neither activate nor inhibit ADP-induced human platelet aggregation. However, as flavorants are chemically altered during heating of e-cig, thermally-derived products of flavorants (e.g., flavor acetals) also will need to be tested for effects on platelet activation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

A series of Eu 3+ ions doped Ca 0.05 Y 1.93- xO 3 :0.02Ho 3+ (CYO:Ho 3+ ,xEu 3+ ) nanophosphors having multicolour tuneability have been synthesised by following a simplistic solution combustion approach. The synthesised samples have been characterised by employing X-ray diffraction (XRD), Transmission electron microscope (TEM), and Fourier transforms infrared spectroscopy (FTIR). The optical properties have been engrossed by UV-visible and photoluminescent excitation and emission spectra, and decay lifetimes measurements. The characteristic emission, which occurs due to the f-f transition of Ho 3+ and Eu 3+ has been observed in emission spectra with excitation of 448 nm. By adjusting the doping ratio of Ho 3+ /Eu 3+ , the as-synthesized nanophosphor accomplishes multicolour tunability from green-yellow to red. Emission spectra and decay lifetime curve recommend dipole-dipole interaction causes energy transfer from Ho 3+  → Eu 3+ . The energy transfer process from Ho 3+ to Eu 3+ has been confirmed through electric dipole-dipole interaction with critical distance 15.146 Å. Moreover, temperature dependent emission spectra show the high thermal stability with an activation energy ⁓ 0.21 eV, with the quantum efficiency of 83.6%. CIE coordinate illustrates that the singly doped Ho 3+ and Eu 3+ lie in the green and red region, respectively, while the as-synthesized CYO:Ho 3+ ,xEu 3+ shows tunability from green to red with low CCT and high colour purity values. Hence, the CYO:Ho 3+ ,xEu 3+ nanophosphor may be a near-UV excited multicolour colour-tunable pertinent candidate with potential prospects for multicolour- display and near-ultraviolet lighting applications., (© 2022. The Author(s).)

Despite the increasing popularity of e-cigarettes, their long-term health effects remain unknown. In animal models, exposure to e-cigarette has been reported to result in pulmonary and cardiovascular injury, and in humans, the acute use of e-cigarettes increases heart rate and blood pressure and induces endothelial dysfunction. In both animal models and humans, cardiovascular dysfunction associated with e-cigarettes has been linked to reactive aldehydes such as formaldehyde and acrolein generated in e-cigarette aerosols. These aldehydes are known products of heating and degradation of vegetable glycerin (VG) present in e-liquids. Here, we report that in mice, acute exposure to a mixture of propylene glycol:vegetable glycerin (PG:VG) or to e-cigarette-derived aerosols significantly increased the urinary excretion of acrolein and glycidol metabolites─3-hydroxypropylmercapturic acid (3HPMA) and 2,3-dihydroxypropylmercapturic acid (23HPMA)─as measured by UPLC-MS/MS. In humans, the use of e-cigarettes led to an increase in the urinary levels of 23HPMA but not 3HPMA. Acute exposure of mice to aerosols derived from PG: 13 C 3 -VG significantly increased the 13 C 3 enrichment of both urinary metabolites 13 C 3 -3HPMA and 13 C 3 -23HPMA. Our stable isotope tracing experiments provide further evidence that thermal decomposition of vegetable glycerin in the e-cigarette solvent leads to generation of acrolein and glycidol. This suggests that the adverse health effects of e-cigarettes may be attributable in part to these reactive compounds formed through the process of aerosolizing nicotine. Our findings also support the notion that 23HPMA, but not 3HPMA, may be a relatively specific biomarker of e-cigarette use.

Objective: Volatile organic compounds (VOCs) are airborne toxicants abundant in outdoor and indoor air. High levels of VOCs are also present at various Superfund and other hazardous waste sites; however, little is known about the cardiovascular effects of VOCs. We hypothesized that ambient exposure to VOCs exacerbate cardiovascular disease (CVD) risk by depleting circulating angiogenic cells (CACs)., Approach and Results: In this cross-sectional study, we recruited 603 participants with low-to-high CVD risk and measured 15 subpopulations of CACs by flow cytometry and 16 urinary metabolites of 12 VOCs by LC/MS/MS. Associations between CAC and VOC metabolite levels were examined using generalized linear models in the total sample, and separately in non-smokers. In single pollutant models, metabolites of ethylbenzene/styrene and xylene, were negatively associated with CAC levels in both the total sample, and in non-smokers. The metabolite of acrylonitrile was negatively associated with CD45 dim /CD146 + /CD34 + /AC133 + cells and CD45 + /CD146 + /AC133 + , and the toluene metabolite with AC133 + cells. In analysis of non-smokers (n = 375), multipollutant models showed a negative association with metabolites of ethylbenzene/styrene, benzene, and xylene with CD45 dim /CD146 + /CD34 + cells, independent of other VOC metabolite levels. Cumulative VOC risk score showed a strong negative association with CD45 dim /CD146 + /CD34 + cells, suggesting that total VOC exposure has a cumulative effect on pro-angiogenic cells. We found a non-linear relationship for benzene, which showed an increase in CAC levels at low, but depletion at higher levels of exposure. Sex and race, hypertension, and diabetes significantly modified VOC associated CAC depletion., Conclusion: Low-level ambient exposure to VOCs is associated with CAC depletion, which could compromise endothelial repair and angiogenesis, and exacerbate CVD risk., (Copyright © 2022. Published by Elsevier Inc.)

Vinyl chloride (VC) is an organochlorine mainly used to manufacture its polymer polyvinyl chloride, which is extensively used in the manufacturing of consumer products. Recent studies suggest that chronic low dose VC exposure affects glucose homeostasis in high fat diet-fed mice. Our data suggest that even in the absence of high fat diet, exposure to VC (0.8 ppm, 6 h/day, 5 day/week, for 12 weeks) induces glucose intolerance (1.0 g/kg, i.p.) in male C57BL/6 mice. This was accompanied with the depletion of hepatic glutathione and a modest increase in lung interstitial macrophages. VC exposure did not affect the levels of circulating immune cells, endothelial progenitor cells, platelet-immune cell aggregates, and cytokines and chemokines. The acute challenge of VC-exposed mice with LPS did not affect lung immune cell composition or plasma IL-6. To examine the effect of VC exposure on vascular inflammation and atherosclerosis, LDL receptor-KO mice on C57BL/6 background maintained on western diet were exposed to VC for 12 weeks (0.8 ppm, 6 h/day, 5 day/week). Unlike the WT C57BL/6 mice, VC exposure did not affect glucose tolerance in the LDL receptor-KO mice. Plasma cytokines, lesion area in the aortic valve, and markers of lesional inflammation in VC-exposed LDL receptor-KO mice were comparable with the air-exposed controls. Collectively, despite impaired glucose tolerance and modest pulmonary inflammation, chronic low dose VC exposure does not affect surrogate markers of cardiovascular injury, LPS-induced acute inflammation in C57BL/6 mice, and chronic inflammation and atherosclerosis in the LDL receptor-KO mice., (© 2021 Wiley Periodicals LLC.)

Benzene is a ubiquitous environmental pollutant abundant in household products, petrochemicals, and cigarette smoke. Benzene is a well-known carcinogen in humans and experimental animals; however, little is known about the cardiovascular toxicity of benzene. Recent population-based studies indicate that benzene exposure is associated with an increased risk for heart failure. Nonetheless, it is unclear whether benzene exposure is sufficient to induce and/or exacerbate heart failure. We examined the effects of benzene (50 ppm, 6 h/day, 5 days/week, and 6 weeks) or high-efficiency particulate absorbing-filtered air exposure on transverse aortic constriction (TAC)-induced pressure overload in male C57BL/6J mice. Our data show that benzene exposure had no effect on cardiac function in the Sham group; however, it significantly compromised cardiac function as depicted by a significant decrease in fractional shortening and ejection fraction, as compared with TAC/Air-exposed mice. RNA-seq analysis of the cardiac tissue from the TAC/benzene-exposed mice showed a significant increase in several genes associated with adhesion molecules, cell-cell adhesion, inflammation, and stress response. In particular, neutrophils were implicated in our unbiased analyses. Indeed, immunofluorescence studies showed that TAC/benzene exposure promotes infiltration of CD11b+/S100A8+/myeloperoxidase+-positive neutrophils in the hearts by 3-fold. In vitro, the benzene metabolites, hydroquinone, and catechol, induced the expression of P-selectin in cardiac microvascular endothelial cells by 5-fold and increased the adhesion of neutrophils to these endothelial cells by 1.5- to 2.0-fold. Benzene metabolite-induced adhesion of neutrophils to the endothelial cells was attenuated by anti-P-selectin antibody. Together, these data suggest that benzene exacerbates heart failure by promoting endothelial activation and neutrophil recruitment., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Occupational exposures to volatile organic compounds (VOCs) have been associated with numerous health complications including steatohepatitis and liver cancer. However, the potential impact of environmental/residential VOC exposures on liver health and function is largely unknown. To address this knowledge gap, the objective of this cross-sectional study is to investigate associations between VOCs and liver injury biomarkers in community residents. Subjects were recruited from six Louisville neighborhoods, and informed consent was obtained. Exposure biomarkers included 16 creatinine-adjusted urinary metabolites corresponding to 12 parent VOCs. Serological disease biomarkers measured included cytokertain-18 (K18 M65 and M30), liver enzymes, and direct bilirubin. Associations between exposure and disease biomarkers were assessed using generalized linear models. Smoking status was confirmed through urinary cotinine levels. The population comprised of approximately 60% females and 40% males; White persons accounted 78% of the population; with more nonsmokers (n = 413) than smokers (n = 250). When compared with nonsmokers, males (45%) and Black persons (26%) were more likely to be smokers. In the overall population, metabolites of acrolein, acrylonitrile, acrylamide, 1,3-butadiene, crotonaldehyde, styrene, and xylene were positively associated with alkaline phosphatase. These associations persisted in smokers, with the exception of crotonaldehyde, and addition of N,N-dimethylformamide and propylene oxide metabolites. Although no positive associations were observed for K18 M30, the benzene metabolite was positively associated with bilirubin, irrespective of smoking status. Taken together, the results demonstrated that selected VOCs were positively associated with liver injury biomarkers. These findings will enable better risk assessment and identification of populations vulnerable to liver disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure by itself is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of the metabolites tested, trans,trans-mucondialdehyde (10 μM, 18h) was the most toxic. It induced caspases-3, -7 and -9 (intrinsic pathway) activation and enhanced microparticle formation by 2.4-fold. Levels of platelet-leukocyte aggregates, platelet macroparticles, and a proportion of CD4 + and CD8 + T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate (PVT). Autophagic effects of PVT were determined by Acridine Orange assay and Transmission Electron Microscopy analysis. Clinical significance of ULK1 in normal and pancreatic cancer patients was evaluated by R2 and GEPIA cancer genomic databases. Modulation of proteins in autophagy signaling was assessed by Western blotting and Immunofluorescence. Apoptotic effects of PVT was evaluated by Annexin-V/APC assay. Subcutaneous xenograft pancreatic tumor model was used to evaluate the autophagy-mediated apoptotic effects of PVT in vivo. Autophagy was induced upon PVT treatment in pancreatic ducal adenocarcinoma (PDAC) cells. Pancreatic cancer patients exhibit reduced levels of autophagy initiator gene, ULK1, which correlated with reduced patient survival. Interestingly, PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, LC3A/B, and cleavage of caspase-3, an indicator of apoptosis in several PDAC cells. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in PDAC cells. Notably, chloroquine abrogated the growth suppressive effects of PVT by 25% in BxPC3 tumor xenografts in nude mice. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis.

Electronic cigarette use has especially risen among adolescents and young adults. The aim of this study was to investigate fasting blood glucose and lipid profiles in chronic combustible cigarette and electronic cigarette users. We evaluated participants aged 21 to 45 ( n = 525, mean age 31 ± 7 years, 45% women) without established cardiovascular disease or risk factors who were combustible cigarette users ( n = 290), electronic cigarette users ( n = 131; 65 sole users and 66 dual users), or never users ( n = 104). In the first wave of enrollment (2014-2017), electronic cigarette users reported their products as first, second and third generation devices (e-cig users) and were all largely current (i.e., dual) or former (sole) combustible cigarette users, whereas in the second wave of enrollment (2019-2020), electronic cigarette users all reported pod-based device use (pod users) and included more sole users who were never smokers. In multivariable-adjusted analyses comparing to never users, both sole e-cig users and combustible cigarette users had higher glucose and triglycerides and lower high-density lipoprotein (HDL) cholesterol levels. Dual e-cig users showed higher triglycerides and very-low-density lipoprotein cholesterol, and lower HDL cholesterol compared to never users. In contrast, pod users (both sole and dual) had lipid profiles and glucose levels similar to never users. Overall, users of early generation electronic cigarettes display adverse metabolic profiles. In contrast, pod-based electronic cigarette users have similar lipid profiles to never users. Future studies are needed to understand the cumulative effects of electronic cigarette use on cardiometabolic health.

Reputations are critical in human social life: they allow people to share and act on information about one another, even when they have never met. Reputations can be conceptualized as information about a target person that is stored in networks of perceivers and transmitted through either direct interaction or hearsay. We present a novel paradigm that integrates the network approach with interpersonal perception research. We apply that paradigm to study the consensus, accuracy, positivity bias, and consequences of personality trait information in hearsay-based reputations. In 2 preregistered studies ( N = 260 and 369), we created naturalistic micronetworks in the lab in which participants interacted and got to know one another, then later described each other to naïve third parties. Across studies, we use the extended Social Accuracy Model (Wessels, Zimmermann, Biesanz, & Leising, 2020) and an extension of the domain-wise correlational approach (Kenny, 1994). Hearsay-based reputations are about as positively biased as direct reputations. They showed strong consensus (agreement) with direct reputations and modest accuracy, suggesting that they can consolidate around an inaccurate representation. Perceivers' extraversion was associated with more biased hearsay reputations. Experimentally manipulating the context of the hearsay exchange had no detectable impact on hearsay consensus or accuracy. Hearsay reputations were consequential, affecting the extent to which perceivers thought targets would be good leaders or friends. These results provide initial insights into reputation networks and suggest several important future directions for the network approach to reputations. We also present open materials and data analysis software for others to extend the reputations-as-networks approach. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

People perceive similarity between their own personality characteristics and the personality characteristics of others. This association has sometimes been labeled "assumed similarity," reflecting the interpretation that it is a cognitive bias. Another possibility, however, is an interpersonal path to perceived similarity: personality traits that are manifested in behavior may elicit similar or dissimilar behavior from others, and people form perceptions based on what they have elicited. Drawing on theories of interpersonal perception and interpersonal theory, we proposed and tested for evidence of such perceiver-elicited similarity effects, as well as trait and state assumed similarity. Previously unacquainted participants ( N = 322) completed personality assessments, interacted in dyads the next day, and then reported perceptions of each other's personalities. The results showed broad support for the expression and accurate perceptions of most Big Five domains and facets. The preregistered directional hypotheses for behavior elicitation and perceiver-elicited similarity were supported for 3 of 5 traits. Participants interpersonally elicited and then accurately perceived similarity in sociability and openness, and dissimilarity in assertiveness. We also found evidence for assumed similarity for agreeableness and energy level, but participants did not elicit similar behavior from their partners for those traits. We discuss implications for treating perceived similarity as a dynamic, multicomponent phenomenon, and the possibility that assumed similarity emerges from the repeated experience of interpersonally elicited and perceived similarity. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Introduction: Exposure to green spaces is beneficial to mental health in a variety of ways, ranging from stress reduction to increased attentiveness and elevated self-esteem. The impact of views of greenness, as opposed to direct exposure, has been examined, but the association between self-reported views and depressive symptoms is not known. The purpose of this study is to examine the relationship between views of greenness and Patient Health Questionnaire-9 (PHQ-9) score., Methods: Questionnaire responses from 191 participants in the Health, Environment, and Action in Louisville (HEAL) study were examined. Univariate statistical analyses included Mann-Whitney U, Kruskal-Wallis, and Spearman rank tests. Inferential statistical analysis was linear regression., Results: Participant satisfaction with residential greenness was significantly associated with reduced PHQ-9 score (partially adjusted: linear coefficient = -0.42; 95% CI: -0.70 - -0.14; fully adjusted: linear coefficient = -0.21; 95% CI: -0.44 - 0.02). Additionally, being satisfied with local greenness was significantly associated with having views of greenness from home (linear coefficient = 1.97; 95% CI: 1.23-2.68)., Conclusions: Though views of greenness were not directly associated with depression, satisfaction with local greenness was associated with reduced PHQ-9 score, and having views of greenness from home was crudely associated with increased greenness satisfaction. The findings suggest urban greening interventions that focus on greenness satisfaction may be a strategy to reduce depression. Further research is necessary to better understand these relationships., Competing Interests: CONFLICTS OF INTEREST The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported.

Triple-negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. In the current study, we investigated the anti-metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We showed that atovaquone induced apoptosis and reduced the survival of several aggressive metastatic TNBC cell lines including metastatic patient-derived cells by reducing the expression of integrin α6, integrin β4, FAK, Src, and Vimentin. In order to study the efficacy of atovaquone in suppressing metastasized breast tumor cells in brain and lungs, we performed three in vivo experiments. We demonstrated that oral administration of 50 mg/kg of atovaquone suppressed MDA-MB-231 breast tumor growth by 90% in lungs in an intravenous metastatic tumor model. Anti-metastatic effect of atovaquone was further determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Our results showed that atovaquone treatment suppressed the growth of metastatic tumors in lungs, liver and brain by 70%, 50% and 30% respectively. In an intracranial model, the growth of HCC1806-luc brain tumors in atovaquone treated mice was about 55% less than that of control. Taken together, our results indicate the anti-metastatic effects of atovaquone in vitro and in vivo in various breast tumor metastasis models.

A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.