Background and Purpose
Disruption of the endothelial glycocalyx is causally related to microvascular endothelial dysfunction, a characteristic of sepsis‐induced acute respiratory distress syndrome ...(ARDS). Recombinant human thrombomodulin (rhTM) attenuates vascular endothelial injuries, but the underlying mechanism remains elusive. Here, we investigated the structural basis and molecular mechanisms of rhTM effects on vascular endothelial injury in a model of sepsis.
Experimental Approach
LPS (20 mg·kg−1) was intraperitoneally injected into 10‐week‐old male C57BL6 mice, and saline or rhTM was intraperitoneally injected 3 and 24 h after LPS injection. Using serum and/or lung tissue, histological, ultrastructural, and microarray analyses were performed.
Key Results
Survival rate of rhTM‐treated mice was significantly higher than that of control mice 48 h after LPS injection. Serum concentrations of IL‐6 and high‐mobility group box 1 were lower in the rhTM‐treated group than in the control. Injury to the endothelial glycocalyx in pulmonary capillaries was attenuated by rhTM treatment. Gene set enrichment analysis revealed up‐regulation of gene sets corresponding to cell proliferation/differentiation and anti‐inflammation, such as the TGF‐β pathway, and negative regulation of IL‐6, upon rhTM treatment. Gene expression of heparan sulfate 6‐O‐sulfotransferase 1 and endothelial cell‐specific molecule 1 (components of the endothelial glycocalyx) was significantly preserved by rhTM treatment, and their protein expression levels were maintained in endothelial cells.
Conclusion and Implications
Our findings show that rhTM treatment affected inflammation, cell proliferation/differentiation, and glycocalyx synthesis in serum and lung tissue, subsequently attenuating ARDS caused by endothelial injury.
Working memory (WM) can influence selective attention. However, the effect of WM load on postural standing tasks has been poorly understood, even though these tasks require attentional resources. The ...purpose of this study was to examine whether WM load would impact anticipatory postural adjustments (APAs) during step initiation. Sixteen healthy young adults performed stepping tasks alone or concurrently with a WM task in a dual-task design. The stepping tasks involved volitional stepping movements in response to visual stimuli and comprised of simple and choice reaction time tasks and the Flanker task which consisted of congruent and incongruent (INC) conditions. In the dual-task condition, subjects were required to memorize either one or six digits before each stepping trial. Incorrect weight transfer prior to foot-lift, termed APA errors, reaction time (RT), and foot-lift time were measured from the vertical force data. The results showed that APA error rate was significantly higher when memorizing six-digit than one-digit numerals in the INC condition. In addition, RT and foot-lift time were significantly longer in the INC condition compared to the other stepping conditions, while there was no significant effect of WM load on RT or foot-lift time. These findings suggest that high WM load reduces the cognitive resources needed for selective attention and decision making during step initiation.
Electrical muscle stimulation (EMS) induces involuntary muscle contraction. Several studies have suggested that EMS has the potential to be an alternative method of voluntary exercise; however, its ...effects on cerebral blood flow (CBF) when applied to large lower limb muscles are poorly understood. Thus, the purpose of this study was to examine the effects of EMS on CBF, focusing on whether the effects differ between the internal carotid (ICA) and vertebral (VA) arteries.
The participants performed the experiments under EMS and control (rest) conditions in a randomized crossover design. The ICA and VA blood flow were measured before and during EMS or control. Heart rate, blood pressure, minute ventilation, oxygen uptake, and end-tidal partial pressure of carbon dioxide (P
CO
) were monitored and measured as well.
The ICA blood flow increased during EMS Pre: 330 ± 69 mL min
; EMS: 371 ± 81 mL min
, P = 0.001, effect size (Cohen's d) = 0.55. In contrast, the VA blood flow did not change during EMS (Pre: 125 ± 47 mL min
; EMS: 130 ± 45 mL min
, P = 0.26, effect size = 0.12). In the EMS condition, there was a significant positive linear correlation between ΔP
CO
and ΔICA blood flow (R = 0.74, P = 0.02). No relationships were observed between ΔP
CO
and ΔVA blood flow (linear: R = - 0.17, P = 0.66; quadratic: R = 0.43, P = 0.55).
The present results indicate that EMS increased ICA blood flow but not VA blood flow, suggesting that the effects of EMS on cerebral perfusion differ between anterior and posterior cerebral circulation, primarily due to the differences in cerebrovascular response to CO
.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD). Smoking susceptibility is important for the onset and development of COPD. We previously reported an association ...between serum iron concentrations and pulmonary function in male smokers. However, the mechanism governing smoking susceptibility in relation to iron deficiency is unclear; this study aimed to elucidate this mechanism. C57BL/6 male mice were fed an iron-deficient or normal diet and then exposed to cigarette smoke. BAL, histological analysis, and pulmonary function tests were performed after cigarette smoke exposure. Human alveolar type II epithelial A549 cells were treated with an iron chelator. Subsequently, A549 cells were exposed to cigarette smoke extract. In mice exposed to cigarette smoke for 2 weeks, the concentration of alveolar macrophages in the BAL fluid recovered from iron-deficient mice was significantly higher than that in normal diet mice. IL-6 and MCP-1 (monocyte chemotactic protein 1) concentrations in the BAL fluid increased significantly from baseline in iron-deficient mice, but not in normal diet mice. In mice exposed to cigarette smoke for 8 weeks, the pathological mean linear intercepts, physiological total lung capacity, and functional residual capacity in the lungs of iron-deficient mice were significantly greater than in normal diet mice. Phosphorylation of NF-κB was enhanced in the lungs of iron-deficient mice exposed to cigarette smoke and in the iron-chelating A549 cells exposed to cigarette smoke extract. Iron deficiency exaggerated cigarette smoke-induced pulmonary inflammation, suggesting that it may accelerate COPD development.
The ladder sleeper, which is a type of longitudinal sleeper with long beams in the longitudinal direction of the rail, was developed for the maintenance-labor saving of ballast tracks. In this study, ...to quantify the load distribution performance of the ladder sleepers at the structural boundary, full-scale model tests were conducted to quantify the vibration transmission reduction effect of the ladder sleepers. Following that, numerical experiments were carried out using a three-dimensional numerical analysis model and it was revealed that the ladder sleeper can reduce the pressure on the sleeper bottom plane by approximately 70% when compared to conventional prestressed concrete sleepers. Furthermore, when laying the ladder sleeper at the structural boundary, it was shown that laying across the structural boundary may be more effective in reducing the pressure on the sleeper bottom plane than laying it in front of the structural boundary. Finally, ladder sleepers were installed on the commercial line and long-term measurements of the longitudinal level irregularity verified the effect of suppressing the longitudinal level irregularity of the ballasted ladder track.
Abstract
OBJECTIVES
We analysed our clinical experience using silk sutures the double-loop technique (DLT) or DeBakey type vascular clamp (DeBakey clamp) for pulmonary artery (PA) troubles during ...anatomical lung resection to validate its practicality and safety.
METHODS
We retrospectively reviewed the records of patients who underwent either of the above clamping techniques during anatomical lung resection at our hospital between April 2007 and August 2022. We measured the PA diameter at the occlusion site on computed tomography images acquired within 1 year pre- and postoperatively. The difference between pre- and postoperative diameters of the occlusion sites was calculated as the change in the PA diameter. We zoned the occlusion site of the PA to adjust for variation. PA deformation was evaluated as an adverse event caused by clamping.
RESULTS
Ultimately, 27 and 26 patients who underwent the DLT and DeBakey clamp, respectively, were included. No additional injury due to the clamp procedure was found in either group. For zone R1/L1, defined as the main PA, the median changes in the PA diameter were 0.02 (–0.7 to 0.27) mm for the DLT and 0.36 (–0.28 to 0.89) mm for the DeBakey clamp. No significant differences were observed between the 2 groups (P = 0.106). Furthermore, no aneurysms, dissections, or stenoses were found in either group.
CONCLUSIONS
The DLT and DeBakey clamp had only minimal effects on the occlusion site of the PA. The DLT is a practical thoracoscopic technique for PA bleeding when primary haemostasis has been achieved.
Traditionally, open conversion and the use of vascular clamp forceps to clamp the pulmonary artery (PA) have been used as the standard methods for cases of PA troubles during anatomical lung resection (ALR) 1, 2.
The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and ...computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate.
Directed evolution of enzymes often fails to obtain desirable variants because of the difficulty in exploring a huge sequence space. To obtain active variants from a very limited number of variants ...available at the laboratory scale, machine learning (ML)-guided engineering of enzymes is becoming an attractive methodology. However, as far as we know, there is no example of an ML-guided functional modification of flavin-containing monooxygenase (FMO). FMOs are known to catalyze a variety of oxidative reactions and are involved in the biosynthesis of many natural products (NPs). Therefore, it is expected that the ML-guided functional enhancement of FMO can contribute to the efficient development of NP derivatives. In this research, we focused on p-hydroxybenzoate hydroxylase (PHBH), a model FMO, and altered only four amino acid residues around the substrate binding site. ML models were trained with a small initial library covering only approximately 0.1% of the whole sequence space, and the ML-predicted second library was enriched with active variants. The variant with the highest activity in the second library was PHBH-MWNL (V47M, W185, L199N, and L210), whose activity was more than 100 times that of the wild-type PHBH. For elucidation of the mechanism of the observed activity enhancement, the crystal structure of PHBH-MWNL in complex with 4-hydroxy-3-methyl benzoic acid was determined. In the PHBH-MWNL crystal structure, the missing water molecule WAT2 was observed due to N199 hydrogen-bonding to WAT2, indicating that the L199N mutation contributed to the observed functional improvement by stabilizing the proton relay network proposed to be important in catalysis.
Two new antiplasmodial peptides, named koshidacins A (1) and B (2), were discovered from the culture broth of the Okinawan fungus Pochonia boninensis FKR-0564. Their structures, including absolute ...configurations, were elucidated by a combination of spectroscopic methods and chemical derivatization. Both compounds showed moderate in vitro antiplasmodial activity against Plasmodium falciparum strains, with IC50 values ranging from 17.1 to 0.83 μM. In addition, compound 2 suppressed 41% of malaria parasites in vivo when administered intraperitoneally at a dose of 30 mg/kg/day for 4 days.
Although emergency resuscitative thoracotomy is performed as a salvage maneuver for critical blunt trauma patients, evidence supporting superior effectiveness of emergency resuscitative thoracotomy ...compared to conventional closed-chest compressions remains insufficient. The objective of this study was to investigate whether emergency resuscitative thoracotomy at the emergency department or in the operating room was associated with favourable outcomes after blunt trauma and to compare its effectiveness with that of closed-chest compressions.
This was a retrospective nationwide cohort study. Data were obtained from the Japan Trauma Data Bank for the period between 2004 and 2012. The primary and secondary outcomes were patient survival rates 24 h and 28 d after emergency department arrival. Statistical analyses were performed using multivariable generalized mixed-effects regression analysis. We adjusted for the effects of different hospitals by introducing random intercepts in regression analysis to account for the differential quality of emergency resuscitative thoracotomy at hospitals where patients in cardiac arrest were treated. Sensitivity analyses were performed using propensity score matching.
In total, 1,377 consecutive, critical blunt trauma patients who received cardiopulmonary resuscitation in the emergency department or operating room were included in the study. Of these patients, 484 (35.1%) underwent emergency resuscitative thoracotomy and 893 (64.9%) received closed-chest compressions. Compared to closed-chest compressions, emergency resuscitative thoracotomy was associated with lower survival rate 24 h after emergency department arrival (4.5% vs. 17.5%, respectively, P < 0.001) and 28 d after arrival (1.2% vs. 6.0%, respectively, P < 0.001). Multivariable generalized mixed-effects regression analysis with and without a propensity score-matched dataset revealed that the odds ratio for an unfavorable survival rate after 24 h was lower for emergency resuscitative thoracotomy than for closed-chest compressions (P < 0.001).
Emergency resuscitative thoracotomy was independently associated with decreased odds of a favorable survival rate compared to closed-chest compressions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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