Comparison of outcomes between stent retriever combined with contact aspiration versus contact aspiration alone in patients without hyperdense artery sign/susceptibility vessel sign.

PURPOSE: To examine the relationship between hyperdense artery sign/susceptibility vessel sign (HAS/SVS) and thrombus composition, and evaluate the effect of HAS/SVS status on the association between first-line thrombectomy techniques and outcomes in patients with acute anterior-circulation large vessel occlusion (LVO). MATERIALS AND METHODS: From January 2018 to June 2021, 103 consecutive acute anterior-circulation LVO patients (75 [63.1%] male; median age, 66 years) who underwent thrombectomy, and for whom the removed clot was available for histological analyses were retrospectively reviewed. The presence of HAS and SVS was respectively assessed in noncontrast computed tomography (NCCT) and susceptibility-weighted imaging (SWI). Association of first-line thrombectomy techniques [stent retriever combined with contact aspiration (SR+CA) versus contact aspiration (CA)] with outcomes was assessed by the HAS/SVS status. RESULTS: Among the included patients, 55 (53.4%) were HAS/SVS(-), and 69 (67.0%) chose first-line SR+CA. Higher relative densities of fibrin/platelets (0.56 vs. 0.51, p<0.001) and lower relative densities of erythrocytes (0.32 vs. 0.42, p<0.001) were observed in HAS/SVS(-) than HAS/SVS(+) patients. First-line SR+CA was associated with reduced odds of distal embolization (aOR, 0.18; 95% CI, 0.04-0.83; p=0.027) and a more favorable 90-day functional outcome (aOR, 5.29; 95% CI, 1.06-26.34; p=0.042) in HAS/SVS(-) patients, and a longer recanalization time (53 min vs. 25 min, p=0.025) and higher risk of subarachnoid hemorrhage (24.2% vs. 0%, p=0.044) in HAS/SVS(+) patients. CONCLUSIONS: HAS/SVS(-) may indicate a higher density of fibrin/platelets in the thrombus, and first-line SR+CA may have a possible better performance than CA in acute LVO patients without HAS/SVS.

First Report of Powdery Mildew on Quercus fabri and Q. robur Caused by Erysiphe quercicola in China.

Quercus (Fagaceae) is a genus of ecologically and economically important shrub and tree species (Yin et al. 2018). In April 2022, powdery mildew symptoms were observed on Quercus fabri and Quercus robur leaves on Longwen hill, Guizhou Normal University, Guiyang, China. The incidence was 30% (Q. fabri, n = 50) and 20% (Q. robur, n = 30), respectively. Powdery mildew fungi from these two Quercus species shared similar morphological characteristics. Mycelia occurred on adaxial and abaxial leaf surfaces, forming small to large patches; hyphae were hyaline, 3-7 µm wide; hyphal appressoria were lobed to multilobed, solitary; conidiophores were erect, straight, 36-80 µm long (n = 30); foot cells were followed by 1-2 shorter cells; conidia formed singly, obovoid to ellipsoid, 24-38 × 12-27 µm (n = 50), without fibrosin bodies; no chasmothecia were observed. Based on these characteristics, powdery mildew fungi on both Q. fabri and Q. robur were identified as Erysiphe quercicola (Takamatsu et al. 2007). To confirm the identification, ribosomal DNA internal transcribed spacer (ITS) sequences of two fungal samples from Q. fabri and Q. robur were separately amplified and sequenced using primer pair ITS1/ITS4 (White et al. 1990). The obtained ITS sequences (GenBank accession nos. QR414372 and QR414373, respectively) shared 100% identity, and 99.38-99.84% identity with diverse ITS sequences of E. quercicola (Takamatsu et al. 2015). In a phylogenetic tree based on ITS sequences of Erysiphe species (Takamatsu et al. 2007), QR414372 and QR414373 were grouped in a clade with ITS sequences of E. quercicola. To fulfil Koch's postulates, leaves of three healthy potted Q. fabri plants and three healthy potted Q. robur plants were inoculated by gently pressing diseased Q. fabri and Q. robur leaves onto healthy leaves. Non-inoculated healthy Q. fabri and Q. robur plants served as controls. All plants were incubated in a greenhouse at 25 ± 2°C with 80% relative humidity. Typical powdery mildew symptoms were observed on all inoculated plants 15 days after inoculation, whereas no symptoms were observed on control plants. Fungi separately reisolated from inoculated Q. fabri and Q. robur were morphologically identical to those on their originally diseased plants, and ITS sequences of reisolated fungi shared 100% identity with QR414372 and QR414373. E. quercicola has previously been reported to infect Quercus species, including Q. robur in Australia, Q. crispula, Q. phillyraeoides and Q. serrata in Japan, and Q. phillyraeoides in Korea (Lee et al. 2011). In China, Q. fabri and Q. robur may be infected by E. alphitoides and E. hypophylla, respectively (Zheng et al. 1987). To our knowledge, this is the first report of powdery mildew caused by E. quercicola on Q. fabri and Q. robur in China. This work provides a foundation to protect Quercus plants against this fungal pathogen.

Dynamic Changes and Clinical Significance of Plasma Galectin-3 in Patients with Acute Ischemic Stroke Undergoing Endovascular Therapy.

Purpose: Galectin-3 is a key regulator of microglial proliferation and activation and may have dual and time-dependent effects on ischemic stroke. This study aimed to prospectively investigate the dynamic changes in Galectin-3 levels in patients with acute ischemic stroke receiving endovascular therapy and its clinical significance. Patients and Methods: A total of 105 patients with acute ischemic stroke who underwent endovascular therapy were prospectively enrolled. Plasma Galectin-3 was quantitatively detected by an enzyme-linked immunosorbent assay before the operation and at 1 day, 3 days and 7 days after the operation. A linear mixed-effect model, Pearson correlation analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate the dynamic changes in the plasma Galectin-3 concentration and its relationship with clinical outcomes. Results: Increases in plasma Galectin-3 levels at 1 day and 3 days after surgery were associated with early neurological deterioration and death (both P <0.05). Increased Galectin-3 levels before surgery and at 1 day and 3 days after surgery were associated with poor prognosis (P <0.05). Pearson correlation analysis revealed that Galectin-3 levels before surgery (r =0.318, P =0.002), at 1 day (r =0.318, P =0.001), 3 days (r =0.429, P < 0.001) and 7 days after surgery (r =0.340, P =0.001) were positively correlated with NIHSS scores. The ROC curve results showed that Galectin-3 concentration had a certain predictive value for death at 1 day (AUC=0.707, P=0.013), 3 days (AUC=0.708, P=0.016) and 7 days after the operation (AUC=0.708, P=0.016), but this predictive value was lower than that of the NIHSS score. Conclusion: In acute ischemic stroke patients receiving endovascular therapy, an increase in the plasma Galectin-3 levels were associated with death, poor prognosis, and early neurological deterioration. Galectin-3 levels were significantly correlated with the NIHSS score and had a certain predictive value for death.

First Report of Rust Disease on Alcea rosea caused by Puccinia modiolae in China.

Alcea rosea, belonging to the Alcea genus in the Malvaceae family, originated from China, but it is now grown worldwide. A. rosea has been widely used in traditional Chinese medicine to alleviate constipation, pain, swelling, and sores. In February 2023, typical symptoms of fungal infection were observed on A. rosea at Guizhou Normal University in Guiyang, Guizhou Province, China. The disease incidence was over 90% (n = 100) for the surveyed A. rosea plants, and the disease severity range from 30% to 90%. The initial symptoms of A. rosea rust were the appearance of chlorotic spots on the leaves. Subsequently, numerous reddish to dark-brown erumpent pustules (telia) were observed. Gradually, the entire plant was covered by rust and the center of each lesion turned brown, necrotic, and ruptured over times, eventually causing defoliation. Voucher specimens of infected A. rosea leaves as representative samples have been deposited at Guizhou Normal University (GNU2023LS008). Telia are round in shape, mostly aggregated in mass, with a diameter of 0.28-0.78 mm (0.46 mm, n = 20). They range in color from reddish-brown to dark brown, and are mainly hypophyllous but occasionally formed on the adaxial leaf surface. The teliospores are fusoid with dimensions of 31.3-93.8 × 10.9-21.3 µm (57.5 × 15.1 µm average, n = 50), hyaline or yellowish to light-brown in color, mostly two-celled, with a smooth wall (1.5-3.0 µm) and a thickened apex (3.0-9.0 µm). However, teliospores which are one-, three-, or four-celled with a notch at the apex, are rarely observed. The morphological characteristics of host symptoms and teliospores were similar to those of Puccinia modiolae (Aime and Abbasi 2018; Albu et al. 2019). For phylogenetic analysis, genomic DNA was extracted from the teliospores of infected leaves. To confirm the species-level identification, PCR was performed on the extracted DNA to amplify the ribosomal DNA internal transcribed spacer (ITS) and large subunit (LSU) regions using primer pairs ITS1/ITS4 (Schoch et al. 2012) and NL1/NL4 (Ziemiecki et al. 1990), respectively. The resulting ITS DNA sequence (GenBank accession no. OR607960) showed 100% identity with P. modiolae sequences (OP369291.1), when the query coverage was 100%. The LSU DNA sequence obtained (OR607961.2) shared 99.85% similarity with P. modiolae (MK458702.1). A phylogenetic tree was constructed using MEGA7.0 and the maximum likelihood method based on the ITS and LSU sequences. The fungal isolates collected in this study and several reference sequences of P. modiolae were grouped within a clade that included the isolates reported on A. rosea in Korea (Ryu et al. 2023), with 100% bootstrap support. Pathogenicity testing was conducted by gently pressing spore powder of naturally diseased leaves onto young leaves of three healthy A. rosea plants, with three noninoculated healthy plants serving as controls. The inoculated and noninoculated plants were kept in a growth chamber at the 26°C with a 12 hour light/dark cycle and 80% humidity. After 2 weeks, all inoculated A. rosea plants showed characteristic disease symptoms of rust infection and telia of P. modiolae, while control plants remained symptomless. The pathogen was identical to that observed on the original diseased leaves. The study results indicate that the causal fungus responsible for the disease is P. modiolae, which has been previously reported on Malvaceae plants (Farr and Rossman 2022). To the best of our knowledge, this is the first report of P. modiolae on A. rosea in China. This study will contribute to an increased understanding of the host range of Puccinia modiolae.

The value of metagenomic next-generation sequencing for the diagnosis of pulmonary tuberculosis using bronchoalveolar lavage fluid.

OBJECTIVE: The aim of this study was to compare metagenomic next-generation sequencing (mNGS) with other methods, including Xpert MTB/RIF, Mycobacterium tuberculosis (MTB) culture, and acid-fast bacillus (AFB) staining in the diagnosis of pulmonary tuberculosis (PTB) using bronchoalveolar lavage fluid (BALF). METHODS: The data of 186 patients with suspected PTB were retrospectively collected from January 2020 to May 2021 at Tongji Hospital. BALF samples were collected from all patients and analyzed using AFB staining, MTB culture, Xpert MTB/RIF, and mNGS. RESULTS: Of the 186 patients, 38 patients were ultimately diagnosed as PTB. Metagenomic next-generation sequencing exhibited a sensitivity of 78.95%, which was higher than AFB staining (27.59%) and MTB culture (44.12%) but similar to Xpert MTB/RIF (72.73%). Utilization of combined methods demonstrates improvement for PTB diagnosis. In support of this, the area under the receiver operating characteristic curve for the combination of mNGS and MTB culture (0.933, 95% CI: 0.871, 0.995) was larger than those of mNGS, Xpert MTB/RIF, MTB culture, and the combination of Xpert MTB/RIF and MTB culture. CONCLUSION: The sensitivity of mNGS in the diagnosis of PTB using BALF specimen is similar to Xpert MTB/RIF. Metagenomic next-generation sequencing in combination with MTB culture may further improve the diagnosis of pulmonary tuberculosis.

Evolution of SARS-CoV-2 Spikes shapes their binding affinities to animal ACE2 orthologs.

IMPORTANCE: Spike-receptor interaction is a critical determinant for the host range of coronaviruses. In this study, we investigated the SARS-CoV-2 WHU01 strain and five WHO-designated SARS-CoV-2 variants of concern (VOCs), including Alpha, Beta, Gamma, Delta, and the early Omicron variant, for their Spike interactions with ACE2 proteins of 18 animal species. First, the receptor-binding domains (RBDs) of Alpha, Beta, Gamma, and Omicron were found to display progressive gain of affinity to mouse ACE2. More interestingly, these RBDs were also found with progressive loss of affinities to multiple ACE2 orthologs. The Omicron RBD showed decreased or complete loss of affinity to eight tested animal ACE2 orthologs, including that of some livestock animals (horse, donkey, and pig), pet animals (dog and cat), and wild animals (pangolin, American pika, and Rhinolophus sinicus bat). These findings shed light on potential host range shift of SARS-CoV-2 VOCs, especially that of the Omicron variant.

Comparison of clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment using different perfusion modalities: a real-world multicenter study.

Background: Advanced perfusion modalities are increasingly popular for various diseases. However, few studies have focused on contrasting perfusion patterns. Objective: This study aimed to compare the time efficiency and clinical outcomes of patients with acute ischemic stroke (AIS) who underwent endovascular treatment (EVT) before one-stop arterial spin labeling (ASL) and computed tomography perfusion (CTP) protocols. Methods: This study retrospectively included 326 patients with AIS who had accepted EVT within 24 h of onset from four comprehensive stroke centers between October 2017 and September 2022. After 1:1 matching of the propensity scores, 202 patients were separated into two groups: the ASL group (n = 101) and the CTP group (n = 101). Results: Functional independence at 90 days (modified Rankin Scale [mRS] 0-2; p = 0.574), onset-to-puncture time (p = 0.231), door-to-puncture time (p = 0.136), and door-to-perfusion time (p = 0.646) were not significantly different between the two groups. The proportion of EVT complications (31.7% in the ASL group vs. 14.9% in the CTP group, p = 0.005) and symptomatic intracranial hemorrhage (sICH) at 24 h (23.8% in the ASL group vs. 9.9% in the CTP group, p = 0.008) in the CTP group were lower than the ASL group. The ischemic core volume was a common predictor of favorable outcomes in both ASL (p < 0.001) and CTP (p < 0.001) groups. Conclusion: There were no significant differences in time efficiency and efficacy outcomes between the two groups of patients receiving one-stop ASL and CTP. The proportion of sICH at 24 h and EVT complications of patients in the CTP group was lower than the ASL group. The ischemic core volume was an independent predictor for favorable outcomes.

Theoretical Insights into the Generation Mechanism of the Tyr122 Radical Catalyzed by Intermediate X in Class Ia Ribonucleotide Reductase.

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides in all organisms. There is an ∼35 Å long-range electron-hole transfer pathway during the catalytic process of class Ia RNR, which can be described as Tyr122ß â†” [Trp48ß]? ↔ Tyr356ß â†” Tyr731α ↔ Tyr730α ↔ Cys439α. The formation of the Y122• radical initiates this long-range radical transfer process. However, the generation mechanism of Y122• is not yet clear due to confusion over the intermediate X structures. Based on the two reported X structures, we examined the possible mechanisms of Y122• generation by density functional theory (DFT) calculations. Our examinations revealed that the generation of the Y122• radical from the two different core structures of X was via a similar two-step reaction, with the first step of proton transfer for the formation of the proton receptor of Y122 and the second step of a proton-coupled long-range electron transfer reaction with the proton transfer from the Y122 hydroxyl group to the terminal hydroxide ligand of Fe1III and simultaneously electron transfer from the side chain of Y122 to Fe2IV. These findings provide an insight into the formation mechanism of Y122• catalyzed by the double-iron center of the ß subunit of class Ia RNR.

Exogenous IL-25 ameliorates airway neutrophilia via suppressing macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma.

BACKGROUND: Severe asthma is associated with substantial mortality and has unmet therapeutic need. A subset of severe asthma is characterized by neutrophilic airway inflammation. Classically activated (or M1) macrophages which express IL-12 and IL-23 are associated with airway neutrophilia in asthma. Exogenous IL-25 was reported to suppress intestinal inflammation in animal models of inflammatory bowel diseases via suppressing IL-12 and IL-23 production. We hypothesize that IL-25 ameliorates airway neutrophilia via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23 in asthma. METHODS: In a mouse model of neutrophil-dominant allergic airway inflammation, the effect of mouse recombinant IL-25 on airway inflammation were assessed by H&E staining and bronchoalveolar lavage (BAL) cell counting. The percentage of M1 macrophages in lung tissue and BAL cells were analyzed by flow cytometry. Quantitative PCR and immunostaining were performed to measure the expression of Il12, Il23, and inflammatory cytokines. Mechanistic experiments were performed in primary culture of macrophages from mouse lungs. The expression of IL-12, IL-23 and IL-25 in sputum was analyzed in a cohort of severe asthma and subjects with eosinophilic or non-eosinophilic asthma. RESULTS: Intranasal administration of IL-25 markedly decreased the number of neutrophils in BAL cells in a murine model of neutrophil-dominant allergic airway inflammation. Moreover, exogenous IL-25 decreased the number of M1 macrophages, and reduced the expression of IL-12, IL-23 in the lungs of the mouse model. Exogenous IL-25 also inhibited the expression of inflammatory cytokines IL-1ß, IFN-γ, TNF-α and IL-17 A. In vitro, IL-25 suppressed IL-12 and IL-23 expression in lipopolysaccharide (LPS)-stimulated primary culture of mouse pulmonary macrophages. Mechanistically, IL-25 inhibited LPS-induced c-Rel translocation to nucleus via STAT3-dependent signaling. In a cohort of severe asthma, IL-25 protein levels in sputum were significantly lower than control subjects. The transcript levels of IL-12 and IL-23 were increased whereas IL-25 transcripts were decreased in sputum cells from subjects with non-eosinophilic asthma compared to eosinophilic asthma. CONCLUSIONS: IL-25 expression is downregulated in subjects with severe or non-eosinophilic asthma. Exogenous IL-25 ameliorates airway neutrophilia, at least in part, via inhibiting macrophage M1 polarization and the expression of IL-12 and IL-23.

The αC-ß4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A.

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic (C) subunit of protein kinase A (PKA). Not only this long-range synergistic action is involved in substrate recognition and fidelity, but it is likely to regulate PKA association with regulatory subunits and other binding partners. To date, a complete understanding of the molecular determinants for this intramolecular mechanism is still lacking. Here, we used an integrated NMR-restrained molecular dynamics simulations and a Markov Model to characterize the free energy landscape and conformational transitions of the catalytic subunit of protein kinase A (PKA-C). We found that the apo-enzyme populates a broad free energy basin featuring a conformational ensemble of the active state of PKA-C (ground state) and other basins with lower populations (excited states). The first excited state corresponds to a previously characterized inactive state of PKA-C with the αC helix swinging outward. The second excited state displays a disrupted hydrophobic packing around the regulatory (R) spine, with a flipped configuration of the F100 and F102 residues at the tip of the αC-ß4 loop. To experimentally validate the second excited state, we mutated F100 into alanine and used NMR spectroscopy to characterize the binding thermodynamics and structural response of ATP and a prototypical peptide substrate. While the activity of PKA-CF100A toward a prototypical peptide substrate is unaltered and the enzyme retains its affinity for ATP and substrate, this mutation rearranges the αC-ß4 loop conformation interrupting the allosteric coupling between nucleotide and substrate. The highly conserved αC-ß4 loop emerges as a pivotal element able to modulate the synergistic binding between nucleotide and substrate and may affect PKA signalosome. These results may explain how insertion mutations within this motif affect drug sensitivity in other homologous kinases.

Leveling the Mountain Range of Excited-State Benchmarking through Multistate Density Functional Theory.

The performance of multistate density functional theory (MSDFT) with nonorthogonal state interaction (NOSI) is assessed for 100 vertical excitation energies against the theoretical best estimates extracted to the full configuration interaction accuracy on the database developed by Loos et al. in 2018 (Loos2018). Two optimization techniques, namely, block-localized excitation and target state optimization, are examined along with two ways of estimating the transition density functional (TDF) for the correlation energy of the Hamiltonian matrix density functional. The results from the two optimization methods are similar. It was found that MSDFT-NOSI using the spin-multiplet degeneracy constraint for the TDF of spin-coupling interaction, along with the M06-2X functional, yields a root-mean-square error (RMSE) of 0.22 eV, which performs noticeably better than time-dependent density functional theory (DFT) at an RMSE of 0.43 eV using the same functional and basis set on the Loos2018 database. In comparison with wave function theory, NOSI has smaller errors than CIS(D∞), LR-CC2, and ADC(3) all of which have an RMSE of 0.28 eV, but somewhat greater than STEOM-CCSD (RMSE of 0.14 eV) and LR-CCSD (RMSE of 0.11 eV) wave function methods. In comparison with Kohn-Sham (KS) DFT calculations, the multistate DFT approach has little double counting of correlation. Importantly, there is no noticeable difference in the performance of MSDFT-NOSI on the valence, Rydberg, singlet, triplet, and double-excitation states. Although the use of another hybrid functional PBE0 leads to a greater RMSE of 0.36 eV, the deviation is systematic with a linear regression slope of 0.994 against the results with M06-2X. The present benchmark reveals that density functional approximations developed for KS-DFT for the ground state with a noninteracting reference may be adopted in MSDFT calculations in which the state interaction is key.

Cryo-EM structures of LHCII in photo-active and photo-protecting states reveal allosteric regulation of light harvesting and excess energy dissipation.

The major light-harvesting complex of photosystem II (LHCII) has a dual regulatory function in a process called non-photochemical quenching to avoid the formation of reactive oxygen. LHCII undergoes reversible conformation transitions to switch between a light-harvesting state for excited-state energy transfer and an energy-quenching state for dissipating excess energy under full sunshine. Here we report cryo-electron microscopy structures of LHCII in membrane nanodiscs, which mimic in vivo LHCII, and in detergent solution at pH 7.8 and 5.4, respectively. We found that, under low pH conditions, the salt bridges at the lumenal side of LHCII are broken, accompanied by the formation of two local α-helices on the lumen side. The formation of α-helices in turn triggers allosterically global protein conformational change, resulting in a smaller crossing angle between transmembrane helices. The fluorescence decay rates corresponding to different conformational states follow the Dexter energy transfer mechanism with a characteristic transition distance of 5.6 Å between Lut1 and Chl612. The experimental observations are consistent with the computed electronic coupling strengths using multistate density function theory.

Multistate Energy Decomposition Analysis of Molecular Excited States.

A multistate energy decomposition analysis (MS-EDA) method is described to dissect the energy components in molecular complexes in excited states. In MS-EDA, the total binding energy of an excimer or an exciplex is partitioned into a ground-state term, called local interaction energy, and excited-state contributions that include exciton excitation energy, superexchange stabilization, and orbital and configuration-state delocalization. An important feature of MS-EDA is that key intermediate states associated with different energy terms can be variationally optimized, providing quantitative insights into widely used physical concepts such as exciton delocalization and superexchange charge-transfer effects in excited states. By introducing structure-weighted adiabatic excitation energy as the minimum photoexcitation energy needed to produce an excited-state complex, the binding energy of an exciplex and excimer can be defined. On the basis of the nature of intermolecular forces through MS-EDA analysis, it was found that molecular complexes in the excited states can be classified into three main categories, including (1) encounter excited-state complex, (2) charge-transfer exciplex, and (3) intimate excimer or exciplex. The illustrative examples in this Perspective highlight the interplay of local excitation polarization, exciton resonance, and superexchange effects in molecular excited states. It is hoped that MS-EDA can be a useful tool for understanding photochemical and photobiological processes.

Stress-enhanced cardiac lncRNA Morrbid protects hearts from acute myocardial infarction.

Myeloid RNA regulator of Bim-induced death (Morrbid) is a newly identified leukocyte-specific long noncoding RNA (lncRNA). However, the expression and biological functions of Morrbid in cardiomyocytes and heart disease are currently unclear. This study was meant to determine the role of cardiac Morrbid in acute myocardial infarction (AMI) and to identify the potential cellular and molecular mechanisms involved. We found that both human and mouse cardiomyocytes could express a significant amount of Morrbid and that its expression was increased in cardiomyocytes with hypoxia or oxidative stress as well as in mouse hearts with AMI. Overexpression of Morrbid reduced the myocardial infarct size and cardiac dysfunction, whereas the infarct size and cardiac dysfunction deteriorated in cardiomyocyte-specific Morrbid-KO (Morrbidfl/fl/Myh6-Cre) mice. We identified that Morrbid had a protective effect against hypoxia- or H2O2-induced apoptosis; this was also confirmed in vivo in mouse hearts after AMI. We further discovered that serpine1 was a direct target gene of Morrbid that was involved in the Morrbid-mediated protective effect on cardiomyocytes. In summary, we have found, for the first time to our knowledge, that the cardiac Morrbid is a stress-enhanced lncRNA that protects hearts from AMI via antiapoptosis through its target gene serpine1. Morrbid may be a novel promising therapeutic target for ischemic heart diseases such as AMI.

Limited value of serum neurofilament light chain in diagnosing amyotrophic lateral sclerosis.

A biomarker specific for the diagnosis of amyotrophic lateral sclerosis must be sensitive across a spectrum of clinical heterogeneity. Neurofilament light chain levels in amyotrophic lateral sclerosis correlate with the rate of disability progression. Previous attempts to establish a diagnostic role for neurofilament light chain have been limited to comparison with healthy individuals or controls with alternative diagnoses unlikely to be confused with amyotrophic lateral sclerosis in real-world clinical practice. In a tertiary amyotrophic lateral sclerosis referral clinic, at first visit, serum was taken for neurofilament light chain measurement after prospectively recording the clinical diagnosis as 'amyotrophic lateral sclerosis', 'primary lateral sclerosis', 'alternative' or 'currently uncertain'. Of 133 referrals, 93 patients were diagnosed with amyotrophic lateral sclerosis (median neurofilament light chain 218.1 pg/ml, interquartile range 130.7-311.9), three primary lateral sclerosis (65.6, 51.5-106.9) and 19 alternative diagnoses (45.2, 13.5-71.9) at first visit. Of 18 initially uncertain diagnoses, eight were subsequently diagnosed with amyotrophic lateral sclerosis (98.5, 45.3-300.1). Neurofilament light chain ≥110.9 pg/ml had a positive predictive value of 0.92 for amyotrophic lateral sclerosis; <110.9 pg/ml had a negative predictive value of 0.48. In a specialized clinic, neurofilament light chain is largely confirmatory to clinical judgement in diagnosing amyotrophic lateral sclerosis and has limited ability to exclude alternative diagnoses. The current, important, value of neurofilament light chain is its potential to stratify patients with amyotrophic lateral sclerosis by disease activity and as a biomarker in therapeutic trials.

Mitochondria dysfunction in airway epithelial cells is associated with type 2-low asthma.

Background: Type 2 (T2)-low asthma can be severe and corticosteroid-resistant. Airway epithelial cells play a pivotal role in the development of asthma, and mitochondria dysfunction is involved in the pathogenesis of asthma. However, the role of epithelial mitochondria dysfunction in T2-low asthma remains unknown. Methods: Differentially expressed genes (DEGs) were identified using gene expression omnibus (GEO) dataset GSE4302, which is originated from airway epithelial brushings from T2-high (n = 22) and T2-low asthma patients (n = 20). Gene set enrichment analysis (GSEA) was implemented to analyze the potential biological pathway involved between T2-low and T2-high asthma. T2-low asthma related genes were identified using weighted gene co-expression network analysis (WGCNA). The mitochondria-related genes (Mito-RGs) were referred to the Molecular Signatures Database (MSigDB). T2-low asthma related mitochondria (T2-low-Mito) DEGs were obtained by intersecting the DEGs, T2-low asthma related genes, and Mito-RGs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to further explore the potential function of the T2-low-Mito DEGs. In addition, the hub genes were further identified by protein-protein interaction (PPI), and the expressions of hub genes were verified in another GEO dataset GSE67472 and bronchial brushings from patients recruited at Tongji Hospital. Results: Six hundred and ninety-two DEGs, including 107 downregulated genes and 585 upregulated genes were identified in airway epithelial brushings from T2-high and T2-low asthma patients included in GSE4302 dataset. GSEA showed that mitochondrial ATP synthesis coupled electron transport is involved in T2-low asthma. Nine hundred and four T2-low asthma related genes were identified using WGCNA. Twenty-two T2-low-Mito DEGs were obtained by intersecting the DEGs, T2-low asthma and Mito-RGs. The GO enrichment analysis of the T2-low-Mito DEGs showed significant enrichment of mitochondrial respiratory chain complex assembly, and respiratory electron transport chain. PPI network was constructed using 22 T2-low-Mito DEGs, and five hub genes, ATP5G1, UQCR10, NDUFA3, TIMM10, and NDUFAB1, were identified. Moreover, the expression of these hub genes was validated in another GEO dataset, and our cohort of asthma patients. Conclusion: This study suggests that mitochondria dysfunction contributes to T2-low asthma.

Ursolic Acid Alleviates Cancer Cachexia and Prevents Muscle Wasting via Activating SIRT1.

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to alleviate muscle atrophy and reduce muscle decomposition in some disease models. This study aimed to explore the role and mechanisms of UA treatment in cancer cachexia. We found that UA attenuated Lewis lung carcinoma (LLC)-conditioned medium-induced C2C12 myotube atrophy and muscle wasting of LLC tumor-bearing mice. Moreover, UA dose-dependently activated SIRT1 and downregulated MuRF1 and Atrogin-1. Molecular docking results revealed a good binding effect on UA and SIRT1 protein. UA rescued vital features wasting without impacting tumor growth, suppressed the elevated spleen weight, and downregulated serum concentrations of inflammatory cytokines in vivo. The above phenomena can be attenuated by Ex-527, an inhibitor of SIRT1. Furthermore, UA remained protective against cancer cachexia in the advanced stage of tumor growth. The results revealed that UA exerts an anti-cachexia effect via activating SIRT1, thereby downregulating the phosphorylation levels of NF-κB and STAT3. UA might be a potential drug against cancer cachexia.

Fe(III) Docking-Activated Sites in Layered Birnessite for Efficient Water Oxidation.

Non-noble metal catalysts for promoting the sluggish kinetics of oxygen evolution reaction (OER) are essential to efficient water splitting for sustainable hydrogen production. Birnessite has a local atomic structure similar to that of an oxygen-evolving complex in photosystem II, while the catalytic activity of birnessite is far from satisfactory. Herein, we report a novel Fe-Birnessite (Fe-Bir) catalyst obtained by controlled Fe(III) intercalation- and docking-induced layer reconstruction. The reconstruction dramatically lowers the OER overpotential to 240 mV at 10 mA/cm2 and the Tafel slope to 33 mV/dec, making Fe-Bir the best of all the reported Bir-based catalysts, even on par with the best transition-metal-based OER catalysts. Experimental characterizations and molecular dynamics simulations elucidate that the catalyst features active Fe(III)-O-Mn(III) centers interfaced with ordered water molecules between neighboring layers, which lower reorganization energy and accelerate electron transfer. DFT calculations and kinetic measurements show non-concerted PCET steps conforming to a new OER mechanism, wherein the neighboring Fe(III) and Mn(III) synergistically co-adsorb OH* and O* intermediates with a substantially reduced O-O coupling activation energy. This work highlights the importance of elaborately engineering the confined interlayer environment of birnessite and more generally, layered materials, for efficient energy conversion catalysis.

Stroke recurrence is associated with unfavorable intracranial venous outflow in patients with symptomatic intracranial atherosclerotic large vessel severe stenosis or occlusion.

Objective: The purpose of this study was to investigate the predictive value of intracranial venous outflow for recurrent cerebral ischemic events (RCIE) in patients with symptomatic intracranial atherosclerotic large-vessel severe stenosis or occlusion (sICAS-S/O). Methods: This retrospective study included sICAS-S/O patients with anterior circulation who underwent dynamic computed tomography angiography (dCTA) and computed tomography perfusion (CTP). Arterial collaterals were evaluated using the pial arterial filling score for dCTA data, tissue-level collaterals (TLC) were assessed using the high-perfusion intensity ratio (HIR, Tmax >10 s/Tmax >6 s), and cortical veins were evaluated using the multi-phase venous score (MVS) for the vein of Labbé (VOL), sphenoparietal sinus (SPS), and superficial cerebral middle vein (SCMV). The relationships between multi-phase venous outflow (mVO), TLC, and 1-year RCIE were analyzed. Results: Ninety-nine patients were included, 37 of whom had unfavorable mVO (mVO-) and 62 of whom had favorable mVO (mVO+). Compared with the mVO+ patients, mVO- patients had a higher admission National Institutes of Health Stroke Scale (NIHSS) score (median, 4 [interquartile range (IQR), 0-9] vs. 1 [IQR, 0-4]; p = 0.048), larger ischemic volume (median, 74.3 [IQR, 10.1-177.9] vs. 20.9 [IQR, 5-86.4] mL; p = 0.042), and worse tissue perfusion (median, 0.04 [IQR, 0-0.17] vs. 0 [IQR, 0-0.03]; p = 0.007). Multivariate regression analysis showed that mVO- was an independent predictor of 1-year RCIE. Conclusion: For patients with sICAS-S/O of the anterior circulation, unfavorable intracranial venous outflow is a potential imaging indicator for predicting higher 1-year RCIE risk.

Excimer Energies.

A multistate energy decomposition analysis (MS-EDA) method is introduced for excimers using density functional theory. Although EDA has been widely applied to intermolecular interactions in the ground state, few methods are currently available for excited-state complexes. Here, the total energy of an excimer state is separated into exciton excitation energy ΔEEx(|ΨX·ΨY⟩*), resulting from the state interaction between locally excited monomer states |ΨX*·ΨY⟩ and |ΨX·ΨY*⟩ , a superexchange stabilization energy ΔESE, originating from the mutual charge transfer between two monomers |ΨX+·ΨY⟩ and |ΨX-·ΨY+⟩ , and an orbital-and-configuration delocalization term ΔEOCD due to the expansion of configuration space and block-localized orbitals to the fully delocalized dimer system. Although there is no net charge transfer in symmetric excimer cases, the resonance of charge-transfer states is critical to stabilizing the excimer. The monomer localized excited and charge-transfer states are variationally optimized, forming a minimal active space for nonorthogonal state interaction (NOSI) calculations in multistate density functional theory to yield the intermediate states for energy analysis. The present MS-EDA method focuses on properties unique to excited states, providing insights into exciton coupling, superexchange and delocalization energies. MS-EDA is illustrated on the acetone and pentacene excimer systems; three configurations of the latter case are examined, including the optimized excimer, a stacked configuration of two pentacene molecules and the fishbone orientation. It is found that excited-state energy splitting is strongly dependent on the relative energies of the monomer excited states and the phase-matching of the monomer wave functions.