Search

Although the technology used in commercial MRI scanners is in a very mature state, there are still many reasons for researchers to keep exploring how it can be optimized, such as the pursuit of higher image quality and greater patient comfort while keeping costs low. Changing the material of the superconducting magnets in MRI scanners is one of these ways. Currently, NbTi is the most commonly used superconducting magnet in MRI scanners, while in situ MgB2 is one of the hottest candidates for MRI superconductors. This paper presents the advantages of NbTi being able to be realistically installed in MRI scanners for many years and also analyzes the match of in situ MgB2 to various requirements of superconducting magnets in MRI scanners. The comparison shows that it is still NbTi that is more advantageous in recent years to come. MgB2, on the other hand, does almost match the requirements of commercial MRI scanners, if cost is not considered. However, this does not mean that MgB2 can be installed in commercial MRI scanners, and a lot of technical modifications and developments are still needed to adapt MgB2 to commercial MRI scanners before that.

At present, big data cloud computing has been widely used in many enterprises, and it serves tens of millions of users. One of the core technologies of big data cloud service is computer virtualization technology. The reasonable allocation of virtual machines on available hosts is of great significance to the performance optimization of cloud computing. We know that with the continuous development of information technology and the increasing number of computer users, different virtualization technologies and the increasing number of virtual machines in the network make the effective allocation of virtualization resources more and more difficult. In order to solve and optimize this problem, we propose a virtual machine allocation algorithm based on statistical machine learning. According to the resource requirements of each virtual machine in cloud service, the corresponding comprehensive performance analysis model is established, and the reasonable virtual machine allocation algorithm description of the host in the resource pool is realized according to the virtualization technology type or mode provided by the model. Experiments show that this method has the advantages of overall performance, load balancing, and supporting different types of virtualization.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) patients suffer from restrictive impairment of pulmonary function (PF) as a consequence of spinal and ribcage deformity. Statistic modelling of scoliotic geometry has been well-established based on low-dose biplanar X-ray device (EOS) imaging. However, the postoperative lung morphology change derived from EOS has not yet been studied adequately till now. METHODS: Twenty-five female AIS patients with severe right-sided major thoracic curve (aged 13–31 years; Cobb angle 45°–92°) underwent posterior spinal fusion (PSF) were prospectively recruited for standing EOS imaging at preoperative, postoperative, and 1-year follow-up (1Y-FU) stages. EOS-based lung morphology at frontal and lateral view was measured respectively to assess serial statistical changes in area and height. RESULTS: At frontal view, left lung area significantly increased postoperatively (104.7 vs. 125.1 cm(2); P0.05). At lateral view, the increase in left lung area was slight without statistically difference (median: 175.8, 178.4, 182.5 cm(2) at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05), while right lung area did not significantly change postoperatively (median: 209.9, 206.7, 212.4 cm(2) at preoperative, postoperative, 1Y-FU stage, respectively; all P>0.05). At both frontal and lateral view, left lung height significantly improved at both postoperative and 1Y-FU stage (all P0.05). CONCLUSIONS: EOS imaging demonstrates that left lung area in severe AIS may improve after PSF surgery. EOS may provide useful information about lung morphology change after PSF in severe AIS.

An oil-in-water (O/W) Pickering emulsion catalysis system was prepared using a self-assembled of lipase/chitosan nanoparticles (CRL/CS NPs). The CRL/CS NPs functioned as both a stabilizer and a catalyst, and every droplet of the emulsion was used as a microreactor for the reactants in the oil phase. Due to an adequate oil–water interface for the “lid” opening of lipase and rapid mass transfer in the CRL/CS NPs, the Pickering emulsion exhibited excellent enzymatic activity toward the hydrolysis of olive oil, achieving 72.80% and 99.62% hydrolysis rates after 15 min and 120 min, respectively. Immobilizing lipase in the self-assembled CS NPs endowed the lipase with exceptional recyclability and provided a shield to protect the enzyme from deactivation.

There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4

The lack of a consistent MRI radiomic signature, partly due to the multitude of initial feature analyses, limits the widespread clinical application of radiomics for the discrimination of salivary gland tumors (SGTs). This study aimed to identify the optimal radiomics feature category and MRI sequence for characterizing SGTs, which could serve as a step towards obtaining a consensus on a radiomics signature. Preliminary radiomics models were built to discriminate malignant SGTs (n = 34) from benign SGTs (n = 57) on T1-weighted (T1WI), fat-suppressed (FS)-T2WI and contrast-enhanced (CE)-T1WI images using six feature categories. The discrimination performances of these preliminary models were evaluated using 5-fold-cross-validation with 100 repetitions and the area under the receiver operating characteristic curve (AUC). The differences between models’ performances were identified using one-way ANOVA. Results show that the best feature categories were logarithm for T1WI and CE-T1WI and exponential for FS-T2WI, with AUCs of 0.828, 0.754 and 0.819, respectively. These AUCs were higher than the AUCs obtained using all feature categories combined, which were 0.750, 0.707 and 0.774, respectively (p < 0.001). The highest AUC (0.846) was obtained using a combination of T1WI + logarithm and FS-T2WI + exponential features, which reduced the initial features by 94.0% (from 1015 × 3 to 91 × 2). CE-T1WI did not improve performance. Using one feature category rather than all feature categories combined reduced the number of initial features without compromising radiomic performance.

Discriminating early-stage nasopharyngeal carcinoma (NPC) from benign hyperplasia (BH) on MRI is a challenging but important task for the early detection of NPC in screening programs. Radiomics models have the potential to meet this challenge, but instability in the feature selection step may reduce their reliability. Therefore, in this study, we aim to discriminate between early-stage T1 NPC and BH on MRI using radiomics and propose a method to improve the stability of the feature selection step in the radiomics pipeline. A radiomics model was trained using data from 442 patients (221 early-stage T1 NPC and 221 with BH) scanned at 3T and tested on 213 patients (99 early-stage T1 NPC and 114 BH) scanned at 1.5T. To verify the improvement in feature selection stability, we compared our proposed ensemble technique, which uses a combination of bagging and boosting (BB-RENT), with the well-established elastic net. The proposed radiomics model achieved an area under the curve of 0.85 (95% confidence interval (CI): 0.82–0.89) and 0.80 (95% CI: 0.74–0.86) in discriminating NPC and BH in the 3T training and 1.5T testing cohort, respectively, using 17 features selected from a pool of 422 features by the proposed feature selection technique. BB-RENT showed a better feature selection stability compared to the elastic net (Jaccard index = 0.39 ± 0.14 and 0.24 ± 0.06, respectively; p < 0.001).

The purpose of this study was to retrospectively evaluate the diagnostic performances of diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM) for discriminating between benign and malignant salivary gland tumors (SGTs).Sixty-seven patients with 71 SGTs who underwent MRI examination at 3 Tesla were included. There were 34 men and 37 women with a mean age of 57 ± 17 (SD) years (age range: 20-90 years). SGTs included 21 malignant tumors (MTs) and 50 benign SGTs (33 pleomorphic adenomas [PAs] and 17 Warthin's tumors [WTs]). For each SGT, DWI and IVIM parameters, mean, skewness, and kurtosis of apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*) and perfusion volume fraction (f) were calculated and further compared between SGTs using univariable analysis. Areas under the curves (AUC) of receiver operating characteristic of significant parameters were compared using the Delong test.Significant differences in ADCIVIM is more accurate than DWI for discriminating between benign and malignant SGTs because of its advantage in detecting WTs. Thresholds set by maximizing specificity for benign SGTs may be advantageous in a clinical setting.

Significance: Red blood cell (RBC)-mediated vasodilation plays an important role in oxygen delivery. This occurs through hemoglobin actions, at least in significant part, to convert heme-bound nitric oxide (NO) (in tense [T]/deoxygenated-state hemoglobin) into vasodilator S-nitrosothiol (SNO) (in relaxed [R]/oxygenated-state hemoglobin), convey SNO through the bloodstream, and release it into tissues to increase blood flow. The coupling of hemoglobin R/T state allostery, both to NO conversion into SNO and to SNO release (along with oxygen), under hypoxia supports the model of a three-gas respiratory cycle (O(2)/NO/CO(2)). Recent Advances: Oxygenation of tissues is dependent on a single, strictly conserved Cys residue in hemoglobin (βCys93). Hemoglobin couples SNO formation/release at βCys93 to O(2) binding/release at hemes (“thermodynamic linkage”). Mice bearing βCys93Ala hemoglobin that is unable to generate SNO-βCys93 establish that SNO-hemoglobin is important for R/T allostery-regulated vasodilation by RBCs that couple blood flow to tissue oxygenation. Critical Issues: The model for RBC-mediated vasodilation originally proposed by Stamler et al. in 1996 has been largely validated: SNO-βCys93 forms in vivo, dilates blood vessels, and is hypoxia-regulated, and RBCs actuate vasodilation proportionate to hypoxia. Numerous compensations in βCys93Ala animals to alleviate tissue hypoxia (discussed herein) are predicted to preserve vasodilatory responses of RBCs but impair linkage to R/T transition in hemoglobin. This is borne out by loss of responsivity of mutant RBCs to oxygen, impaired blood flow responses to hypoxia, and tissue ischemia in βCys93-mutant animals. Future Directions: SNO-hemoglobin mediates hypoxic vasodilation in the respiratory cycle. This fundamental physiology promises new insights in vascular diseases and blood disorders.

An electroconductive nanoparticles (NPs) film consisting of sodium poly(γ-glutamate) (γ-PGANa) and 3,4-diaminothiophene dihydrochloride (DATh) was simply prepared through macromolecular self-assembly and electropolymerization methods. Firstly, the γ-PGANa and the DATh underwent a complexation to form DATh/γ-PGANa composites through the electrostatic interaction; the DATh/γ-PGANa composites were then self-assembled into DATh/γ-PGANa NPs through decreasing the pH value in aqueous solution. Next, an electroconductive NPs film was formed on the surface of a gold electrode by casting the DATh/γ-PGANa NPs and subsequently electropolymerizing the DATh. Last, horseradish peroxidase and Nafion were cast onto the NPs film to obtain an enzymatic biosensor for H2O2 detection. The electroconductive DATh/γ-PGANa NPs film endowed the biosensor with high sensitivity. Under the optimal conditions, the prepared biosensor showed a linear range from 1 × 10−11 to 1 × 10−4 mol·L−1 with a detection limit of 3 × 10−12 mol·L−1 for H2O2 detection. The biosensor can retain its detection performance for 4 weeks. The response currents of the biosensor changed little after adding the interferent into the analyte. The standard deviation of the response between different biosensors did not exceed 2.5%.

Natural killer (NK) cells are the first lymphocyte population to recover after allogenic hematopoietic stem cell transplantation (allo-HSCT) and mediate potent graft versus leukemia effect, particularly in the settings of T-cell depletion. However, the significance of NK cells after unmanipulated transplantation is less clear, and factors affecting early NK reconstitution remain elusive. We retrospectively analyze 180 patients with acute myeloid leukemia or myelodysplastic syndrome who received unmanipulated allografts. We focus on the early NK reconstitution and its association with disease relapse, overall survival, and cytomegalovirus (CMV) reactivation. We also analyze factors that affect NK recovery, such as dose of CD34

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

Three-dimensional porous carbon was fabricated using lotus leaves as a renewable precursor. The as-synthesized carbon had a high surface area (3601 m2/g), suitable O–N–S self-doping, and three-dimensional (3D) architecture with interconnected micro/meso/macropores, together with proper pore size distribution. Consequently, these admirable features endowed porous carbon as a superadsorbent for dye removal with ultrahigh adsorption capacity for rhodamine B (9444.39 mg/g) and reliable cyclability (>97% capacitance retention after 10 cycles). The adsorption of dye onto the as-prepared carbon was a spontaneous endothermic process and followed the pseudo-second-order kinetic model and the Langmuir isotherm model. The π–π stacking, hydrogen bond, and acid–base interactions were proposed to mainly account for the combination of the adsorbate and the adsorbent. Overall, these values indicated the high-performance biomass-derived carbon as a dye adsorbent and may boost the large-scale production and application of 3D hierarchical porous carbon with heteroatom doping in the field of wastewater treatment.

Introducing lysozyme (Lys) to dopamine-modified poly (γ-glutamic acid) (PGA-DA), the self-assembled colloidal nanoparticles (Lys/PGA-DA) were obtained through the electrostatic, hydrogen bonding and hydrophobic interactions. After mixing vigorously colloidal nanoparticles and white oil, o/w gel-like emulsion formed. The influences of ionic strength on the properties and emulsifying performances of colloidal nanoparticles and the activity of Lys in emulsions were investigated in detail. Scanning electron microscopy (SEM) characterization and rheological measurements demonstrated that emulsifying properties of colloidal nanoparticles were significantly improved with increasing salt concentration. Moreover, fluorescence and circular dichroism (CD) measurements showed that the addition of salt might induce conformational changes of Lys in colloidal nanoparticles resulting in a more ordered secondary structure, thereby leading to an increase in enzyme activity. In vitro cytotoxicity of emulsions revealed that emulsions showed a low cytotoxicity and a high bioactivity. All results verified that the obtained emulsion could have potential application in food, pharmaceutical, and cosmetic fields.

A continuous supply of oxygen is essential for the survival of multi-cellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells, RBCs) as passive carriers of oxygen to recognizing the complex interplay between hemoglobin and oxygen, carbon dioxide, and nitric oxide – the three-gas respiratory cycle – that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in hemoglobin in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of hemoglobin (aka S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native SNO-replete RBCs and by SNO-Hb itself, whereby SNO is released from hemoglobin and RBCs during deoxygenation, in proportion to the degree of hemoglobin deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in hemoglobin or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery—steps towards effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure.Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of KLF2 mRNA. Using a mouse model of Angiotensin II-induced non-ischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic Angiotensin II infusion activated a neutrophil KLF2-NETosis pathway that triggered sporadic thrombosis in small myocardial vessels leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, NETs or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to Angiotensin II at the molecular level, partly through the crosstalk with HIF1 signaling.Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

Parallel and distributed processing has always been a hot field of scientific and technological research, development, and application. It is an important solution in the fields of scientific computing and data service processing, such as weather prediction, wind tunnel Reynolds numerical calculation, and financial services. Intelligent cloud computing has higher requirements for high-capacity and efficient computing. The ability of existing computing system has been difficult to meet its needs. It is necessary to establish an intelligent computing system with the self-organizing ability and realize efficient task scheduling. Since the coordination of computing and storage resource scheduling becomes the key to scheduling, this study designs scheduling tasks based on a large-scale multi-task distributed system, establishes the model of distributed intelligent computing system and the multi-objective optimization model of the task scheduling problem, and designs the IPSO algorithm combined with improved particle swarm optimization algorithm according to the model. First, the particle swarm optimization algorithm is used to generate the initial scheduling scheme, then the ant colony algorithm is initialized, and the final scheduling results are generated. Simulation results show that the performance of the algorithm has obvious performance advantages compared with the improved particle swarm optimization algorithm and the improved ant colony algorithm. In addition, this study presents the task migration conditions and optimization methods under the dual objectives of makespan and availability. This optimization operation increases the system availability without increasing the scheduling length. In the distributed system with heterogeneous availability, the algorithm is effective in the dual objective performance optimization of task completion time and system availability.

We retrospectively compared the outcomes of 387 consecutive patients with acquired aplastic anemia (AA) who underwent hematopoietic stem cell transplantation (HSCT) with a fludarabine-based conditioning regimen from matched sibling donors (MSD) (n = 108) or haploidentical donors (HID) (n = 91) and immunosuppressive therapy (IST) (n = 188) from 2014 to 2020 at our hospital. Compared with HID-HSCT, MSD-HSCT had a lower incidence of graft failure (1% vs. 7%, p = 0.062), grade II–IV acute graft versus host disease (aGvHD) (16% vs. 35%, p = 0.001), and mild to severe chronic GvHD (cGvHD) (8% vs. 23%, p = 0.007), but an equivalent incidence of grade III–IV aGvHD (8% vs. 12%, p = 0.237) and moderate to severe cGvHD (3% vs. 9%, p = 0.076). HSCT had superior blood count recovery at 3, 6, and 12 months compared with IST (p < 0.001). The estimated 5-year overall survival (OS) of the MSD, HID, and IST groups were 86%, 72%, and 79% (p = 0.02), respectively; accordingly, the failure-free survival (FFS) rates were 85%, 68%, and 56%, respectively (p < 0.001). For patients aged ≤40 years, the OS rate was still significantly superior for MSD-HSCT receipients compared to HID-HSCT receipients (89% vs. 76%, p = 0.024) while the HID-HSCT recipients showed similar OS (76% vs. 78%, p = 0.166) but superior FFS (p = 0.047) when follow-up was longer than 14.5 months in contrast to IST. In a multivariate analysis, HID-HSCT and a conditioning regimen that included busulfan were adversely related to OS among patients who received allografts. In conclusion, MSD-HSCT was the frontline choice for patients with severe AA aged ≤40 years, while HID-HSCT was as effective as IST for patients without an MSD.

A simple, practical, and high chemo-selective method for the synthesis of propargyl alcohol and allenyl alcohols via Cu-catalyzed, Mn-mediated propargylation and allenylation of aldehydes with propargyl bromides has been established. When 3-bromo-1-propyne was conducted under the standard condition, the aldehydes were transformed to the corresponding propargylation products completely, while when 1-bromo-2-pentyne was used, allenic alcohol was the only product. Variety of homopropargyl alcohols and allenyl alcohols were obtained in high yields and the reaction is compatible with broad substrate scopes. In addition, the large-scale reaction could also be proceeded smoothly indicating the potential synthetic applications of this transformation. Graphical Abstract

A molecularly imprinted biosensor for lysozyme based on the polymer nanoparticles self-assembled from water-soluble and electroactive poly (γ-glutamic acid) modified with 3-aminothiophene copolymer were prepared. The water-soluble copolymer made imprinting of lysozyme in aqueous solution possible and thus facilitated improvement of the activity of LYS. Subsequent electro-polymerization not only locked the recognition site between copolymer and lysozyme but also created a conductive polymer network, which can enhance the electron transfer rate and increase the conductivity of the film. The prepared molecularly imprinted biosensor exhibited a wide linear range from 1 × 10−10 to 1 × 10−5 mg mL−1, and satisfactory selectivity, stability, repeatability for lysozyme detection.

The heterostructure of Cu7.2S4 nanosheets/trisoctahedron Cu2O were successfully constructed on the {3 3 2} high-index facets of Cu2O. The results show that oxygen defects amount of the Cu7.2S4/Cu2O samples are closely related to the thickness of Cu7.2S4 nanosheets. Compared with the unmodified cuprous oxide and the Cu7.2S4/Cu2O modified with thick Cu7.2S4 nanosheets, the Cu7.2S4/Cu2O grafted with 10 nm thickness of Cu7.2S4 show higher oxygen defects content and photocatalytic performance for MO decoloration. UV–VIS DRS and PL detection show that the Cu7.2S4 nanosheets grafting on Cu2O with high-index facets accelerates the charge carrier separation, which results in an elevated degradation properties for MO.

A kind of bioadhesive hydrocaffeic acid modified chitosan colloidal particles (HCA-CS/TPP CPs) containing synthetic catecholamine groups was prepared via amidation reaction and ionic gelation. The ...

The heterogeneous decarboxylative cyclization reaction between 2-benzoylpyridines and α-amino acids was achieved in toluene at 120 °C in the presence of 15 mol% of l -proline-functionalized MCM-41-supported copper(II) complex [ l -Proline-MCM-41-Cu(OTf)2] and iodine with di-tert-butyl peroxide (DTBP) as oxidant, yielding a variety of 1,3-disubstituted imidazo[1,5-a]pyridines in good to excellent yields. The new supported copper catalyst can be prepared from commercially available and inexpensive reagents, and recovered from the reaction mixture by a simple filtration and recycled up to eight times with almost consistent activity.

An efficient heterogeneous gold-catalyzed oxidative cross-coupling of propargylic acetates with arylboronic acids has been developed that proceeds smoothly in the presence of Selectfluor and provides a general and powerful tool for the preparation of various valuable α-arylenones with moderate to good yields, excellent E-selectivity, and recyclability of the gold catalyst. The reaction is the first example of heterogeneous gold-catalyzed arylative rearrangement of propargylic acetates for construction of complex enones.

Lotus leaf stem is successfully exploited as a sustainable biomass to fabricate multi-heteroatom co-doped carbon with multiscale pore architecture by a readily scalable and effective strategy of pr...

Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5(−/−)) and conditional smooth muscle (smooth muscle/adh5(−/−)) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5(−/−) mice were protected from all three aspects of BPD, whereas smooth muscle/adh5(−/−) mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.

The β

Skeletal muscle is a major determinant of systemic metabolic homeostasis that plays a critical role in glucose metabolism and insulin sensitivity. By contrast, despite being a major user of fatty acids, and evidence that muscular disorders can lead to abnormal lipid deposition (e.g., nonalcoholic fatty liver disease in myopathies), our understanding of skeletal muscle regulation of systemic lipid homeostasis is not well understood. Here we show that skeletal muscle Krüppel-like factor 15 (KLF15) coordinates pathways central to systemic lipid homeostasis under basal conditions and in response to nutrient overload. Mice with skeletal muscle-specific KLF15 deletion demonstrated (a) reduced expression of key targets involved in lipid uptake, mitochondrial transport, and utilization, (b) elevated circulating lipids, (c) insulin resistance/glucose intolerance, and (d) increased lipid deposition in white adipose tissue and liver. Strikingly, a diet rich in short-chain fatty acids bypassed these defects in lipid flux and ameliorated aspects of metabolic dysregulation. Together, these findings establish skeletal muscle control of lipid flux as critical to systemic lipid homeostasis and metabolic health.