Systematic investigation of cytokine signaling activity at the tissue and single-cell levels.

Cytokines are critical for intercellular communication in human health and disease, but the investigation of cytokine signaling activity has remained challenging due to the short half-lives of cytokines and the complexity/redundancy of cytokine functions. To address these challenges, we developed the Cytokine Signaling Analyzer (CytoSig; https://cytosig.ccr.cancer.gov/ ), providing both a database of target genes modulated by cytokines and a predictive model of cytokine signaling cascades from transcriptomic profiles. We collected 20,591 transcriptome profiles for human cytokine, chemokine and growth factor responses. This atlas of transcriptional patterns induced by cytokines enabled the reliable prediction of signaling activities in distinct cell populations in infectious diseases, chronic inflammation and cancer using bulk and single-cell transcriptomic data. CytoSig revealed previously unidentified roles of many cytokines, such as BMP6 as an anti-inflammatory factor, and identified candidate therapeutic targets in human inflammatory diseases, such as CXCL8 for severe coronavirus disease 2019.

Decoupling FcRn and tumor contributions to elevated immune checkpoint inhibitor clearance in cancer cachexia.

High baseline clearance of immune checkpoint inhibitors (ICIs), independent of dose or systemic exposure, is associated with cachexia and poor outcomes in cancer patients. Mechanisms linking ICI clearance, cachexia and ICI therapy failure are unknown. Here, we evaluate in four murine models and across multiple antibodies whether altered baseline catabolic clearance of administered antibody requires a tumor and/or cachexia and whether medical reversal of cachexia phenotype can alleviate altered clearance. Key findings include mild cachexia phenotype and lack of elevated pembrolizumab clearance in the MC38 tumor-bearing model. We also observed severe cachexia and decreased, instead of increased, baseline pembrolizumab clearance in the tumor-free cisplatin-induced cachexia model. Liver Fcgrt expression correlated with altered baseline catabolic clearance, though elevated clearance was still observed with antibodies having no (human IgA) or reduced (human H310Q IgG1) FcRn binding. We conclude cachexia phenotype coincides with altered antibody clearance, though tumor presence is neither sufficient nor necessary for altered clearance in immunocompetent mice. Magnitude and direction of clearance alteration correlated with hepatic Fcgrt, suggesting changes in FcRn expression and/or recycling function may be partially responsible, though factors beyond FcRn also contribute to altered clearance in cachexia.

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma.

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (WEE1 inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The WEE1 inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a WEE1 inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a WEE1 inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a WEE1 inhibitor is considered a candidate treatment strategy for ESCC.

Myositis-associated interstitial lung disease.

PURPOSE OF REVIEW: In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and myositis-associated (MSA and MAA) antibodies, can predict the clinical phenotype and progression over time. This review will focus on the characteristics and management of antisynthetase syndrome related ILD and anti-MDA5 positive ILD, which are the most clinically relevant subtypes. RECENT FINDINGS: The prevalence of ILD in IIM has been estimated in Asia, North America and Europe at 50, 23 and 26%, respectively, and is increasing. In antisynthetase syndrome related ILD, the clinical presentation, progression and prognosis varies among anti-ARS antibodies. ILD is more common and severe in patients with anti-PL-7/anti-PL-12 antibodies when compared with anti Jo-1 patients. The prevalence of anti-MDA5 antibodies is higher in Asians (11-60%) than in whites (7-16%). Sixty-six percent of antisynthetase syndrome patients had 'chronic ILD' compared with the more rapidly progressive ILD (RP-ILD) seen in 69% of patients with anti-MDA5 antibodies. SUMMARY: ILD is most common in the antisynthetase subtype of IIM and can be a chronic indolent or RP- ILD. The MSA and MAAs are associated with different clinical phenotypes of ILD. Treatments typically involve combinations of corticosteroids and other immunosuppressants.

Ultrasound-Based Machine Learning Approach for Detection of Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Current diagnosis of nonalcoholic fatty liver disease (NAFLD) relies on biopsy or MR-based fat quantification. This prospective study explored the use of ultrasound with artificial intelligence for the detection of NAFLD. METHODS: One hundred and twenty subjects with clinical suspicion of NAFLD and 10 healthy volunteers consented to participate in this institutional review board-approved study. Subjects were categorized as NAFLD and non-NAFLD according to MR proton density fat fraction (PDFF) findings. Ultrasound images from 10 different locations in the right and left hepatic lobes were collected following a standard protocol. MRI-based liver fat quantification was used as the reference standard with >6.4% indicative of NAFLD. A supervised machine learning model was developed for assessment of NAFLD. To validate model performance, a balanced testing dataset of 24 subjects was used. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy with 95% confidence interval were calculated. RESULTS: A total of 1119 images from 106 participants was used for model development. The internal evaluation achieved an average precision of 0.941, recall of 88.2%, and precision of 89.0%. In the testing set AutoML achieved a sensitivity of 72.2% (63.1%-80.1%), specificity of 94.6% (88.7%-98.0%), positive predictive value (PPV) of 93.1% (86.0%-96.7%), negative predictive value of 77.3% (71.6%-82.1%), and accuracy of 83.4% (77.9%-88.0%). The average agreement for an individual subject was 92%. CONCLUSIONS: An ultrasound-based machine learning model for identification of NAFLD showed high specificity and PPV in this prospective trial. This approach may in the future be used as an inexpensive and noninvasive screening tool for identifying NAFLD in high-risk patients.

Enhanced Nitric Oxide Sensing Performance of Conjugated Polymer Films through Incorporation of Graphitic Carbon Nitride.

Organic field-effect transistor (OFET) gas sensors based on conjugated polymer films have recently attracted considerable attention for use in environmental monitoring applications. However, the existing devices are limited by their poor sensing performance for gas analytes. This drawback is attributed to the low charge transport in and the limited charge-analyte interaction of the conjugated polymers. Herein, we demonstrate that the incorporation of graphitic carbon nitride (g-C3N4) into the conjugated polymer matrix can improve the sensing performance of OFET gas sensors. Moreover, the effect of graphitic carbon nitride (g-C3N4) on the gas sensing properties of OFET sensors based on poly(3-hexylthiophene) (P3HT), a conjugated polymer, was systematically investigated by changing the concentration of the g-C3N4 in the P3HT/g-C3N4 composite films. The obtained films were applied in OFET to detect NO gas at room temperature. In terms of the results, first, the P3HT/g-C3N4 composite films containing 10 wt.% g-C3N4 exhibited a maximum charge carrier mobility of ~1.1 × 10-1 cm2 V-1 S-1, which was approximately five times higher than that of pristine P3HT films. The fabricated P3HT/g-C3N4 composite film based OFET sensors presented significantly enhanced NO gas sensing characteristics compared to those of the bare P3HT sensor. In particular, the sensors based on the P3HT/g-C3N4 (90/10) composite films exhibited the best sensing performance relative to that of the bare P3HT sensor when exposed to 10 ppm NO gas: responsivity = 40.6 vs. 18.1%, response time = 129 vs. 142 s, and recovery time = 148 vs. 162 s. These results demonstrate the enormous promise of g-C3N4 as a gas sensing material that can be hybridized with conjugated polymers to efficiently detect gas analytes.

Antivirulence Bispecific Monoclonal Antibody-Mediated Protection against Pseudomonas aeruginosa Ventilator-Associated Pneumonia in a Rabbit Model.

Ventilator-associated pneumonia is an important clinical manifestation of the nosocomial pathogen Pseudomonas aeruginosa. We characterized the correlates of protection with MEDI3902, a bispecific human IgG1 monoclonal antibody that targets the P. aeruginosa type 3 secretion system PcrV protein and the Psl exopolysaccharide, in a rabbit model of ventilator-associated pneumonia using lung-protective, low-tidal-volume mechanical ventilation. Rabbits infused with MEDI3902 prophylactically were protected, whereas those pretreated with irrelevant isotype-matched control IgG (c-IgG) succumbed between 12 and 44 h postinfection (100% survival [8/8 rabbits] versus 0% survival [8/8 rabbits]; P < 0.01 by log rank test). Lungs from rabbits pretreated with c-IgG, but not those pretreated with MEDI3902, had bilateral, multifocal areas of marked necrosis, hemorrhage, neutrophilic inflammatory infiltrate, and diffuse fibrinous edema in alveolar spaces. All rabbits pretreated with c-IgG developed worsening bacteremia that peaked at the time of death, whereas only 38% of rabbits pretreated with MEDI3902 (3/8 rabbits) developed such high-grade bacteremia (two-sided Fisher's exact test, P = 0.026). Biomarkers associated with acute respiratory distress syndrome were evaluated longitudinally in blood samples collected every 2 to 4 h to assess systemic pathophysiological changes in rabbits pretreated with MEDI3902 or c-IgG. Biomarkers were sharply increased or decreased in rabbits pretreated with c-IgG but not those pretreated with MEDI3902, including the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen of <300, hypercapnia or hypocapnia, severe lactic acidosis, leukopenia, and neutropenia. Cytokines and chemokines associated with acute respiratory distress syndrome were significantly downregulated in lungs from rabbits pretreated with MEDI3902, compared with c-IgG. These results suggest that MEDI3902 prophylaxis could have potential clinical utility for decreasing the severity of P. aeruginosa ventilator-associated pneumonia.

The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer.

The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.

Effect of pH on the Structure and Dynamics of Wormlike Micelles in an Amino Acid-Derived Surfactant Composition.

We studied the impact of pH as a thickening mechanism on the structure and dynamics of wormlike micelles in a mixture of sodium lauroyl sarcosinate (SLSar) and cocamidopropyl hydroxysultaine (CAHS). The viscoelastic properties were obtained using mechanical rheometry and diffusing wave spectroscopy, which provided access to a wide range of frequencies. By using a mesoscopic simulation method [Zou; Larson. J. Rheol. 2014, 58 (3), 681-721], characteristic micelle lengths and times were extracted including contour length, persistence length, entanglement length, reptation time, breakage time, breakage rate, and breakage rate constant. The interplay of pH-dependent reptation times (10-1000 ms) and breakage times (4-38 ms) leads to a minimum in the ratio of reptation time to breakage time of about 0.02 at pH 4.8. This minimum was closely associated with the sharp increase and decrease of the observed viscosity maximum at pH 4.8 in this system. These values may be contrasted with much longer breakage times (20-300 ms) that have been measured in more easily thickened sulfate-based systems. The low breakage times of the SLSar/CAHS system were attributed to the high and pH-sensitive breakage rate constants (0.01-0.17 ms-1 µm-1).

Rheology Control Using Nonionic Cosurfactants and pH Titration in an Amino Acid-Derived Surfactant Composition.

Sulfate-based formulations can be easily thickened by adding salt or amphoteric cosurfactants. However, sulfate-free and amino acid-based surfactants cannot. We explored an alternative thickening mechanism by studying the thickening effect of adding nonionic cosurfactants to a mixture of an amino acid-based surfactant, sodium lauroyl sarcosinate (SLSar), and a zwitterionic cosurfactant, cocamidopropyl hydroxysultaine (CAHS) at a 6:9 weight ratio. To characterize the formulations, we combined traditional rheometry with a state-of-the-art mesoscopic analysis of micelle dynamics obtained via diffusing wave spectroscopy. In addition, the formulations were characterized by cross-polarized light microscopy and dynamic light scattering. The cosurfactants studied included fatty alcohols, alkanediols, a fatty acid, and fatty alcohol ethoxylates (CnE3 and CnE6). Adding the nonionic cosurfactants increased the zero-shear viscosity up to 350 times the viscosity of the no-additive system at neutral pH. When pH titration was incorporated as a second thickening mechanism, the viscosity maximum was lower than the no-additive mixture. Furthermore, the pH of the viscosity maximum was shifted to higher pH for all systems except for CnE6, which shifted the maximum to lower pH. The nonionic amphiphiles also broadened the viscosity maximum, particularly in the C10OH system. Consequently, the C10OH system had a more favorable profile for development as a practical thickening system for an amino acid-based cleanser. Analysis according to the Zou and Larson micelle dynamics model revealed that the broadening effect was associated with substantially longer breakage times for the C10OH system (4-208 ms) compared to the no-additive system (4-38 ms).

Evaluation of Alitretinoin for the Treatment of Mycosis Fungoides and Sézary Syndrome.

BACKGROUND: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). There is currently no cure for CTCL, and treatment is aimed at limiting disease progression. This study evaluated the efficacy and tolerability of alitretinoin in CTCL management. METHODS: A retrospective, multicenter study was conducted on CTCL patients treated with alitretinoin as a primary agent or in combination with standard therapies. RESULTS: Forty-eight patients with MF (n = 40) and SS (n = 8) with a median age of 59.7 years (±14.3) were eligible for study inclusion. Treatment response data were evaluated in 40 patients and safety in 42 patients. 40.0% of the patients had early-stage, 43.8% had advanced-stage CTCL, and in 16.7% of patients there was insufficient information for staging. 40.0% (16/40) of the patients achieved a complete or partial response, whereas 47.5% (19/40) achieved stable disease, 12.5% (5/40) had progressive disease, and there were no cases of disease relapses in responders. Both early and advanced stages of CTCL were responsive to alitretinoin as a primary or combined modality. Alitretinoin was well tolerated, and 64.3% (27/42) of patients did not report any side effects. The most commonly observed side effect was hypertriglyceridemia. CONCLUSIONS: This retrospective analysis supports the efficacy and safety of alitretinoin in clearing skin disease and preventing disease progression in CTCL as a monotherapy or in combination with standard therapies.

Predictors of hepatitis C treatment outcomes in a harm reduction-focused primary care program in New York City.

BACKGROUND: The social determinants of health that influence steps in the entire Hepatitis C Virus (HCV) treatment cascade must be identified to achieve HCV elimination goals. This project aimed to evaluate the association of these factors with HCV treatment completion and return for sustained virologic response (SVR) testing. METHODS: We used retrospective cohort data from our primary care-based HCV treatment program that provides comprehensive harm reduction care to those who use or formerly used drugs. Among persons who began direct-acting antiviral HCV treatment between December 2014 and March 2018, we identified two outcomes: HCV treatment completion and return for SVR assessment 12 weeks after treatment end. Several predictors were ascertained including sociodemographic information, substance use, psychiatric symptoms and history, housing instability, and HCV treatment regimen. We then evaluated associations between predictors and outcomes using univariate and multivariable statistical methods. RESULTS: From a cohort of 329 patients treated in an urban primary care center, multivariable analysis identified housing instability as a single significant predictor for HCV treatment completion (odds ratio [OR]: 0.3; 95% confidence interval [CI]: 0.1-0.9). Among patients completing treatment, 226 (75%) returned for SVR assessment; the sole predictor of this outcome was Medicaid as primary insurance (compared to other insurances; OR 0.3; 0.1-0.7). CONCLUSIONS: Innovative strategies to help unstably housed persons complete HCV treatment are urgently needed in order to reach HCV elimination targets. Educational and motivational strategies should be developed to promote individuals with Medicaid in particular to return for SVR viral load testing, a critical post-treatment component of the HCV treatment cascade. Trial registration Not applicable.

Efficacy of Active Immunization With Attenuated α-Hemolysin and Panton-Valentine Leukocidin in a Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia.

Staphylococcus aureus is a common pathogen causing infections in humans with various degrees of severity, with pneumonia being one of the most severe infections. In as much as staphylococcal pneumonia is a disease driven in large part by α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL), we evaluated whether active immunization with attenuated forms of Hla (HlaH35L/H48L) alone, PVL components (LukS-PVT28F/K97A/S209A and LukF-PVK102A) alone, or combination of all 3 toxoids could prevent lethal challenge in a rabbit model of necrotizing pneumonia caused by the USA300 community-associated methicillin-resistant S. aureus (MRSA). Rabbits vaccinated with Hla toxoid alone or PVL components alone were only partially protected against lethal pneumonia, whereas those vaccinated with all 3 toxoids had 100% protection against lethality. Vaccine-mediated protection correlated with induction of polyclonal antibody response that neutralized not only α-hemolysin and PVL, but also other related toxins, produced by USA300 and other epidemic MRSA clones.

Protective Efficacy of Monoclonal Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in a Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia.

Staphylococcus aureus is a major human pathogen that causes a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (MAb) neutralizing alpha-hemolysin or a broadly cross-reactive MAb neutralizing Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysins HlgAB and HlgCB conferred only partial protection, whereas the combination of those two MAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 methicillin-resistant S. aureus epidemic clone.

Can thrombophilia predict recurrent catheter-related deep vein thrombosis in children?

The role of thrombophilia testing in predicting catheter-related deep vein thrombosis (DVT) after an incident (ie, first) catheter-related DVT in children remains unclear. The present study investigated the association between thrombophilia and recurrent catheter-related DVT. Children with thrombophilia testing, performed according to the clinician's judgment and the family's preference, and a history of objectively confirmed catheter-related DVT were included in the study. Recurrent catheter-related DVT after placement of a new catheter was the main outcome. Thrombophilia was classified as minor, major, or none. Analysis was conducted using mixed effect logistic regression. A total of 245 patients had 1,365 catheters inserted; 941 of these catheters were placed after the incident catheter-related DVT. Anticoagulants as treatment or prophylaxis were administered in 78.1% of inserted catheters for at least 50% of the time they were in place. Minor thrombophilia was found in 12.7% of patients, whereas major thrombophilia was seen in 8.2% of children. The incidence rate of recurrent events was 0.23/100 catheter-days (95% confidence interval, 0.19-0.28 catheter-days); 34.3% (95% confidence interval, 28.6%-40.0%) of patients requiring a new catheter after their incident thrombotic event had at least 1 recurrent event. The incidence proportion of bleeding complications was 4.6/100 patients receiving anticoagulation. Young age of the patient at the time of catheter insertion and lack of administration of treatment or prophylactic doses of anticoagulant were predictive of recurrent events. In contrast, thrombophilia was not predictive of recurrent catheter-related DVT during subsequent catheter insertions among tested patients. Our findings suggest that thrombophilia testing to predict recurrence in these patients may be unnecessary.

Treatment Efficacy of MEDI3902 in Pseudomonas aeruginosa Bloodstream Infection and Acute Pneumonia Rabbit Models.

Pseudomonas aeruginosa is a challenge for clinicians due to increasing drug resistance and dwindling treatment options. We report on the activity of MEDI3902, an antibody targeting type 3 secretion protein PcrV and Psl exopolysaccharide, in rabbit bloodstream and lung infection models. MEDI3902 prophylaxis or treatment was protective in both acute models and exhibited enhanced activity when combined with a subtherapeutic dose of meropenem. These findings further support MEDI3902 for the prevention or treatment of serious P. aeruginosa infections.

Predominant N-Haloacetamide and Haloacetonitrile Formation in Drinking Water via the Aldehyde Reaction Pathway.

In drinking water disinfection, switching from free chlorine to alternative chemical disinfectants such as monochloramine may result in the formation of different classes of toxic disinfection byproducts (DBPs). Haloacetonitriles (HANs) and haloacetamides (HAMs) are two currently unregulated nitrogen-containing DBP (N-DBP) groups commonly found in water disinfected with monochloramine that have been shown to be more cyto- and genotoxic than regulated DBPs. For the first time, this study confirms the formation of HAN and HAM dominant species found in disinfected water, dichloroacetonitrile and dichloroacetamide, from the reaction between monochloramine and dichloroacetaldehyde via the aldehyde reaction pathway. Results from experiments with natural water treated with labeled 15 N-monochloramine confirmed the relevance of the aldehyde pathway. Monochloramine reacted quickly with dichloroacetaldehyde reaching equilibrium with the carbinolamine 2,2-dichloro-1-(chloroamino)ethanol ( K1 = 1.87 × 104 M-1 s-1). Then, 2,2-dichloro-1-(chloroamino)ethanol underwent two parallel reactions where, (1) it slowly dehydrated to 1,1-dichloro-2-(chloroimino)ethane ( k2 = 1.09 × 10-5 s-1) and further decomposed to dichloroacetonitrile, and (2) it was oxidized by monochloramine ( k3 = 4.87 × 10-2 M-1 s-1) to form a recently reported N-DBP, the N-haloacetamide N,2,2-trichloroacetamide. At high pH, dichloroacetonitrile hydrolyzed to dichloroacetamide ( k40 = 3.12 × 10-7 s-1, k4OH = 3.54 M-1 s-1). Additionally, trichloroacetaldehyde was also produced from the reaction of dichloracetaldehyde and monochloramine ( k5 = 2.12 × 10-2 M-1 s-1) under the presence of monochlorammonium ion, a product of monochloramine protonation. Within the N-haloacetamide family, N,2,2-trichloroacetamide (LC50 = 3.90 × 10-4 M) was found to be more cytotoxic than N-chloroacetamide but slightly less potent than N,2-dichloroacetamide.

Difficulties in tuberculosis infection control in a general hospital of Vietnam: a knowledge, attitude, and practice survey and screening for latent tuberculosis infection among health professionals.

BACKGROUND: In Vietnam, a country with a high tuberculosis (TB) burden, health professionals in both TB-specialized and non-TB-specialized general hospitals have a high risk of acquiring TB. The aims of the present study were to clarify the difficulties in TB infection control at non-TB specialized hospitals and whether any associated risks of latent TB infection exist among health professionals in Vietnam. METHODS: We conducted a cross-sectional study in a national tertiary and general hospital of Hanoi, Vietnam. Participants were health professionals, including physicians, nurses, and other health professionals. We assessed difficulties in TB infection control by conducting a knowledge, attitude, and practice (KAP) survey. We also collected data on the results of tuberculin skin tests (TSTs) conducted during health check-ups for hospital staff to determine whether health professionals had latent TB infection or TB disease. KAP scores were compared among health professional groups (physicians vs. nurses vs. other health professionals). Factors influencing knowledge scores were evaluated using multiple regression analysis. RESULTS: A total 440 health professionals at the study site participated in the KAP survey, and we collected the results of TSTs from a total of 299 health professionals. We observed a high prevalence of latent TB infection (74.2%), especially among participants in the emergency department. Although participants had high KAP scores, some topics were less understood, such as symptoms and risks of TB, proper use of protective equipment such as N95 respirators, and preventing transmission by patients with confirmed or suspected TB. Factors influencing knowledge scores associated with TB were age, a belief that TB is the most important infectious disease, being a medical professional, having previously attended workshops or seminars, and knowing that Vietnam has a high burden of TB. CONCLUSION: In a non-TB specialized hospital of Vietnam, we observed a risk of TB infection among health professionals and difficulties in properly controlling TB infection. Early awareness regarding patients with suspected TB, to apply proper measures and prevent transmission, and education regarding obtaining updated knowledge through scientific information are crucial to enhancing TB infection control in general hospitals of Vietnam.

Investigation of compacted DNA structures induced by Na+ and K+ monovalent cations using biological nanopores.

In aqueous solutions, an elongated, negatively charged DNA chain can quickly change its conformation into a compacted globule in the presence of positively charged molecules, or cations. This well-known process, called DNA compaction, is a method with great potential for gene therapy and delivery. Experimental conditions to induce these compacted DNA structures are often limited to the use of common compacting agents, such as cationic surfactants, polymers, and multivalent cations. In this study, we show that in highly concentrated buffers of 1 M monovalent cation solutions at pH 7.2 and 10, biological nanopores allow real-time sensing of individual compacted structures induced by K+ and Na+, the most abundant monovalent cations in human bodies. Herein, we studied the ratio between compacted and linear structures for 15-mer single-stranded DNA molecules containing only cytosine nucleotides, optimizing the probability of linear DNA chains being compacted. Since the binding affinity of each nucleotide to cation is different, the ability of the DNA strand to fold into a compacted structure greatly depends on the type of cations and nucleotides present. Our experimental results compare favorably with findings from previous molecular dynamics simulations for the DNA compacting potential of K+ and Na+ monovalent cations. We estimate that the majority of single-stranded DNA molecules in our experiment are compacted. From the current traces of nanopores, the ratio of compacted DNA to linear DNA molecules is approximately 30 : 1 and 15 : 1, at a pH of 7.2 and 10, respectively. Our comparative studies reveal that Na+ monovalent cations have a greater potential of compacting the 15C-ssDNA than K+ cations.

The Synthetic Elicitor 2-(5-Bromo-2-Hydroxy-Phenyl)-Thiazolidine-4-Carboxylic Acid Links Plant Immunity to Hormesis.

Synthetic elicitors are drug-like compounds that induce plant immune responses but are structurally distinct from natural defense elicitors. Using high-throughput screening, we previously identified 114 synthetic elicitors that activate the expression of a pathogen-responsive reporter gene in Arabidopsis (Arabidopsis thaliana). Here, we report on the characterization of one of these compounds, 2-(5-bromo-2-hydroxy-phenyl)-thiazolidine-4-carboxylic acid (BHTC). BHTC induces disease resistance of plants against bacterial, oomycete, and fungal pathogens and has a unique mode of action and structure. Surprisingly, we found that low doses of BHTC enhanced root growth in Arabidopsis, while high doses of this compound inhibited root growth, besides inducing defense. These effects are reminiscent of the hormetic response, which is characterized by low-dose stimulatory effects of a wide range of agents that are toxic or inhibitory at higher doses. Like its effects on defense, BHTC-induced hormesis in Arabidopsis roots is partially dependent on the WRKY70 transcription factor. Interestingly, BHTC-induced root hormesis is also affected in the auxin-response mutants axr1-3 and slr-1. By messenger RNA sequencing, we uncovered a dramatic difference between transcriptional profiles triggered by low and high doses of BHTC. Only high levels of BHTC induce typical defense-related transcriptional changes. Instead, low BHTC levels trigger a coordinated intercompartmental transcriptional response manifested in the suppression of photosynthesis- and respiration-related genes in the nucleus, chloroplasts, and mitochondria as well as the induction of development-related nuclear genes. Taken together, our functional characterization of BHTC links defense regulation to hormesis and provides a hypothetical transcriptional scenario for the induction of hormetic root growth.