An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells.

Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.

Generation of parthenocarpic tomato plants in multiple elite cultivars using the CRISPR/Cas9 system.

Tomato (Solanum lycopersicum L.) is one of the most important crops in the world for its fruit production. Advances in cutting-edge techniques have enabled the development of numerous critical traits related to the quality and quantity of tomatoes. Genetic engineering techniques, such as gene transformation and gene editing, have emerged as powerful tools for generating new plant varieties with superior traits. In this study, we induced parthenocarpic traits in a population of elite tomato (ET) lines. At first, the adaptability of ET lines to genetic transformation was evaluated to identify the best-performing lines by transforming the SlANT1 gene overexpression cassette and then later used to produce the SlIAA9 knockout lines using the CRISPR/Cas9 system. ET5 and ET8 emerged as excellent materials for these techniques and showed higher efficiency. Typical phenotypes of knockout sliaa9 were clearly visible in G0 and G1 plants, in which simple leaves and parthenocarpic fruits were observed. The high efficiency of the CRISPR/Cas9 system in developing new tomato varieties with desired traits in a short period was demonstrated by generating T-DNA-free homozygous sliaa9 knockout plants in the G1 generation. Additionally, a simple artificial fertilization method was successfully applied to recover seed production from parthenocarpic plants, securing the use of these varieties as breeding materials. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01452-1.

Evaluation of transfusion reactions in patients following transfusion of blood components containing antibodies to HLA class I - An attempt to prevent TRALI in patients.

In an attempt to mitigate transfusion-related acute lung injury (TRALI), the Oslo Blood Center screened 1369 thrombapheresis donors for human leucocyte antigen (HLA)-specific antibodies. Anti-HLA antibodies were found in 200 donors who were deferred from donation of plasma-rich products. In a retrospective study, 2562 transfusions of thrombocytes (both apheresis and whole blood-derived) from 150 of these donors were subject to a thorough look back-investigation. Reports of 14 transfusion reactions were identified, none of which were classified as TRALI. Our study supports previous data indicating that the risk of TRALI is low. The value of screening for anti-HLA antibodies and subsequent deferral of donors with high levels of such antibodies remains questionable.

Phosphorylation of the auxin signaling transcriptional repressor IAA15 by MPKs is required for the suppression of root development under drought stress in Arabidopsis.

Since plants are sessile organisms, developmental plasticity in response to environmental stresses is essential for their survival. Upon exposure to drought, lateral root development is suppressed to induce drought tolerance. However, the molecular mechanism by which the development of lateral roots is inhibited by drought is largely unknown. In this study, the auxin signaling repressor IAA15 was identified as a novel substrate of mitogen-activated protein kinases (MPKs) and was shown to suppress lateral root development in response to drought through stabilization by phosphorylation. Both MPK3 and MPK6 directly phosphorylated IAA15 at the Ser-2 and Thr-28 residues. Transgenic plants overexpressing a phospho-mimicking mutant of IAA15 (IAA15DD OX) showed reduced lateral root development due to a higher accumulation of IAA15. In addition, MPK-mediated phosphorylation strongly increased the stability of IAA15 through the inhibition of polyubiquitination. Furthermore, IAA15DD OX plants showed the transcriptional downregulation of two key transcription factors LBD16 and LBD29, responsible for lateral root development. Overall, this study provides the molecular mechanism that explains the significance of the MPK-Aux/IAA module in suppressing lateral root development in response to drought.

Discovery of Alkyl Triphenylphosphonium Pinostrobin Derivatives as Potent Anti-Breast Cancer Agents.

Pinostrobin demonstrated anticancer properties, but its hydrophobic feature led to a reduction in bioavailability. The mitochondria-targeted approach successfully synthesized eight new alkyl triphenylphosphonium pinostrobin derivatives (1-8) with good yield in this study. Seven compounds (1-3, 5-8) showed greater cytotoxic potency against the human MCF-7 breast cancer cell line than pinostrobin. Molecular docking studies were performed with two important targets in hormone-dependent anticancer strategies, estrogen receptor α (ERα) ligand binding domains, 3ERT (antagonist recognition and antiproliferative function), and 1GWR (agonist recognition and pro-proliferative function). In addition, the MD simulation study of the two most potent compounds (2 and 3) complexed with both ERα forms suggested that compounds 2 and 3 could serve as favourable antagonists. Furthermore, the in silico ADMET prediction indicated that compounds 2 and 3 could be potential drug candidates.

Phosphatidylserine-mediated oral tolerance.

Phosphatidylserine (PS) is an anionic phospholipid exposed on the surface of apoptotic cells. The exposure of PS typically recruits and signals phagocytes to engulf and silently clear these dying cells to maintain tolerance via immunological ignorance. However, recent and emerging evidence has demonstrated that PS converts an "immunogen" into a "tolerogen", and PS exposure on the surface of cells or vesicles actively promotes a tolerogenic environment. This tolerogenic property depends on the biophysical characteristics of PS-containing vesicles, including PS density on the particle surface to effectively engage tolerogenic receptors, such as TIM-4, which is exclusively expressed on the surface of antigen-presenting cells. We harnessed the cellular and molecular mechanistic insight of PS-mediated immune regulation to design an effective oral tolerance approach. This immunotherapy has been shown to prevent/reduce immune response against life-saving protein-based therapies, food allergens, autoantigens, and the antigenic viral capsid peptide commonly used in gene therapy, suggesting a broad spectrum of potential clinical applications. Given the good safety profile of PS together with the ease of administration, oral tolerance achieved with PS-based nanoparticles has a very promising therapeutic impact.

A Hybrid Structure-Based Machine Learning Approach for Predicting Kinase Inhibition by Small Molecules.

Kinases have been the focus of drug discovery programs for three decades leading to over 70 therapeutic kinase inhibitors and biophysical affinity measurements for over 130,000 kinase-compound pairs. Nonetheless, the precise target spectrum for many kinases remains only partly understood. In this study, we describe a computational approach to unlocking qualitative and quantitative kinome-wide binding measurements for structure-based machine learning. Our study has three components: (i) a Kinase Inhibitor Complex (KinCo) data set comprising in silico predicted kinase structures paired with experimental binding constants, (ii) a machine learning loss function that integrates qualitative and quantitative data for model training, and (iii) a structure-based machine learning model trained on KinCo. We show that our approach outperforms methods trained on crystal structures alone in predicting binary and quantitative kinase-compound interaction affinities; relative to structure-free methods, our approach also captures known kinase biochemistry and more successfully generalizes to distant kinase sequences and compound scaffolds.

External iliac artery extension causes greater aneurysm sac regression than the bell-bottom technique or iliac branch endoprosthesis for repair of concomitant infrarenal aortic and iliac artery aneurysm.

OBJECTIVE: Aneurysmal extension of abdominal aortic aneurysms (AAAs) to the common iliac artery (CIA) presents a technical challenge to successful endovascular abdominal aortic aneurysm repair (EVAR). In the present study, we compared sac shrinkage and perioperative outcomes after the bell-bottom technique (BBT), internal iliac artery embolization and external iliac artery extension (EIE), and iliac branch endoprosthesis (IBE). METHODS: Using the Vascular Quality Initiative database, a retrospective analysis was conducted for patients who had undergone EVAR from 2013 to 2019. The demographic, anatomic, and perioperative data were analyzed. All patients with a proximal aortic neck length <10 mm and aortic graft diameter >32 mm were excluded from the analysis. The patients were subdivided into four groups according to the distal limb strategy: group 1, control group with a bilateral common iliac artery limb <20 mm; group 2, BBT with either a unilateral or bilateral limb >20 mm; group 3, EIE technique; and group 4, IBE. The primary endpoint was the maximal change in the aortic diameter during follow-up. The secondary endpoints included postoperative complications and the rate of endoleak. RESULTS: The records for 14,455 patients who had undergone EVAR were queried and 5788 met the anatomic criteria. The average age was 73 years, and 86.3% were men. The maximal change in the aortic diameter in the control, BBT, IBE, and EIE groups was -7.2 mm, -6.1 mm, -4.6 mm, and -6.8 mm, respectively (P = .06). The differences were not statistically significant on univariate analysis at an average follow-up of 405 days. However, on multivariable analysis (P = .01), compared with the control group, the BBT and IBE groups were 18.4% (odds ratio [OR], 0.816; 95% confidence interval [CI], 0.68-0.98) and 48.0% (OR, 0.52; 95% CI, 0.33-0.82) less likely to experience aneurysmal shrinkage, respectively. In contrast, the EIE group showed no significant difference in shrinkage compared with that in the control group. Multivariable analysis of the groups also revealed that compared directly with the BBT group, the EIE group was 69.5% more likely to have experienced shrinkage in the aortic aneurysmal diameter (OR, 1.70; 95% CI, 1.05-2.75). The BBT and IBE groups had a significantly higher rate of type II endoleaks (17.63% and 16.95%, respectively; P = .03). The EIE group had a higher rate of type Ib endoleaks (1.9%) compared with the BBT (1.1%), IBE (1.7%), and control (0.3%) groups (P = .01). No differences were found between the groups in terms of postoperative myocardial infarction (P = .47) or respiratory (P = .61) or intestinal (P = .71) complications. However, the rates of limb complications and reoperation were higher in the EIE group. CONCLUSIONS: The present study revealed that the EIE technique was more likely to demonstrate shrinkage in the aortic aneurysmal diameter than were the BBT and IBE groups compared with the control group on multivariable analysis. The EIE technique was also more likely to result in aneurysmal sac shrinkage than was the BBT group, albeit with greater rates of limb-related complications.

Spinal Cord Ischemia following Simultaneous EVAR and TEVAR for Concomitant Thoracic and Abdominal Aortic Aneurysms.

BACKGROUND: In patients with abdominal aortic aneurysms, 10-20% has concomitant thoracic aortic pathologies. These are typically managed with staged endovascular aneurysm repair (EVAR) and thoracic endovascular aortic repair (TEVAR) due to a perceived higher risk of spinal cord ischemia from a simultaneous intervention. We aimed to determine the outcomes of patients undergoing simultaneous EVAR and TEVAR for concomitant aneurysms. METHODS: A retrospective cohort study was performed using the Vascular Quality Initiative registry from December 2003 to January 2021. Patients undergoing same day EVAR and TEVAR were included and analyzed in accordance with the Society for Vascular Surgery reporting standards. Primary outcomes were technical success and spinal cord ischemia. RESULTS: Simultaneous EVAR and TEVAR were performed in 25 patients. Median age was 75.0 (interquartile range [IQR], 63.0-79.0) years and 20 (80.0%) patients were male. Two (4.0%) patients were symptomatic and 4 (16.0%) presented with rupture. Median maximum infrarenal and thoracic aortic diameter was 57.0 (IQR, 52.0-65.0). Infrarenal aortic neck length was 15.0 mm (IQR, 10.0-25.0), and diameter was 27.0 mm (IQR, 24.5-30.0). Median procedure time was 185.0 min (IQR, 117.8-251.3), fluoroscopy time 32.7 min (IQR, 21.8-63.1), and contrast volume 165 mL (IQR, 115.0-207.0). There were 3 (12.0%) Type Ia endoleaks and 3 (12.0%) Type II endoleaks in EVAR's, with 1 (4.0%) Type Ia and 1 (4.0%) Type II endoleak in TEVARs. In-hospital mortality occurred in 3 (12.0%) patients (1 elective, 2 ruptures). Spinal cord ischemia occurred in 1 (4.0%) patient. This patient had a symptomatic aneurysm. Thoracic coverage extended from Zone 4 to Zone 5 and an emergent spinal drain was placed postoperatively. Symptoms were present on discharge. There was 1 (4.0%) conversion to open repair which occurred in a ruptured aneurysm. Technical success was achieved in 19 (76.0%) patients, however when excluding ruptured aneurysms, was achieved in 17 (81.0%) patients. Follow-up data was available for 19 (76.0%) patients at a median of 426.0 (IQR, 329.0-592.5) days postoperatively. A total of 3 (12.0%) patients died during the late mortality period, at a mean of 509.0 (±503.7) days. Median change in abdominal and thoracic aortic sac diameter was -1.35 mm (IQR, -11.5 to 2.5) and 8.0 (IQR, -10.5 to 12.0), respectively. CONCLUSIONS: Simultaneous EVAR and TEVAR for concomitant abdominal and thoracic aortic aneurysms can be performed with low rates of spinal cord ischemia. Short- and mid-term outcomes are acceptable.

Inflammatory markers calprotectin, NETs, syndecan-1 and neopterin in COVID-19 convalescent blood donors.

Persisting inflammation has been discovered in lungs and other parenchymatous organs of some COVID-19 convalescents. Calprotectin, neutrophil extracellular traps (NETs), syndecan-1 and neopterin are general key inflammatory markers, and systemically enhanced levels of them may remain after the COVID-19 infection. These inflammatory markers were therefore measured in serum samples of 129 COVID-19 convalescent and 27 healthy blood donors or employees at Oslo Blood bank, Norway. Also antibodies against SARS-CoV-2 nucleocapsid antigen were measured, and timing of sampling and severity of infection noted. Whereas neopterin and NETs values remained low and those for syndecan-1 were not raised to statistically significant level, concentrations for calprotectin, as measured by a novel mixed monoclonal assay, were significantly increased in the convalescents. Antibodies against SARS-CoV-2 nucleocapsid antigen were elevated, but did not correlate with levels of inflammatory markers. Difference between the groups in only one biomarker makes evaluation of ongoing or residual inflammation in the convalescents difficult. If there is a low-grade inflammation, it would in that case involve neutrophils.

A New abeo-Icetexane-Type Diterpenoid from the Stem Barks of Taxus wallichiana.

From a CH2 Cl2 -soluble fraction of the stem barks of Taxus wallichiana, one new abeo-icetexane-type diterpenoid, taxamairin I (1), was isolated. Its absolute configuration was elucidated based on spectroscopic interpretation and time-dependent density functional theory (TD-DFT) calculation of optical rotation. In addition, the plausible biosynthesis pathway for the formation of the new abeo-icetexane-type diterpenoid was proposed. Taxamairin I (1), at a concentration of 100 µM, did not show cytotoxicity against Hep3B human liver cancer cell lines.

IFN-ß, but not IFN-α, is Responsible for the Pro-Bacterial Effect of Type I Interferon.

BACKGROUND/AIMS: During an immune response, type I interferon (IFN-I) signaling induces a wide range of changes, including those which are required to overcome viral infection and those which suppress cytotoxic T cells to avoid immunopathology. During certain bacterial infections, IFN-I signaling exerts largely detrimental effects. Although the IFN-I family of proteins all share one common receptor, biologic responses to signaling vary depending on IFN-I subtype. Here, we asked if one IFN-I subtype dominates the pro-bacterial effect of IFN-I signaling and found that control of Listeria monocytogenes (L.m.) infection is more strongly suppressed by IFN-ß than IFN-α. METHODS: To study this, we measured bacterial titers in IFNAR-/-, IFN-ß­/­, Stat2-/-, Usp18fl/fl and Usp18fl/fl x CD11c-Cre mice models in addition to IFN-I blocking antibodies. Moreover, we measured interferon stimulated genes in bone marrow derived dendritic cells after treatment with IFN-α4 and IFN-ß. RESULTS: Specifically, we show that genetic deletion of IFN-ß or antibody-mediated IFN-ß neutralization was sufficient to reduce bacterial titers to levels similar to those observed in mice that completely lack IFN-I signaling (IFNAR-/- mice). However, IFN-α blockade failed to significantly reduce L.m. titers, suggesting that IFN-ß is the dominant IFN-I subtype responsible for the pro-bacterial effect of IFN-I. Mechanistically, when focusing on IFN-I signals to dendritic cells, we found that IFN-ß induces ISGs more robustly than IFN-α, including USP18, the protein we previously identified as driving the pro-bacterial effects of IFN-I. Further, we found that this induction was STAT1/STAT2 heterodimer- or STAT2/STAT2 homodimer-dependent, as STAT2-deficient mice were more resistant to L.m. infection. CONCLUSION: In conclusion, IFN-Β is the principal member of the IFN-I family responsible for driving the pro-bacterial effect of IFN-I.

Outcomes of Endovascular Management of Isolated Profunda Femoris Artery Occlusive Disease.

BACKGROUND: Endovascular management of isolated profunda femoris artery occlusive disease has not been well studied. Our aim is to analyze the outcomes of endovascular management of profunda artery occlusive disease. METHODS: This is a retrospective analysis using data from the Vascular Quality Initiative. All patients from 2013 to 2018 treated percutaneously for isolated profunda artery occlusive disease were included. Endovascular treatment included plain balloon alone, stent, stent graft, atherectomy, and drug-coated balloon without any concomitant endovascular or surgical treatment. Demographic, procedural, and follow-up data were obtained. Primary end points were primary patency, improvement of symptoms, and need for reintervention. Univariate and multivariable analysis was used to assess for significant variables. RESULTS: Of the 105,568 lower extremity endovascular interventions performed during this time period, there were 361 procedures (0.3%) performed on 341 patients for isolated profunda artery occlusive disease. The average age of these patients was 67.8 years (+/- 11.8), with 59.8% being men. The most common indication for treatment of the profunda artery was claudication (44.8%), followed by tissue loss (28.5%) and rest pain (26.0%). The most common treatment modality was plain balloon (58.5%), followed by stent (18.6%), drug-coated balloon (10.0%), atherectomy (9.4%), and stent graft (3.6%). At a mean follow-up of 13 months (+/-4.6), data were available for 238 patients (69.7%). Overall primary patency at 13 months was 92.9%. There was no significant difference in terms of patency for each treatment modality (Table I). Preoperative ambulatory status, aspirin, and statin were significantly associated with patency. At most recent follow-up, 67% of patients had improvement of their symptoms, whereas 29% were unchanged. Reintervention data were available for 247 patients, with a reintervention rate of 15.8% (n = 39) and a mean reintervention time of 226 days (+/- 173), with the majority of reinterventions (62%) occurring in the plain balloon group. Reinterventions were primarily endovascular (64%) with 9 patients (23%) undergoing surgical reintervention. CONCLUSIONS: Endovascular management of profunda femoris artery occlusive disease has acceptable one-year patency rates with low reintervention rates. Endovascular treatment may be an acceptable alternative to selected patients who are high-risk for surgery.

Early Essential Newborn Care can still be used with mothers who have COVID-19 if effective infection control measures are applied.

We describe the first infant born to a woman with COVID-19 in Vietnam, by Caesarean section at 36 weeks and 5 days of gestation. The mother and baby remained together during their hospital stay and prolonged skin-to-skin contact and early and exclusive breastfeeding were achieved. This was in line with the World Health Organization's Early Essential Newborn Care (EENC) recommendations, the national Vietnamese standard of care since 2014. The baby remained virus-free throughout the 34-day postpartum follow-up. CONCLUSION: The EENC approach can still be used with mothers who have COVID-19 if effective infection control measures are applied.

Caloric restriction upregulates the expression of DNMT3.1, lacking the conserved catalytic domain, in Daphnia magna.

DNA methylation plays an important role in many aspects of biology, including development, disease, and phenotypic plasticity. In the branchiopod crustacean, Daphnia, de novo DNA methylation has been detected in specific environmental contexts. However, fundamental information on de novo DNA methyltransferase DNMT3 orthologs, including domain organization, developmental expression, and response to environmental stimuli, is lacking. In this study, we examined two DNMT3 orthologs in Daphnia magna, DapmaDNMT3.1 and DapmaDNMT3.2. Amino acid sequence alignment revealed that DapmaDNMT3.1 and DapmaDNMT3.2 lack the conserved methyltransferase motifs of the catalytic domain and the PWWP domain, respectively. We profiled the expression of the two orthologs during embryogenesis and under various feeding levels. During embryogenesis, in contrast to the low DapmaDNMT3.1 expression, DapmaDNTM3.2 was highly expressed at specific stages, that is, in the one cell-stage and at 48 hr post ovulation. In nutrient-rich condition, both genes were lowly expressed, whereas DapmaDNMT3.1 was upregulated at the lower food levels, suggesting a potential role of DapmaDNMT3.1 in gene regulation in response to caloric restriction. These findings provide a basis for understanding the developmental stage- and stress-dependent function of DNMT3 orthologs in D. magna.

Calosides A-F, Cardenolides from Calotropis gigantea and Their Cytotoxic Activity.

Phytochemical analysis of the roots of Calotropis gigantea led to the isolation of six new cardenolide glycosides, calosides A-F (1-6), and five known cardenolides (7-11). The structures of 1-6 were elucidated based on NMR and ECD spectroscopic data interpretation. Caloside D (4) is the first naturally occurring example of a cardenolide containing a C-8/C-19 oxygen bridge. In turn, calosides E (5) and F (6) represent the first naturally occurring 3-epi-cannogenol diglycosides having potent cytotoxicity against the PANC-1 cell line (IC50, 0.081 and 0.070 µM, respectively) and HeLa (IC50, both 0.17 µM) cells, under normoglycemic conditions.

Various Approaches to Open Removal of Inferior Vena Cava Filters.

BACKGROUND: Inferior vena cava (IVC) filters may lead to complications of IVC filter placement including strut migration and caval erosion into adjacent organs. While percutaneous techniques for removal are preferred, in certain cases, this is not possible, and open retrieval is necessary. We present outcomes of 4 different approaches to 6 cases of open IVC filter retrieval. METHODS: We included 6 patients who underwent open IVC filter retrieval at our institution from 2013 to 2018. CASE REPORTS: Of the 6 patients, only one patient had a prior retrieval attempt that was unsuccessful. Four patients presented with abdominal pain alone due to erosion into the duodenum. One patient presented with back pain due to strut erosion into the vertebral body. One patient presented with abdominal and back pain due to erosion into the duodenum, aorta, and vertebral body, and one patient presented with chest pain due to strut migration and perforation of the left ventricular wall with development of pericardial tamponade. Five patients underwent computed tomography scans and were deemed irretrievable percutaneously. One patient had an attempted but failed percutaneous attempt. Various approaches were used to remove the filters. All patients underwent either a midline or subcostal incision for exposure of the IVC. In 3 patients, after the IVC was clamped and the filter was removed, the cavotomy was repaired primarily. In one patient, the IVC was repaired using a bovine pericardial patch because it was scarred down and primary repair would have narrowed the lumen. In one patient, without clamping the IVC, the struts were cut at the point that protruded out of the IVC into the adjacent organs and sutured in place on the IVC wall. In one patient, the hook of the IVC filter protruded out of the IVC, and a snare was used to capture the filter, whereas a purse string suture was applied to repair the venotomy. One patient required sternotomy and retrieval of a strut from the left ventricle with primary repair, as well as an open retrieval of the IVC filter, which were performed separately. All patients had resolution of symptoms after removal with no morbidity or mortality. CONCLUSIONS: While open IVC filter retrieval is rarely required, various approaches can be successfully and safely used for retrieval with low morbidity.

Health Literacy, eHealth Literacy, Adherence to Infection Prevention and Control Procedures, Lifestyle Changes, and Suspected COVID-19 Symptoms Among Health Care Workers During Lockdown: Online Survey.

BACKGROUND: The COVID-19 pandemic has imposed a heavy burden on health care systems and governments. Health literacy (HL) and eHealth literacy (as measured by the eHealth Literacy Scale [eHEALS]) are recognized as strategic public health elements but they have been underestimated during the pandemic. HL, eHEALS score, practices, lifestyles, and the health status of health care workers (HCWs) play crucial roles in containing the COVID-19 pandemic. OBJECTIVE: The aim of this study is to evaluate the psychometric properties of the eHEALS and examine associations of HL and eHEALS scores with adherence to infection prevention and control (IPC) procedures, lifestyle changes, and suspected COVID-19 symptoms among HCWs during lockdown. METHODS: We conducted an online survey of 5209 HCWs from 15 hospitals and health centers across Vietnam from April 6 to April 19, 2020. Participants answered questions related to sociodemographics, HL, eHEALS, adherence to IPC procedures, behavior changes in eating, smoking, drinking, and physical activity, and suspected COVID-19 symptoms. Principal component analysis, correlation analysis, and bivariate and multivariate linear and logistic regression models were used to validate the eHEALS and examine associations. RESULTS: The eHEALS had a satisfactory construct validity with 8 items highly loaded on one component, with factor loadings ranked from 0.78 to 0.92 explaining 76.34% of variance; satisfactory criterion validity as correlated with HL (ρ=0.42); satisfactory convergent validity with high item-scale correlations (ρ=0.80-0.84); and high internal consistency (Cronbach α=.95). HL and eHEALS scores were significantly higher in men (unstandardized coefficient [B]=1.01, 95% CI 0.57-1.45, P<.001; B=0.72, 95% CI 0.43-1.00, P<.001), those with a better ability to pay for medication (B=1.65, 95% CI 1.25-2.05, P<.001; B=0.60, 95% CI 0.34-0.86, P<.001), doctors (B=1.29, 95% CI 0.73-1.84, P<.001; B 0.56, 95% CI 0.20-0.93, P=.003), and those with epidemic containment experience (B=1.96, 95% CI 1.56-2.37, P<.001; B=0.64, 95% CI 0.38-0.91, P<.001), as compared to their counterparts, respectively. HCWs with higher HL or eHEALS scores had better adherence to IPC procedures (B=0.13, 95% CI 0.10-0.15, P<.001; B=0.22, 95% CI 0.19-0.26, P<.001), had a higher likelihood of healthy eating (odds ratio [OR] 1.04, 95% CI 1.01-1.06, P=.001; OR 1.04, 95% CI 1.02-1.07, P=.002), were more physically active (OR 1.03, 95% CI 1.02-1.03, P<.001; OR 1.04, 95% CI 1.03-1.05, P<.001), and had a lower likelihood of suspected COVID-19 symptoms (OR 0.97, 95% CI 0.96-0.98, P<.001; OR 0.96, 95% CI 0.95-0.98, P<.001), respectively. CONCLUSIONS: The eHEALS is a valid and reliable survey tool. Gender, ability to pay for medication, profession, and epidemic containment experience were independent predictors of HL and eHEALS scores. HCWs with higher HL or eHEALS scores had better adherence to IPC procedures, healthier lifestyles, and a lower likelihood of suspected COVID-19 symptoms. Efforts to improve HCWs' HL and eHEALS scores can help to contain the COVID-19 pandemic and minimize its consequences.

4-Hydroxypanduratin A and Isopanduratin A Inhibit Tumor Necrosis Factor α-Stimulated Gene Expression and the Nuclear Factor κB-Dependent Signaling Pathway in Human Lung Adenocarcinoma A549 Cells.

Tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine, regulates inflammatory and immune responses by up-regulating gene expression in a manner that is dependent on the transcription factor nuclear factor κB (NF-κB). In the present study, we found that 4-hydroxypanduratin A and isopanduratin A, constituents of the rhizomes of Boesenbergia pandurata, inhibited the TNF-α-stimulated up-regulation of intercellular adhesion molecule-1 (ICAM-1) in human lung adenocarcinoma A549 cells. 4-Hydroxypanduratin A and isopanduratin A also reduced ICAM-1 mRNA expression and NF-κB-responsive luciferase activity in TNF-α-stimulated A549 cells. Moreover, 4-hydroxypanduratin A and isopanduratin A prevented the TNF-α-stimulated translocation of the NF-κB subunit p65 to the nucleus and the phosphorylation and proteasomal degradation of the inhibitor of the NF-κB α protein. The present results revealed that 4-hydroxypanduratin A and isopanduratin A inhibit TNF-α-stimulated gene expression and the NF-κB-dependent signaling pathway in A549 cells.

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification.

Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and down-modulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions.