Computer-aided exploration of multiobjective optimal temperature profiles in slow freezing for human induced pluripotent stem cells.

Human induced pluripotent stem (hiPS) cells have demonstrated promising potential in regenerative medical therapeutics. After successful clinical trials, the demand for hiPS cells has steadily increased. Therefore, the optimization of hiPS cell freezing processes for storage and transportation is essential. Here, we presented a computer-aided exploration of multiobjective optimal temperature profiles in slow freezing for hiPS cells. This study was based on a model that calculates cell survival rates after thawing, and the model was extended to evaluate cell potentials until 24 h after seeding. To estimate parameter values for this extension, freezing experiments were performed using constant cooling rates. Using quality and productivity indicators, we evaluated 16,206 temperature profiles using our model, and a promising profile was obtained. Finally, an experimental investigation of the profile was undertaken, and the contribution of the temperature profile to both quality and productivity was confirmed.

Associations of fractional exhaled nitric oxide with airway dimension and mucus plugs on ultra-high-resolution computed tomography in former smokers and nonsmokers with asthma.

BACKGROUND: Associations of fractional exhaled nitric oxide (FeNO) with airway wall remodeling and mucus plugs remain to be explored in smokers and nonsmokers with asthma. Ultra-high-resolution computed tomography (U-HRCT), which allows accurate structural quantification of airways >1 mm in diameter, was used in this study to examine whether higher FeNO was associated with thicker walls of the 3rd to 6th generation airways and mucus plugging in patients with asthma. METHODS: The retrospective analyses included consecutive former smokers and nonsmokers with asthma who underwent U-HRCT in a hospital. The ratio of wall area to summed lumen and wall area was calculated as the wall area percent (WA%). Mucus plugging was visually scored. RESULTS: Ninety-seven patients with asthma (including 59 former smokers) were classified into low (<20 ppb), middle (20-35 ppb), and high (>35 ppb) FeNO groups (n = 24, 26, and 47). In analysis including all patients and subanalysis including nonsmokers or former smokers, WA% in the 6th generation airways was consistently higher in the high FeNO group than in the low FeNO group, whereas WA% in the 3rd to 5th generation airways was not. In multivariable models, WA% in the 6th generation airways and the rate of mucus plugging were higher in the high FeNO group than in the low FeNO group after adjusting for age, sex, body mass index, smoking status, lung volume, and allergic rhinitis presence. CONCLUSIONS: Higher FeNO may reflect the inflammation and remodeling of relatively peripheral airways in asthma in both former smokers and nonsmokers.

Mucus plugging on computed tomography and the sputum microbiome in patients with asthma, chronic obstructive pulmonary disease, and asthma-COPD overlap.

BACKGROUND: Despite clinical implications, the pathogenesis of mucus plugging in asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) remains unclear. We hypothesized that distinct airway microbiomes might affect mucus plugging differently among ACO, asthma, and COPD and among different extents of airway eosinophilic inflammation. METHODS: The sputum microbiome, sputum cell differential count, and mucus plug score on computed tomography were cross-sectionally evaluated in patients with chronic airflow limitation. RESULTS: Patients with ACO, asthma, or COPD were enrolled (n = 56, 10, and 25). Higher mucus plug scores were associated with a greater relative abundance of the phylum Proteobacteria (rho = 0.29) only in patients with ACO and a greater relative abundance of the phylum Actinobacteria (rho = 0.46) only in patients with COPD. In multivariable models including only patients with ACO, the presence of mucus plugs was associated with a greater relative abundance of the phylum Proteobacteria and the genus Haemophilus, independent of smoking status, airflow limitation, and emphysema severity. Moreover, the mucus score was associated with a greater relative abundance of the genus Streptococcus (rho = 0.46) in patients with a high sputum eosinophil count (n = 22) and with that of the genus Haemophilus (rho = 0.46) in those with a moderate sputum eosinophil count (n = 26). CONCLUSIONS: The associations between mucus plugging and the microbiome in ACO differed from those in COPD and asthma. Greater relative abundances of the phylum Proteobacteria and genus Haemophilus may be involved in mucus plugging in patients with ACO and moderate airway eosinophilic inflammation.

Aberrant accumulation of NIK promotes tumor growth by dysregulating translation and post-translational modifications in breast cancer.

BACKGROUND: In vivo investigations with cancer cells have powerful tools to discover cancer progression mechanisms and preclinical candidate drugs. Among these in vivo experimental models, the establishment of highly malignancy cell lines with xenograft has been frequently used. However, few previous researches targeted malignancy-related genes whose protein levels translationally changed. Therefore, this study aimed to identify malignancy-related genes which contributed to cancer progression and changed at the protein level in the in vivo selected cancer cell lines. METHODS: We established the high malignancy breast cancer cell line (LM05) by orthotopic xenograft as an in vivo selection method. To explore the altered genes by translational or post-translational regulation, we analyzed the protein production by western blotting in the highly malignant breast cancer cell line. Functional analyses of the altered genes were performed by in vitro and in vivo experiments. To reveal the molecular mechanisms of the regulation with protein level, we evaluated post-translational modification by immunoprecipitation. In addition, we evaluated translational production by click reaction-based purification of nascent protein. RESULTS: As a result, NF-κB inducing kinase (NIK) increased at the protein level and promoted the nuclear localization of NF-κB2 (p52) and RelB in the highly malignant breast cancer cell line. The functional analyses indicated the NIK upregulation contributed to tumor malignancy via cancer-associated fibroblasts (CAFs) attraction and partially anti-apoptotic activities. Additionally, the immunoprecipitation experiment revealed that the ubiquitination of NIK decreased in LM05 cells. The decline in NIK ubiquitination was attributed to the translational downregulation of cIAP1. CONCLUSIONS: Our study identified a dysregulated mechanism of NIK production by the suppression of NIK post-modification and cIAP1 translation. The aberrant NIK accumulation promoted tumor growth in the highly malignant breast cancer cell line.

Is narrowest QRS the best? A case of cardiac resynchronization therapy in a patient with left anterior fascicular block.

The efficacy of cardiac resynchronization therapy (CRT) in patients with a narrow QRS duration has not been established. We present a patient with a narrow QRS duration and left anterior fascicular block in which CRT was effective. Left ventricular lead implantation at the optimal site and appropriately-timed left ventricular pacing (LVP) resulted in left ventricle reverse remodeling. Left ventricular dyssynchrony did not improve with LVP at a timing that resulted in narrower QRS than an intrinsic QRS duration. The optimization of LVP timing in CRT for patients with a narrow QRS duration is discussed.

Treatment for Intracorneal Hematoma by Anterior Chamber Gas Tamponade Combined With Keratocentesis.

PURPOSE: To report a new surgical method for intracorneal hematoma removal using combination of keratocentesis and gas tamponade in the anterior chamber. METHODS: We reviewed the clinical course and outcomes of surgical intervention. RESULTS: An 82-year-old woman visited our department because of a sudden decline in visual acuity (20/800 on the Snellen chart) in her left eye. We observed neovascularization from the superior corneal limbus and a hematoma near the Descemet membrane, deep in the stroma of the corneal center. Filtered air was injected into the anterior chamber, keratocentesis was performed at four locations from the corneal epithelium through the stroma, and the hematoma was removed from the puncture sites. The corneal hematoma disappeared, and the best-corrected visual acuity reached 20/20 at postoperative month 4. DISCUSSION: Combination of keratocentesis and gas tamponade in the anterior chamber is a simple and effective method for removing intracorneal hematomas.

Micro- and Nanostructure Analysis of Vapor-Phase-Grown AlN on Face-to-Face Annealed Sputtered AlN/Nanopatterned Sapphire Substrate Templates.

Micro- and nanostructures in vapor-phase-grown AlN on face-to-face annealed sputtered AlN (FFA Sp-AlN) templates formed on nanopatterned sapphire substrates (NPSS) were comprehensively analyzed using transmission electron microscopy. The comparison between metal-organic vapor-phase epitaxy-grown AlN/FFA Sp-AlN/hole-type NPSS (Sample MOH) and hydride vapor-phase epitaxy-grown AlN/FFA Sp-AlN/cone-type NPSS (Sample HVC) showed apparent differences in the morphology of dislocation propagation, presence of voids, shape of polarity inversion boundaries, and crystal structure on the slope region of NPSS. Notably, cross-sectional and plan-view observations revealed that the quality of FFA Sp-AlN significantly affects the threading dislocation density in the vapor-phase-grown layer. At the slope region of the AlN/NPSS interface, γ-AlON was observed in the MOH sample, while highly misaligned AlN grains were observed in the HVC sample. These characteristic crystal structures affect the occurrence of dislocations via different mechanisms in each sample. This study provides practical information for strategically controlling the micro- and nanostructures formed in AlN/NPSS structures for high-performance AlGaN-based deep-ultraviolet emitters. Supplementary Information: The online version contains supplementary material available at 10.1007/s11664-023-10348-3.

Anomalous Epithelial Variations and Ectopic Inflammatory Response in Chronic Obstructive Pulmonary Disease.

Phenotypic alterations in the lung epithelium have been widely implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but the precise mechanisms orchestrating this persistent inflammatory process remain unknown because of the complexity of lung parenchymal and mesenchymal architecture. To identify cell type-specific mechanisms and cell-cell interactions among the multiple lung resident cell types and inflammatory cells that contribute to COPD progression, we profiled 57,918 cells from lungs of patients with COPD, smokers without COPD, and never-smokers using single-cell RNA sequencing technology. We predicted pseudotime of cell differentiation and cell-to-cell interaction networks in COPD. Although epithelial components in never-smokers were relatively uniform, smoker groups represent extensive heterogeneity in epithelial cells, particularly in alveolar type 2 (AT2) clusters. Among AT2 cells, which are generally regarded as alveolar progenitors, we identified a unique subset that increased in patients with COPD and specifically expressed a series of chemokines including CXCL1 and CXCL8. A trajectory analysis revealed that the inflammatory AT2 cell subpopulation followed a unique differentiation path, and a prediction model of cell-to-cell interactions inferred significantly increased intercellular networks of inflammatory AT2 cells. Our results identify previously unidentified cell subsets and provide an insight into the biological and clinical characteristics of COPD pathogenesis.

Bachmann's bundle-ridge related biatrial tachycardia with a long epicardial circuit.

Biatrial tachycardia (BiAT), involving Bachmann's bundle in the circuit, has sometimes been observed after mitral anterior line ablation. In this article, we present a case of BiAT, involving a long epicardial circuit, composed of Bachmann's bundle and the left atrial ridge (LAR). We discuss the optimal ablation technique for this tachycardia based on our experience in addition to the relationship between Bachmann's bundle and the LAR. Furthermore, the evaluation method for the mitral anterior block line is also discussed.

Achievement rate and learning curve of left bundle branch capture in left bundle branch area pacing procedure performed to demonstrate output-dependent QRS transition.

INTRODUCTION: Recently, output-dependent QRS transition was reported to be required to confirm left bundle branch (LBB) capture in LBB area pacing (LBBAP) procedure. This study aimed to evaluate the achievement rate and the learning curve of LBB capture in LBBAP procedure performed with the goal of demonstrating output-dependent QRS transition, and investigate predictors of LBB capture. METHODS AND RESULTS: The LBBAP procedure was performed in 126 patients with bradyarrhythmia. LBB capture was defined as a demonstration of output-dependent QRS transition. The following pacing definitions were used for evaluation: (1) LBBAP, which met the previously reported LBBAP criteria, (2) LBB pacing (LBBP), LBB capture was confirmed, and (3) available LBBP, LBB threshold was clinically usable (<3 V at 0.4 ms). The learning curve was evaluated by division into three time-periods. The achievement rates of LBBAP, LBBP, and available LBBP were 88.1%, 41.2%, and 35.7%, respectively. The achievement rates of all three pacing definitions significantly increased with experience (p < .01), but the achievement rate of available LBBP was still 50% in the third period. As predictors of LBB capture, the interval between LBB-Purkinje potential and QRS onset ≥22 ms had high specificity of 98.3%, while R wave peak time in V6 < 68 ms had insufficient sensitivity of 79% and specificity of 68%. CONCLUSION: Even if LBB capture was aimed in LBBAP procedure, it was not easy to achieve, and there was a clear learning curve. Much of LBBAP may be left ventricular septal pacing that does not capture LBB.

A Scoping Review of Computer-Based and Telecommunication Technology Interventions to Address Drug and Alcohol Misuse and Smoking in Women.

BACKGROUND: Computer-based and telecommunication technology has become increasingly common to address addiction among women. This review assessed the effect of technology-based interventions on substance misuse, alcohol use, and smoking outcomes among women. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (PRISMA-ScR) guideline was used to conduct the scoping review. Four databases (PubMed, Web of Science, PsycINFO, and Scopus) were used to search for peer-reviewed articles published in English on computer-based and telecommunication technology use to address substance misuse, alcohol use, and smoking among women. RESULTS: A total of 30 articles were selected after the final full-text review from the U.S., England, Japan, and the Netherlands. The types of technology used in the interventions included computer software (standalone or web-based), mobile applications, video calling, phone, and text messaging. Intervention outcomes included alcohol and other substance misuse reduction as polysubstance misuse (n = 5), smoking cessation (n = 10), substance misuse reduction only (n = 6), and alcohol use reduction only (n = 9). The populations reached included women who were pregnant (n = 13), postpartum (n = 4), or non-pregnant (n = 14) ranging from adolescent to adulthood. Interventions that targeted polysubstance misuse showed statistically significant reductions (p < .05). CONCLUSION: Although effective in reducing alcohol and other substance misuse, mixed findings were identified for other outcomes targeting a single substance. Technology-based interventions might maximize their effects by targeting polysubstance misuse and addressing associated contextual issues in the form of a computer-delivered module(s).

Establishment and characterization of highly osteolytic luminal breast cancer cell lines by intracaudal arterial injection.

Bone is one of the most common metastatic sites of breast cancer, and bone metastasis profoundly affects the quality of life of breast cancer patients. Bone metastasis is commonly observed among all the subtypes of breast cancer; however, its molecular mechanism has been analyzed only in triple-negative subtype of breast cancer (TNBC). To characterize the molecular mechanisms of bone metastasis of luminal breast cancer, we established a bone-metastatic model of the MCF7, luminal breast cancer cell line, with enhanced osteolytic activity by intracaudal arterial injection (CAI). Pathological analysis of the established cell lines revealed that they exhibited fierce osteolytic ability by promoting osteoclast differentiation and activity. The signature genes extracted from highly osteolytic MCF7 cell lines were differed from those of bone-metastatic TNBC cell lines. Our results suggest that unique mechanisms of osteolysis in bone-metastatic lesions of luminal breast cancer. In addition, several up-regulated genes in MCF7-BM (Bone Metastasis) 02 cell lines correlated with poor prognosis with luminal breast cancer patients. Our findings support further study on the bone-metastatic mechanisms of luminal breast cancer.

Systematic review on use of health incentives in U.S. to change maternal health behavior.

Use of financial incentives contingent on health outcomes has shown effective in health behavior change. Evidence-based information on the effect of incentive use for maternal health behavior change can inform whether and how to proceed with future research as well as incorporate incentive-based interventions in the existing healthcare system. This systematic literature review was conducted among prospective studies on incentive use for maternal health behavior change in a U.S. cohort according to the PRISMA methodology. Databases subject to the search included PubMed, Web of Science, PsycINFO, and EBSCOhost. Studies published in peer-reviewed journals on or before January 7, 2019, written in English, conducted in U.S., using incentives contingent on maternal health behavior change, and prospectively designed were included. Two authors independently searched titles and abstracts. An abstraction table was constructed, and the risk of bias was assessed using the GRADE approach. The review showed that incentives such as vouchers and other financial incentives were effective in improving outcomes especially related to substance use, tobacco use, and breastfeeding. Mixed evidence was found in improving treatment adherence outcomes; however the studies with randomized trials on the outcome of treatment adherence also showed low certainty. Continued improvements need to be made in implementing an incentive-based approach in the context of comprehensive treatment and routine healthcare, exploring electronic- or mobile-based implementation of the approach, and implementing the approach for a wider variety of outcomes during both prenatal and postpartum periods.

Characteristics and proposed mechanisms of QRS morphology observed during the left bundle branch pacing procedure.

BACKGROUND: In performing left bundle branch pacing (LBBP), various QRS morphologies are observed as the lead penetrates the ventricular septum (VS). This study aimed to evaluate these characteristics and infer the mechanism underlying each QRS morphology. METHODS: In 19 patients who met the strict criteria for LBB capture, we classified the QRS morphologies observed during the LBBP procedure into seven patterns, the first five of which were determined by the depth of penetration: right ventricular septal pacing (RVSP), intraventricular septal pacing (IVSP1 and IVSP2), endocardial side of left ventricular septal pacing (LVSeP), nonselective LBBP (NS-LBBP), selective LBBP (S-LBBP), and NS-LBBP with anodal capture. The parameters of the QRS morphologies in these seven patterns were evaluated. RESULTS: Among the first five patterns, stimulus-QRSend duration (s-QRSend) was the narrowest in IVSP1 rather than in NS-LBBP, and stimulus-to-peak of R wave in V6 (s-LVAT) was significantly shortened in two steps, from RVSP to IVSP1 (96 ± 11; 82 ± 8 ms, p < .01) and from LVSeP to NS-LBBP (76 ± 7; 60 ± 4 ms, p < .01). The late-R duration in V1 was significantly prolonged in the order of LVSeP, NS-LBBP, and S-LBBP (45 ± 7; 53 ± 10; 71 ± 15 ms, respectively, p < .01). CONCLUSIONS: s-QRSend was the narrowest in IVSP1 rather than in NS-LBBP among the QRS morphologies observed during lead penetration through the VS. The prolonged late-R duration in V1 and abrupt shortening of the s-LVAT in V6 may help determine LBB capture during lead penetration.

Computational screening of cryoprotective agents for regenerative medical products using quantum chemistry and molecular dynamics simulations.

Cryoprotective agents (CPAs) are essential for the cryopreservation of cells. Thus far, dimethyl sulfoxide (DMSO) has been widely used as a CPA; however, DMSO is known to be toxic to cells. The damaged cells by the toxicity can present abnormal conditions, and should not be used for regenerative medical products because the cells/products are implanted directly into human bodies. With the aim of searching for an alternative CPA to DMSO, this work presents a computational screening of CPA candidate compounds using quantum chemistry and molecular dynamics (MD) simulations. Forty compounds were evaluated in regard to the solvation free energy and partition coefficient by quantum chemistry simulation and the root mean square deviation (RMSD) of a phospholipid bilayer which composes a cell membrane by MD simulation. The solvation free energy, partition coefficient, and RMSD were defined as indicators of osmoregulatory ability, affinity with a cell membrane, and ability to spread a cell membrane, respectively. The quantum chemistry simulation elucidated that the six compounds of trimethylglycine, formamide, urea, thiourea, diethylene glycol, and dulcitol were better than DMSO in either or both of the physical properties considered. This finding is based on the inherent physical property and is thus case-independent. Further characterization with the MD simulation suggested that formamide, thiourea, and urea should be the first candidates to investigate, although the result was valid only in the simulated condition. This work serves as the first step of multi-faceted computational evaluation of multiple compounds in the search for an effective CPA compound after DMSO.

Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice.

Although diabetic polyneuropathy (DPN) is the commonest diabetic complication, its pathology remains to be clarified. As previous papers have suggested the neuroprotective effects of glucagon-like peptide-1 in DPN, the current study investigated the physiological indispensability of glucagon gene-derived peptides (GCGDPs) including glucagon-like peptide-1 in the peripheral nervous system (PNS). Neurological functions and neuropathological changes of GCGDP deficient (gcg-/-) mice were examined. The gcg-/- mice showed tactile allodynia and thermal hyperalgesia at 12-18 weeks old, followed by tactile and thermal hypoalgesia at 36 weeks old. Nerve conduction studies revealed a decrease in sensory nerve conduction velocity at 36 weeks old. Pathological findings showed a decrease in intraepidermal nerve fiber densities. Electron microscopy revealed a decrease in circularity and an increase in g-ratio of myelinated fibers and a decrease of unmyelinated fibers in the sural nerves of the gcg-/- mice. Effects of glucagon on neurite outgrowth were examined using an ex vivo culture of dorsal root ganglia. A supraphysiological concentration of glucagon promoted neurite outgrowth. In conclusion, the mice with deficiency of GCGDPs developed peripheral neuropathy with age. Furthermore, glucagon might have neuroprotective effects on the PNS of mice. GCGDPs might be involved in the pathology of DPN.

High Sensitivity In Vivo Imaging of Cancer Metastasis Using a Near-Infrared Luciferin Analogue seMpai.

Bioluminescence imaging (BLI) is useful to monitor cell movement and gene expression in live animals. However, D-luciferin has a short wavelength (560 nm) which is absorbed by tissues and the use of near-infrared (NIR) luciferin analogues enable high sensitivity in vivo BLI. The AkaLumine-AkaLuc BLI system (Aka-BLI) can detect resolution at the single-cell level; however, it has a clear hepatic background signal. Here, to enable the highly sensitive detection of bioluminescence from the surrounding liver tissues, we focused on seMpai (C15H16N3O2S) which has been synthesized as a luciferin analogue and has high luminescent abilities as same as AkaLumine. We demonstrated that seMpai BLI could detect micro-signals near the liver without any background signal. The solution of seMpai was neutral; therefore, seMpai imaging did not cause any adverse effect in mice. seMpai enabled a highly sensitive in vivo BLI as compared to previous techniques. Our findings suggest that the development of a novel mutated luciferase against seMpai may enable a highly sensitive BLI at the single-cell level without any background signal. Novel seMpai BLI system can be used for in vivo imaging in the fields of life sciences and medicine.

Role of non-macrophage cell-derived HMGB1 in oxaliplatin-induced peripheral neuropathy and its prevention by the thrombin/thrombomodulin system in rodents: negative impact of anticoagulants.

BACKGROUND: Macrophage-derived high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) protein, plays a key role in the development of chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel in rodents. Endothelial thrombomodulin (TM) promotes thrombin-induced degradation of HMGB1, and TMα, a recombinant human soluble TM, abolishes peripheral HMGB1-induced allodynia in mice. We thus examined whether HMGB1, particularly derived from macrophages, contributes to oxaliplatin-induced neuropathy in mice and analyzed the anti-neuropathic activity of the TM/thrombin system. METHODS: CIPN models were created by the administration of oxaliplatin in mice and rats, and the nociceptive threshold was assessed by von Frey test or paw pressure test. Macrophage-like RAW264.7 cells were stimulated with oxaliplatin in vitro. Proteins were detected and/or quantified by Western blotting, immunostaining, or enzyme-linked immunosorbent assay. RESULTS: Intraperitoneal administration of an anti-HMGB1-neutralizing antibody (AB) at 1 mg/kg prevented the oxaliplatin-induced allodynia in mice and rats. Antagonists of Toll-like receptor (TLR) 4, receptor for advanced glycation end products (RAGE) and CXCR4 among the HMGB1-targeted pro-nociceptive receptors, also mimicked the anti-neuropathic activity of AB in mice. Macrophage accumulation in the sciatic nerve was observed in mice treated with paclitaxel, but not oxaliplatin, and neither macrophage depletion nor inhibitors of macrophage activation affected oxaliplatin-induced allodynia. Oxaliplatin was 10- to 100-fold less potent than paclitaxel in releasing HMGB1 from macrophage-like RAW264.7 cells. Like AB, TMα at 10 mg/kg prevented the oxaliplatin-induced allodynia in mice as well as rats, an effect abolished by argatroban at 10 mg/kg, a thrombin inhibitor. The anti-neuropathic activity of TMα in oxaliplatin-treated mice was suppressed by oral anticoagulants such as warfarin at 1 mg/kg, dabigatran at 75 mg/kg, and rivaroxaban at 10 mg/kg, but not antiplatelet agents such as aspirin at 50 mg/kg and clopidogrel at 10 mg/kg. Repeated administration of the anticoagulants gradually developed neuropathic allodynia and elevated plasma HMGB1 levels in mice treated with a subeffective dose of oxaliplatin. CONCLUSIONS: Our data thus suggests a causative role of HMGB1 derived from non-macrophage cells in oxaliplatin-induced peripheral neuropathy and a thrombin-dependent anti-neuropathic activity of exogenous TMα and, most probably, endogenous TM.

A Behavioral Economic Analysis of Demand for Texting while Driving.

The overarching goal of the present study was to determine whether a behavioral economic framework of demand analysis is applicable to texting while driving. To this end, we developed a novel hypothetical task designed to quantify the intensity and elasticity of the demand for social interaction from texting while driving. This task involved a scenario in which participants receive a text message while driving, and they rated the likelihood of replying to a text message immediately versus waiting to reply until arriving at a destination when the amounts of a fine for texting while driving ranged from $1 to $300. To assess the construct validity of the task, the scenario presented two delays to a destination (15 min and 60 min). The demand for social interaction from texting was more intense (greater at the lowest amount of the fine) and less elastic (less sensitive to the increase in the amounts of the fine) for drivers who self-reported a higher frequency of texting while driving than for those who self-reported a lower frequency of texting while driving. Demand was also more intense and less elastic under the 60-min delay condition than under the 15-min condition. The results of this proof-of-concept study suggest that behavioral economic demand analyses are potentially useful for understanding and predicting texting while driving.

Human soluble thrombomodulin-induced blockade of peripheral HMGB1-dependent allodynia in mice requires both the lectin-like and EGF-like domains.

Thrombomodulin (TM), an endothelial protein with anti-coagulant activity, is composed of 5 domains, D1-D5. Recombinant human soluble TM (TMα) consisting of D1-D3, which is generated in CHO cells, suppresses inflammatory and nociceptive signals by inactivating high mobility group box 1 (HMGB1), one of damage-associated molecular patterns. TMα sequesters HMGB1 with the lectin-like D1 and promotes its degradation by thrombin binding to the EGF-like D2. We prepared TM's D123, D1 and D2 by the protein expression system of yeast, and evaluated their effects on HMGB1 degradation in vitro and on the allodynia caused by HMGB1 in distinct redox forms in mice in vivo. TMα and TM's D123, but not D1, promoted the thrombin-dependent degradation of all-thiol (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), an effect mimicked by TM's D2, though to a lesser extent. Intraplantar administration of TMα and TM's D123, but not D1, D2 or D1 plus D2, strongly prevented the mechanical allodynia caused by intraplantar at-HMGB1, ds-HMGB1 or lipopolysaccharide in mice. Our data suggest that, apart from the role of D3, TMα and TM's D123 require both lectin-like D1 capable of sequestering HMGB1 and EGF-like D2 responsible for thrombin-dependent degradation of HMGB1, in abolishing the allodynia caused by exogenous or endogenous HMGB1.