A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

Incidence, Management, and Prognosis of Graft Failure and Autologous Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: This study presents outcomes of management in graft failure (GF) after allogeneic hematopoietic stem cell transplantation (HCT) and provides prognostic information including rare cases of autologous reconstitution (AR). METHODS: We analyzed risk factors and outcomes of primary and secondary GF, and occurrence of AR in 1,630 HCT recipients transplanted over period of 18 years (January 2000-September 2017) at our center. RESULTS: Primary and secondary GF occurred in 13 (0.80%), and 69 patients (10-year cumulative incidence, 4.5%) respectively. No peri-transplant variables predicted primary GF, whereas reduced intensity conditioning (RIC) regimen (relative risk [RR], 0.97-28.0, P < 0.001) and lower CD34⁺ cell dose (RR, 2.44-2.84, P = 0.002) were associated with higher risk of secondary GF in multivariate analysis. Primary GF demonstrated 100% mortality, in the secondary GF group, the 5-year Kaplan-Meier survival rate was 28.8%, relapse ensued in 18.8%, and AR was observed in 11.6% (n = 8). In survival analysis, diagnosis of aplastic anemia (AA), chronic myeloid leukemia and use of RIC had a positive impact. There were 8 patients who experienced AR, which was rarely reported after transplantation for acute leukemia. Patient shared common characteristics such as young age (median 25 years), use of RIC regimen, absence of profound neutropenia, and had advantageous survival rate of 100% during follow period without relapse. CONCLUSION: Primary GF exhibited high mortality rate. Secondary GF had 4.5% 10-year cumulative incidence, median onset of 3 months after HCT, and showed 5-year Kaplan-Meier survival of 28.8%. Diagnosis of severe AA and use of RIC was both associated with higher incidence and better survival rate in secondary GF group. AR occurred in 11.6% in secondary GF, exhibited excellent prognosis.

Comparison of Postextubation Outcomes Associated with High-Flow Nasal Cannula vs. Conventional Oxygen Therapy in Patients at High Risk of Reintubation: a Randomized Clinical Trial.

BACKGROUND: Liberation and extubation are important for patients supported by mechanical ventilation. Extubation success is related to the duration of an intensive care unit (ICU) stay and mortality rate. High-flow nasal cannula (HFNC) oxygen therapy has physiological and clinical benefits in respiratory care. The present study compared clinical outcomes associated with HFNC and conventional oxygen therapy (COT) among patients at high risk for reintubation. METHODS: A single-center randomized clinical trial was conducted between March 2018 and June 2019. Sixty adults admitted to the ICU and who were at high-risk of reintubation and met the inclusion criteria were enrolled in this study. "High risk" for reintubation was defined as having at least one of the following risk factors: age > 65 years, Acute Physiology and Chronic Health Evaluation II score > 12 points on extubation day, obesity, poor expectoration, airway patency problems, difficult or prolonged weaning, and more than one comorbidity. The primary outcome of interest was reintubation within 72 hours. Secondary outcomes included duration of ICU and hospital stay, mortality rate, and time to reintubation. RESULTS: Of 60 patients, 31 received HFNC and 29 received COT (mean age, 78 ± 7.8 vs. 76 ± 6.5 years, respectively). Reintubation rate within 72 hours did not differ between the groups (3 patients [9.7%] vs. 1 patient [3.4%], respectively). Reintubation time was shorter among patients who received COT than among patients who received HFNC (0.5 hour vs. 25 hours), but this difference was not statistically significant. Duration of ICU did not differ between the groups (14.7 ± 9.6 days vs. 13.8 ± 15.7 days, for HFNC and COT, respectively). CONCLUSION: Among patients at high risk for reintubation, compared with COT, HFNC did not reduce the risk of reintubation within 72 hours.

Experimental Realization of Few Layer Two-Dimensional MoS2 Membranes of Near Atomic Thickness for High Efficiency Water Desalination.

A globally imminent shortage of freshwater has been demanding viable strategies for improving desalination efficiencies with the adoption of cost- and energy-efficient membrane materials. The recently explored 2D transition metal dichalcogenides (2D TMDs) of near atomic thickness have been envisioned to offer notable advantages as high-efficiency membranes owing to their structural uniqueness; that is, extremely small thickness and intrinsic atomic porosity. Despite theoretically projected advantages, experimental realization of near atom-thickness 2D TMD-based membranes and their desalination efficiency assessments have remained largely unexplored mainly due to the technical difficulty associated with their seamless large-scale integration. Herein, we report the experimental demonstration of high-efficiency water desalination membranes based on few-layer 2D molybdenum disulfide (MoS2) of only ∼7 nm thickness. Chemical vapor deposition (CVD)-grown centimeter-scale 2D MoS2 layers were integrated onto porous polymeric supports with well-preserved structural integrity enabled by a water-assisted 2D layer transfer method. These 2D MoS2 membranes of near atomic thickness exhibit an excellent combination of high water permeability (>322 L m-2 h-1 bar-1) and high ionic sieving capability (>99%) for various seawater salts including Na+, K+, Ca2+, and Mg2+ with a range of concentrations. Moreover, they present near 100% salt ion rejection rates for actual seawater obtained from the Atlantic coast, significantly outperforming the previously developed 2D MoS2 layer membranes of micrometer thickness as well as conventional reverse osmosis (RO) membranes. Underlying principles behind such remarkably excellent desalination performances are attributed to the intrinsic atomic vacancies inherent to the CVD-grown 2D MoS2 layers as verified by aberration-corrected electron microscopy characterization.

Phosphomimetic S3D cofilin binds but only weakly severs actin filaments.

Many biological processes, including cell division, growth, and motility, rely on rapid remodeling of the actin cytoskeleton and on actin filament severing by the regulatory protein cofilin. Phosphorylation of vertebrate cofilin at Ser-3 regulates both actin binding and severing. Substitution of serine with aspartate at position 3 (S3D) is widely used to mimic cofilin phosphorylation in cells and in vitro The S3D substitution weakens cofilin binding to filaments, and it is presumed that subsequent reduction in cofilin occupancy inhibits filament severing, but this hypothesis has remained untested. Here, using time-resolved phosphorescence anisotropy, electron cryomicroscopy, and all-atom molecular dynamics simulations, we show that S3D cofilin indeed binds filaments with lower affinity, but also with a higher cooperativity than wild-type cofilin, and severs actin weakly across a broad range of occupancies. We found that three factors contribute to the severing deficiency of S3D cofilin. First, the high cooperativity of S3D cofilin generates fewer boundaries between bare and decorated actin segments where severing occurs preferentially. Second, S3D cofilin only weakly alters filament bending and twisting dynamics and therefore does not introduce the mechanical discontinuities required for efficient filament severing at boundaries. Third, Ser-3 modification (i.e. substitution with Asp or phosphorylation) "undocks" and repositions the cofilin N terminus away from the filament axis, which compromises S3D cofilin's ability to weaken longitudinal filament subunit interactions. Collectively, our results demonstrate that, in addition to inhibiting actin binding, Ser-3 modification favors formation of a cofilin-binding mode that is unable to sufficiently alter filament mechanical properties and promote severing.

Biophysical characterization of actin bundles generated by the Chlamydia trachomatis Tarp effector.

Chlamydia trachomatis entry into host cells is mediated by pathogen-directed remodeling of the actin cytoskeleton. The chlamydial type III secreted effector, translocated actin recruiting phosphoprotein (Tarp), has been implicated in the recruitment of actin to the site of internalization. Tarp harbors G-actin binding and proline rich domains required for Tarp-mediated actin nucleation as well as unique F-actin binding domains implicated in the formation of actin bundles. Little is known about the mechanical properties of actin bundles generated by Tarp or the mechanism by which Tarp mediates actin bundle formation. In order to characterize the actin bundles and elucidate the role of different Tarp domains in the bundling process, purified Tarp effectors and Tarp truncation mutants were analyzed using Total Internal Reflection Fluorescence (TIRF) microscopy. Our data indicate that Tarp mediated actin bundling is independent of actin nucleation and the F-actin binding domains are sufficient to bundle actin filaments. Additionally, Tarp-mediated actin bundles demonstrate distinct bending stiffness compared to those crosslinked by the well characterized actin bundling proteins fascin and alpha-actinin, suggesting Tarp may employ a novel actin bundling strategy. The capacity of the Tarp effector to generate novel actin bundles likely contributes to chlamydia's efficient mechanism of entry into human cells.

Site-specific cation release drives actin filament severing by vertebrate cofilin.

Actin polymerization powers the directed motility of eukaryotic cells. Sustained motility requires rapid filament turnover and subunit recycling. The essential regulatory protein cofilin accelerates network remodeling by severing actin filaments and increasing the concentration of ends available for elongation and subunit exchange. Although cofilin effects on actin filament assembly dynamics have been extensively studied, the molecular mechanism of cofilin-induced filament severing is not understood. Here we demonstrate that actin filament severing by vertebrate cofilin is driven by the linked dissociation of a single cation that controls filament structure and mechanical properties. Vertebrate cofilin only weakly severs Saccharomyces cerevisiae actin filaments lacking this "stiffness cation" unless a stiffness cation-binding site is engineered into the actin molecule. Moreover, vertebrate cofilin rescues the viability of a S. cerevisiae cofilin deletion mutant only when the stiffness cation site is simultaneously introduced into actin, demonstrating that filament severing is the essential function of cofilin in cells. This work reveals that site-specific interactions with cations serve a key regulatory function in actin filament fragmentation and dynamics.

Identification of cation-binding sites on actin that drive polymerization and modulate bending stiffness.

The assembly of actin monomers into filaments and networks plays vital roles throughout eukaryotic biology, including intracellular transport, cell motility, cell division, determining cellular shape, and providing cells with mechanical strength. The regulation of actin assembly and modulation of filament mechanical properties are critical for proper actin function. It is well established that physiological salt concentrations promote actin assembly and alter the overall bending mechanics of assembled filaments and networks. However, the molecular origins of these salt-dependent effects, particularly if they involve nonspecific ionic strength effects or specific ion-binding interactions, are unknown. Here, we demonstrate that specific cation binding at two discrete sites situated between adjacent subunits along the long-pitch helix drive actin polymerization and determine the filament bending rigidity. We classify the two sites as "polymerization" and "stiffness" sites based on the effects that mutations at the sites have on salt-dependent filament assembly and bending mechanics, respectively. These results establish the existence and location of the cation-binding sites that confer salt dependence to the assembly and mechanics of actin filaments.

Regulation of actin by ion-linked equilibria.

Actin assembly, filament mechanical properties, and interactions with regulatory proteins depend on the types and concentrations of salts in solution. Salts modulate actin through both nonspecific electrostatic effects and specific binding to discrete sites. Multiple cation-binding site classes spanning a broad range of affinities (nanomolar to millimolar) have been identified on actin monomers and filaments. This review focuses on discrete, low-affinity cation-binding interactions that drive polymerization, regulate filament-bending mechanics, and modulate interactions with regulatory proteins. Cation binding may be perturbed by actin post-translational modifications and linked equilibria. Partial cation occupancy under physiological and commonly used in vitro solution conditions likely contribute to filament mechanical heterogeneity and structural polymorphism. Site-specific cation-binding residues are conserved in Arp2 and Arp3, and may play a role in Arp2/3 complex activation and actin-filament branching activity. Actin-salt interactions demonstrate the relevance of ion-linked equilibria in the operation and regulation of complex biological systems.

Competitive displacement of cofilin can promote actin filament severing.

Cofilin is an essential actin filament severing protein that functions in the dynamic remodeling of the actin cytoskeleton. Filament severing activity is most efficient at sub-stoichiometric cofilin binding densities (i.e. <1 cofilin per actin filament subunit), and peaks when the number density of boundaries (i.e. junctions) between bare and cofilin-decorated segments is maximal. A model in which local topological and mechanical discontinuities lead to preferential fragmentation at boundaries accounts for available experimental data, including direct visualization of cofilin and actin during real-time severing events. The boundary-severing model predicts that ligands (e.g. other actin-binding proteins) that compete with cofilin for actin filament binding and modulate cofilin occupancy on filaments will alter the bare-decorated segment boundary density, and thus, the filament severing activity of cofilin. Here, we directly test this model prediction by evaluating the effects of phalloidin and myosin, two ligands that compete with cofilin for filament binding, on the actin filament binding and severing activities of cofilin. Our experiments demonstrate that competitive displacement of cofilin lowers cofilin occupancy and promotes severing when initial cofilin occupancy is high (i.e. >50%). Even in the presence of competitive ligands, maximum severing activity occurs when cofilin-decorated boundary density is highest, consistent with preferential fragmentation at boundaries. We propose a general "severodyne" framework for the modulation of cofilin-mediated actin filament severing by small molecule or actin-binding protein ligands that compete with cofilin for actin filament binding.

Saccadic eye movement speed is related to variations in phantom array effect visibility.

The phantom array effect is one of the temporal light artefacts that can decrease performance and increase fatigue. The phantom array effect visibility shows large individual differences; however, the dominant factors that can explain these individual differences remain unclear. We investigated the relationship between saccadic eye movement speed and phantom array visibility at two different angles and four different directions of saccadic eye movement. The peak speed of saccadic eye movement and the phantom array effect visibility were measured at different modulation frequencies of the light source. Our results show that phantom array visibility increased as eye movement speed increased; the phantom array visibility was higher at a wide viewing angle with fast eye movement speed than at a narrow viewing angle. Moreover, when clustered into subgroups according to individual eye movement speed, the mean speed of the saccadic eye movement of each subgroup is related to the variations in the visibility of the phantom array effect of the subgroup. Therefore, saccadic eye movement speed is related to variations in phantom array effect visibility.

FT-GAT: Graph neural network for predicting spontaneous breathing trial success in patients with mechanical ventilation.

BACKGROUND AND OBJECTIVES: Intensive care unit (ICU) physicians perform weaning procedures considering complex clinical situations and weaning protocols; however, liberating critical patients from mechanical ventilation (MV) remains challenging. Therefore, this study aims to aid physicians in deciding the early liberation of patients from MV by developing an artificial intelligence model that predicts the success of spontaneous breathing trials (SBT). METHODS: We retrospectively collected data of 652 critical patients (SBT success: 641, SBT failure: 400) who received MV at the Chungbuk National University Hospital (CBNUH) ICU from July 2020 to July 2022, including mixed and trauma ICUs. Patients underwent SBTs according to the CBNUH weaning protocol or physician's decision, and SBT success was defined as extubation performed by the physician on the SBT day. Additionally, our dataset comprised 11 numerical and 2 categorical features that can be obtained for any ICU patient, such as vital signs and MV setting values. To predict SBT success, we analyzed tabular data using a graph neural network-based approach. Specifically, the graph structure was designed considering feature correlation, and a novel deep learning model, called feature tokenizer graph attention network (FT-GAT), was developed for graph analysis. FT-GAT transforms the input features into high-dimensional embeddings and analyzes the graph via the attention mechanism. RESULTS: The quantitative evaluation results indicated that FT-GAT outperformed conventional models and clinical indicators by achieving the following model performance (AUROC): FT-GAT (0.80), conventional models (0.69-0.79), and clinical indicators (0.65-0.66) CONCLUSIONS: Through timely detection critical patients who can succeed in SBTs, FT-GAT can help prevent long-term use of MV and potentially lead to improvement in patient outcomes.

Characteristics and intrasubject variation in the respiratory microbiome in interstitial lung disease.

Recent studies have reported that the lower airway microbiome may play an essential role in the development and progression of interstitial lung disease (ILD). The aim of the current study was to evaluate the characteristics of the respiratory microbiome and intrasubject variation in patients with ILD. Patients with ILD were recruited prospectively for 12 months. The sample size was small (n = 11) owing to delayed recruitment during the COVID-19 pandemic. All subjects were hospitalized and were evaluated by a questionnaire survey, blood sampling, pulmonary function test, and bronchoscopy. Bronchoalveolar lavage fluid (BALF) was obtained at 2 sites, the most and least disease-affected lesions. Sputum collection was also performed. Furthermore, 16S ribosomal RNA gene sequencing was performed using the Illumina platform and indexes of α- and ß-diversity were evaluated. Species diversity and richness tended to be lower in the most-affected lesion than in the least-affected lesion. However, taxonomic abundance patterns were similar in these 2 groups. The phylum Fusobacteria was more prevalent in fibrotic ILD than in nonfibrotic ILD. Inter-sample differences in relative abundances were more prominent in BALF versus sputum specimens. Rothia and Veillonella were more prevalent in the sputum than in BALF. We did not detect site-specific dysbiosis in the ILD lung. BALF was an effective respiratory specimen type for evaluating the lung microbiome in patients with ILD. Further studies are needed to evaluate the causal links between the lung microbiome and the pathogenesis of ILD.

The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients-a randomized trial.

Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 108/kg and 1.4 × 108/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8+ effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.

Which factors are helpful for the early determination of treatment level in patients with interstitial lung disease in the intensive care unit to minimize the suffering in their end of life?: A retrospective study.

Interstitial lung disease (ILD) is widely known to be associated with high mortality and poor prognosis, especially in patients admitted to the intensive care unit (ICU). The objective of this study was to investigate clinical predictors for assisting relatively early decision of treatment level in the ICU. We retrospectively investigated patients with ILD who were admitted to the ICU between January 1, 2014, and September 30, 2019. A total of 64 patients were analyzed. We found the ICU and hospital mortality rates to be 67.2% and 69.8%, respectively. Nonsurvivors had a higher fraction of inspired oxygen (FiO2) on days 1 (79 ±â€…21 vs 60% ±â€…21%, P = .001) and 3 (61 ±â€…31 vs 46% ±â€…19%, P = .004). They showed lower partial pressure of oxygen/FiO2 (PF) ratio on days 1 (134 ±â€…80 vs 173 ±â€…102, P = .049) and 3 (147 ±â€…74 vs 235 ±â€…124, P = .003) than the survivor group. The lactic acid levels obtained on day 1 and PF ratio measured on day 3 were associated with mortality (odds ratio, 1.89; 95% confidence interval 1.03-3.47 and odds ratio, 0.99; 95% confidence interval 0.98-1.00, respectively). Among the 31 ICU survivors, 10 patients died in the general ward, 12 patients died after hospital discharge; only 9 patients survived after 1 year. We suggest that these clinical predictors could be used to determine the level of further treatment or withdrawal on day 3 of admission in patients with ILD admitted to the ICU to minimize the prolonged suffering in a relatively early period.

Predicting Long-term Survival After Allogeneic Hematopoietic Cell Transplantation in Patients With Hematologic Malignancies: Machine Learning-Based Model Development and Validation.

BACKGROUND: Scoring systems developed for predicting survival after allogeneic hematopoietic cell transplantation (HCT) show suboptimal prediction power, and various factors affect posttransplantation outcomes. OBJECTIVE: A prediction model using a machine learning-based algorithm can be an alternative for concurrently applying multiple variables and can reduce potential biases. In this regard, the aim of this study is to establish and validate a machine learning-based predictive model for survival after allogeneic HCT in patients with hematologic malignancies. METHODS: Data from 1470 patients with hematologic malignancies who underwent allogeneic HCT between December 1993 and June 2020 at Asan Medical Center, Seoul, South Korea, were retrospectively analyzed. Using the gradient boosting machine algorithm, we evaluated a model predicting the 5-year posttransplantation survival through 10-fold cross-validation. RESULTS: The prediction model showed good performance with a mean area under the receiver operating characteristic curve of 0.788 (SD 0.03). Furthermore, we developed a risk score predicting probabilities of posttransplantation survival in 294 randomly selected patients, and an agreement between the estimated predicted and observed risks of overall death, nonrelapse mortality, and relapse incidence was observed according to the risk score. Additionally, the calculated score demonstrated the possibility of predicting survival according to the different transplantation-related factors, with the visualization of the importance of each variable. CONCLUSIONS: We developed a machine learning-based model for predicting long-term survival after allogeneic HCT in patients with hematologic malignancies. Our model provides a method for making decisions regarding patient and donor candidates or selecting transplantation-related resources, such as conditioning regimens.

Multidisciplinary team approach on tracheoesophageal fistula in a patient with home ventilator.

A 68-year-old man was transferred to our tertiary hospital. Ten years ago, he received radiation therapy for tonsil cancer, and while there was no evidence of recurrence, he suffered from recurrent aspiration. We treated his aspiration pneumonia in the intensive care unit. Prior to his discharge, he received percutaneous dilatational tracheostomy (PDT) before he was transferred to a nursing hospital. Nine months later, he was readmitted owing to tracheoesophageal fistula (TEF). However, he was considered unsuitable for conservative intervention after a multidisciplinary team discussion. Esophageal stent insertion was impossible due to the high level of TEF in the esophagus. Additionally, the size of the TEF could not be covered by an endosponge and endoluminal vacuum therapy, and there was no tracheal stent that could cover his large trachea. The preceding percutaneous enteral gastrostomy (PEG) procedure was required for the primary closure operation of the esophagus; however, family's consent could not be obtained. After 1month, the patient and his family changed their minds and agreed to the procedure and we attempted to perform PEG procedure. However, we could not proceed with PEG owing to stenosis in the inlet of the esophagus. Then, the patient deteriorated clinically and died due to pneumonia with septic shock.

Clinical characteristics, radiological features, and disease severity of bronchiectasis according to the spirometric pattern.

Bronchiectasis show various ventilatory disorders in pulmonary function. The characteristics and severity of patients with bronchiectasis according to these pulmonary dysfunctions are still very limited. This study aimed to evaluate the clinical, radiologic feature and the disease severity of patients with bronchiectasis according to spirometric patterns. We retrospectively evaluated 506 patients with bronchiectasis who underwent pulmonary lung function test (PFT) at a referral hospital between 2014 to 2021. The results showed that cylindrical type was the most common (70.8%) type of bronchiectasis on chest Computed tomography (CT), and 70% of patients had bilateral lung involvement. On the other hand, obstructive ventilatory disorder was the most common (51.6%), followed by normal ventilation (30%) and restrictive ventilatory disorder (18.4%). The modified Medical Research Council (mMRC) was highest in patients with obstructive ventilatory disorders, Modified Reiff score [median (interquartile range)] [6 (3-10), P < 0.001], FACED (FEV1, Age, Chronic colonization, Extension, and Dyspnea) score [3 (1-4), P < 0.001], and Bronchiectasis Severity (BSI) score [8 (5-11), P < 0.001] showed significantly highest values of obstructive ventilatory disorder rather than restrictive ventilatory disorder and normal ventilation. More than half of patients with bronchiectasis had obstructive ventilatory disorder. Bronchiectasis with obstructive ventilatory disorders has more dyspnea symptom, more disease severity and more radiologic severity. There was no significant association between spirometric pattern and radiologic type, but the more severe the radiologic severity, the more severe the lung function impairment.

Cofilin-linked changes in actin filament flexibility promote severing.

The actin regulatory protein, cofilin, increases the bending and twisting elasticity of actin filaments and severs them. It has been proposed that filaments partially decorated with cofilin accumulate stress from thermally driven shape fluctuations at bare (stiff) and decorated (compliant) boundaries, thereby promoting severing. This mechanics-based severing model predicts that changes in actin filament compliance due to cofilin binding affect severing activity. Here, we test this prediction by evaluating how the severing activities of vertebrate and yeast cofilactin scale with the flexural rigidities determined from analysis of shape fluctuations. Yeast actin filaments are more compliant in bending than vertebrate actin filaments. Severing activities of cofilactin isoforms correlate with changes in filament flexibility. Vertebrate cofilin binds but does not increase the yeast actin filament flexibility, and does not sever them. Imaging of filament thermal fluctuations reveals that severing events are associated with local bending and fragmentation when deformations attain a critical angle. The critical severing angle at boundaries between bare and cofilin-decorated segments is smaller than in bare or fully decorated filaments. These measurements support a cofilin-severing mechanism in which mechanical asymmetry promotes local stress accumulation and fragmentation at boundaries of bare and cofilin-decorated segments, analogous to failure of some nonprotein materials.