Structural basis for directional chitin biosynthesis.

Chitin, the most abundant aminopolysaccharide in nature, is an extracellular polymer consisting of N-acetylglucosamine (GlcNAc) units1. The key reactions of chitin biosynthesis are catalysed by chitin synthase2-4, a membrane-integrated glycosyltransferase that transfers GlcNAc from UDP-GlcNAc to a growing chitin chain. However, the precise mechanism of this process has yet to be elucidated. Here we report five cryo-electron microscopy structures of a chitin synthase from the devastating soybean root rot pathogenic oomycete Phytophthora sojae (PsChs1). They represent the apo, GlcNAc-bound, nascent chitin oligomer-bound, UDP-bound (post-synthesis) and chitin synthase inhibitor nikkomycin Z-bound states of the enzyme, providing detailed views into the multiple steps of chitin biosynthesis and its competitive inhibition. The structures reveal the chitin synthesis reaction chamber that has the substrate-binding site, the catalytic centre and the entrance to the polymer-translocating channel that allows the product polymer to be discharged. This arrangement reflects consecutive key events in chitin biosynthesis from UDP-GlcNAc binding and polymer elongation to the release of the product. We identified a swinging loop within the chitin-translocating channel, which acts as a 'gate lock' that prevents the substrate from leaving while directing the product polymer into the translocating channel for discharge to the extracellular side of the cell membrane. This work reveals the directional multistep mechanism of chitin biosynthesis and provides a structural basis for inhibition of chitin synthesis.

Coronary Artery Calcification on Low-Dose Lung Cancer Screening CT in South Korea: Visual and Artificial Intelligence-Based Assessment and Association With Cardiovascular Events.

BACKGROUND. Coronary artery calcification (CAC) on lung cancer screening low-dose chest CT (LDCT) is a cardiovascular risk marker. South Korea was the first Asian country to initiate a national LDCT lung cancer screening program, although CAC-related outcomes are poorly explored. OBJECTIVE. The purpose of this article is to evaluate CAC prevalence and severity using visual analysis and artificial intelligence (AI) methods and to characterize CAC's association with major adverse cardiovascular events (MACEs) in patients undergoing LDCT in Korea's national lung cancer screening program. METHODS. This retrospective study included 1002 patients (mean age, 62.4 ± 5.4 [SD] years; 994 men, eight women) who underwent LDCT at two Korean medical centers between April 2017 and May 2023 as part of Korea's national lung cancer screening program. Two radiologists independently assessed CAC presence and severity using visual analysis, consulting a third radiologist to resolve differences. Two AI software applications were also used to assess CAC presence and severity. MACE occurrences were identified by EMR review. RESULTS. Interreader agreement for CAC presence and severity, expressed as kappa, was 0.793 and 0.671, respectively. CAC prevalence was 53.4% by consensus visual assessment, 60.1% by AI software I, and 56.6% by AI software II. CAC severity was mild, moderate, and severe by consensus visual analysis in 28.0%, 10.3%, and 15.1%; by AI software I in 39.9%, 14.0%, and 6.2%; and by AI software II in 34.9%, 14.3%, and 7.3%. MACEs occurred in 36 of 625 (5.6%) patients with follow-up after LDCT (median, 1108 days). MACE incidence in patients with no, mild, moderate, and severe CAC for consensus visual analysis was 1.1%, 5.0%, 2.9%, and 8.6%, respectively (p < .001); for AI software I, it was 1.3%, 3.0%, 7.9%, and 11.3% (p < .001); and for AI software II, it was 1.2%, 3.4%, 7.7%, and 9.6% (p < .001). CONCLUSION. For Korea's national lung cancer screening program, MACE occurrence increased significantly with increasing CAC severity, whether assessed by visual analysis or AI software. The study is limited by the large sex imbalance for Korea's national lung cancer screening program. CLINICAL IMPACT. The findings provide reference data for health care practitioners engaged in developing and overseeing national lung cancer screening programs, highlighting the importance of routine CAC evaluation.

Effect of DPP-4i inhibitors on renal function in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

AIMS: About 20-40% patients with type 2 diabetes mellitus (T2DM) had an increased risk of developing diabetic nephropathy (DN). Dipeptidyl peptidase-4 inhibitors (DPP-4i) were recommended for treatment of T2DM, while the impact of DPP-4i on renal function remained unclear. This study aimed to explore the effect of DPP-4i on renal parameter of estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) in T2DM. METHODS: A systematic search was performed across PubMed, Embase and Cochrane Library. A fixed or random-effects model was used for quantitative synthesis according to the heterogeneity, which was assessed with I2 index. Sensitivity analysis and publication bias were performed with standard methods, respectively. RESULTS: A total of 17 randomized controlled trials were identified. Administration of DPP-4i produced no significant effect on eGFR (WMD, -0.92 mL/min/1.73m2, 95% CI, -2.04 to 0.19) in diabetic condition. DPP-4i produced a favorable effect on attenuating ACR (WMD, -2.76 mg/g, 95% CI, -5.23 to -0.29) in patients with T2DM. The pooled estimate was stable based on the sensitivity test. No publication bias was observed according to Begg's and Egger's tests. CONCLUSIONS: Treatment with DPP-4i preserved the renal parameter of eGFR in diabetic condition. Available evidences suggested that administration of DPP-4i produced a favorable effect on attenuating ACR in patients with T2DM. INTERNATIONAL PROSPECTIVE REGISTER FOR SYSTEMATIC REVIEW (PROSPERO) NUMBER: CRD.42020144642.

Low albumin combined with low-molecular-weight heparin as risk factors for liver injury using azvudine: Evidence from an analysis of COVID-19 patients in a national prospective pharmacovigilance database.

OBJECTIVE: Azvudine is an effective treatment for patients infected with common COVID-19. However, physicians have reported a series of adverse reactions, including multiple cases of liver injury, caused by azvudine in clinical practice. This study assessed the incidence, clinical features, and associated risk factors of liver injury induced by azvudine in real-world settings, offering guidance for safe clinical use. MATERIALS AND METHODS: This study utilized the Chinese Hospital Pharmacovigilance System (CHPS) to retrospectively analyze the treatment of COVID-19 patients with azvudine at Changsha Central Hospital from December 19, 2022, to June 6, 2023. A case-control study was conducted to analyze the occurrence of azvudine-induced liver injury in COVID-19 patients who triggered a CHPS alert compared to normal COVID-19 patients. RESULTS: Among the total of 2,141 COVID-19 patients, 31 (1.45%) developed azvudine-induced liver injury, which is classified as an occasional adverse reaction. Liver injury was observed in 93.55% of patients between days 4 and 12 of the azvudine treatment, with elevated transaminases as the primary clinical manifestation. Univariate and binary logistic regression analyses indicated that low albumin levels and co-administration of low-molecular-weight heparin were statistically significant risk factors (p < 0.05). CONCLUSION: This study represents the first investigation of azvudine-induced liver injury and high-risk patients using the CHPS. The findings provide valuable insights to promote the safety of anti-COVID-19 drugs, serving as an important reference for future drug safety measures.

Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent chronic liver condition. However, the potential therapeutic benefits and underlying mechanism of nicotinate-curcumin (NC) in the treatment of NASH remain uncertain. METHODS: A rat model of NASH induced by a high-fat and high-fructose diet was treated with nicotinate-curcumin (NC, 20, 40 mg·kg- 1), curcumin (Cur, 40 mg·kg- 1) and metformin (Met, 50 mg·kg- 1) for a duration of 4 weeks. The interaction between NASH, Cur and Aldo-Keto reductase family 1 member B10 (AKR1B10) was filter and analyzed using network pharmacology. The interaction of Cur, NC and AKR1B10 was analyzed using molecular docking techniques, and the binding energy of Cur and NC with AKR1B10 was compared. HepG2 cells were induced by Ox-LDL (25 µg·ml- 1, 24 h) in high glucose medium. NC (20µM, 40µM), Cur (40µM) Met (150µM) and epalrestat (Epa, 75µM) were administered individually. The activities of ALT, AST, ALP and the levels of LDL, HDL, TG, TC and FFA in serum were quantified using a chemiluminescence assay. Based on the changes in the above indicators, score according to NAS standards. The activities of Acetyl-CoA and Malonyl-CoA were measured using an ELISA assay. And the expression and cellular localization of AKR1B10 and Acetyl-CoA carboxylase (ACCα) in HepG2 cells were detected by Western blotting and immunofluorescence. RESULTS: The results of the animal experiments demonstrated that NASH rat model induced by a high-fat and high-fructose diet exhibited pronounced dysfunction in liver function and lipid metabolism. Additionally, there was a significant increase in serum levels of FFA and TG, as well as elevated expression of AKR1B10 and ACCα, and heightened activity of Acetyl-CoA and Malonyl-CoA in liver tissue. The administration of NC showed to enhance liver function in rats with NASH, leading to reductions in ALT, AST and ALP levels, and decrease in blood lipid and significant inhibition of FFA and TG synthesis in the liver. Network pharmacological analysis identified AKR1B10 and ACCα as potential targets for NASH treatment. Molecular docking studies revealed that both Cur and NC are capable of binding to AKR1B10, with NC exhibiting a stronger binding energy to AKR1B10. Western blot analysis demonstrated an upregulation in the expression of AKR1B10 and ACCα in the liver tissue of NASH rats, accompanied by elevated Acetyl-CoA and Malonyl-CoA activity, and increased levels of FFA and TG. The results of the HepG2 cell experiments induced by Ox-LDL suggest that NC significantly inhibited the expression and co-localization of AKR1B10 and ACCα, while also reduced levels of TC and LDL-C and increased level of HDL-C. These effects are accompanied by a decrease in the activities of ACCα and Malonyl-CoA, and levels of FFA and TG. Furthermore, the impact of NC appears to be more pronounced compared to Cur. CONCLUSION: NC could effectively treat NASH and improve liver function and lipid metabolism disorder. The mechanism of NC is related to the inhibition of AKR1B10/ACCα pathway and FFA/TG synthesis of liver.

Chiral Two-Dimensional Hybrid Organic-Inorganic Perovskites for Piezoelectric Ultrasound Detection.

Hybrid organic-inorganic perovskites (HOIPs) have exhibited striking application potential in piezoelectric energy harvesting and sensing due to their high piezoelectricity, light weight, and solution processability. However, to date, the application of piezoelectric HOIPs in ultrasound detection has not yet been explored. Here, we report the synthesis of a pair of chiral two-dimensional piezoelectric HOIPs, R-(4-bromo-2-butylammonium)2PbBr4 and S-(4-bromo-2-butylammonium)2PbBr4 [R-(BrBA)2PbBr4 and S-(BrBA)2PbBr4], which show low mechanical strength and significant piezoelectric strain coefficients that are advantageous for mechanoelectrical energy conversion. Benefiting from these virtues, the R-(BrBA)2PbBr4@PBAT and S-(BrBA)2PbBr4@PBAT [PBAT = poly(butyleneadipate-co-terephthalate)] composite films show prominent underwater ultrasound detection performance with a transmission effectivity of 12.0% using a 10.0 MHz probe, comparable with that of a polyvinylidene fluoride (PVDF) device fabricated in the same conditions. Density functional theory calculations reveal that R-(BrBA)2PbBr4 and S-(BrBA)2PbBr4 have a beneficial acoustic impedance (5.07-6.76 MRayl) compatible with that of water (1.5 MRayl), which is responsible for the facile ultrasound-induced electricity generation. These encouraging results open up new possibilities for applying piezoelectric HOIPs in underwater ultrasound detection and imaging technologies.

A dimer-monomer transition captured by the crystal structures of cyanobacterial apo flavodoxin.

In cyanobacteria and algae (but not plants), flavodoxin (Fld) replaces ferredoxin (Fd) under stress conditions to transfer electrons from photosystem I (PSI) to ferredoxin-NADP+ reductase (FNR) during photosynthesis. Fld constitutes a small electron carrier noncovalently bound to flavin mononucleotide (FMN), and also an ideal model for revealing the protein/flavin-binding mechanism because of its relative simplicity compared to other flavoproteins. Here, we report two crystal structures of apo-Fld from Synechococcus sp. PCC 7942, one dimeric structure of 2.09 Å and one monomeric structure of 1.84 Å resolution. Analytical ultracentrifugation showed that in solution, apo-Fld exists both as monomers and dimers. Our dimer structure contains two ligand-binding pockets separated by a distance of 45 Å, much longer than the previous structures of FMN-bound dimers. These results suggested a potential dimer-monomer transition mechanism of cyanobacterial apo-Fld. We further propose that the dimer represents the "standby" state to stabilize itself, while the monomer constitutes the "ready" state to bind FMN. Furthermore, we generated a new docking model of cyanobacterial Fld-FNR complex based on the recently reported cryo-EM structures, and mapped the special interactions between Fld and FNR in detail.

Interstitial Lung Abnormalities at CT in the Korean National Lung Cancer Screening Program: Prevalence and Deep Learning-based Texture Analysis.

Background Interstitial lung abnormalities (ILAs) are associated with worse clinical outcomes, but ILA with lung cancer screening CT has not been quantitatively assessed. Purpose To determine the prevalence of ILA at CT examinations from the Korean National Lung Cancer Screening Program and define an optimal lung area threshold for ILA detection with CT with use of deep learning-based texture analysis. Materials and Methods This retrospective study included participants who underwent chest CT between April 2017 and December 2020 at two medical centers participating in the Korean National Lung Cancer Screening Program. CT findings were classified by three radiologists into three groups: no ILA, equivocal ILA, and ILA (fibrotic and nonfibrotic). Progression was evaluated between baseline and last follow-up CT scan. The extent of ILA was assessed visually and quantitatively with use of deep learning-based texture analysis. The Youden index was used to determine an optimal cutoff value for detecting ILA with use of texture analysis. Demographics and ILA subcategories were compared between participants with progressive and nonprogressive ILA. Results A total of 3118 participants were included in this study, and ILAs were observed with the CT scans of 120 individuals (4%). The median extent of ILA calculated by the quantitative system was 5.8% for the ILA group, 0.7% for the equivocal ILA group, and 0.1% for the no ILA group (P < .001). A 1.8% area threshold in a lung zone for quantitative detection of ILA showed 100% sensitivity and 99% specificity. Progression was observed in 48% of visually assessed fibrotic ILAs (15 of 31), and quantitative extent of ILA increased by 3.1% in subjects with progression. Conclusion ILAs were detected in 4% of the Korean lung cancer screening population. Deep learning-based texture analysis showed high sensitivity and specificity for detecting ILA with use of a 1.8% lung area cutoff value. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Egashira and Nishino in this issue.

Prevalence and Long-term Outcomes of CT Interstitial Lung Abnormalities in a Health Screening Cohort.

Background The association between interstitial lung abnormalities (ILAs) and long-term outcomes has not been reported in Asian health screening populations. Purpose To investigate ILA prevalence in an Asian health screening cohort and determine rates and risks for ILA progression, lung cancer development, and mortality within the 10-year follow-up. Materials and Methods This observational, retrospective multicenter study included patients aged 50 years or older who underwent chest CT at three health screening centers over a 4-year period (2007-2010). ILA status was classified as none, equivocal ILA, and ILA (nonfibrotic or fibrotic). Progression was evaluated from baseline to the last follow-up CT examination, when available. The log-rank test was performed to compare mortality rates over time between ILA statuses. Multivariable Cox proportional hazards models were used to assess factors associated with hazards of ILA progression, lung cancer development, and mortality. Results Of the 2765 included patients (mean age, 59 years ± 7 [SD]; 2068 men), 94 (3%) had a finding of ILA (35 nonfibrotic and 59 fibrotic ILA) and 119 (4%) had equivocal ILA. The median time for CT follow-up and the entire observation was 8 and 12 years, respectively. ILA progression was observed in 80% (48 of 60) of patients with ILA over 8 years. Those with fibrotic and nonfibrotic ILA had a higher mortality rate than those without ILA (P < .001 and P = .01, respectively) over 12 years. Fibrotic ILA was independently associated with ILA progression (hazard ratio [HR], 10.3; 95% CI: 6.4, 16.4; P < .001), lung cancer development (HR, 4.4; 95% CI: 2.1, 9.1; P < .001), disease-specific mortality (HR, 6.7; 95% CI: 3.7, 12.2; P < .001), and all-cause mortality (HR, 2.5; 95% CI: 1.6, 3.8; P < .001) compared with no ILA. Conclusion The prevalence of interstitial lung abnormalities (ILAs) in an Asian health screening cohort was approximately 3%, and fibrotic ILA was an independent risk factor for ILA progression, lung cancer development, and mortality. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Hatabu and Hata in this issue.

Metabolism and disposition of JNJ-10450232 (NTM-006) in rats, dogs, monkeys and humans.

JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.6% (rats) and 73.7% (dogs) of oral dose. The compound was extensively metabolized based on low recovery of unchanged drug in excreta from rats (11.3%) and dogs (18.4%). Clearance is driven by O-glucuronidation, amide hydrolysis, O-sulfation and methyl oxidation pathways. The combination of metabolic pathways driving clearance in human is covered in at least one preclinical species despite a few species-dependent pathways. O-Glucuronidation was the major primary metabolic pathway of JNJ-10450232 (NTM-006) in dogs, monkeys and humans, although amide hydrolysis was another major primary metabolic pathway in rats and dogs. A minor bioactivation pathway to quinone-imine is observed only in monkeys and humans. Unchanged drug was the major circulatory component in all species investigated. Except for metabolic pathways unique to the 5-methyl-1H-pyrazole-3-carboxamide moiety, metabolism and disposition of JNJ-10450232 (NTM-006) are similar to acetaminophen across species.

External validation of deep learning-based automated detection algorithm for chest radiograph: practical issues in outpatient clinic.

BACKGROUND: There have been no reports on diagnostic performance of deep learning-based automated detection (DLAD) for thoracic diseases in real-world outpatient clinic. PURPOSE: To validate DLAD for use at an outpatient clinic and analyze the interpretation time for chest radiographs. MATERIAL AND METHODS: This is a retrospective single-center study. From 18 January 2021 to 18 February 2021, 205 chest radiographs with DLAD and paired chest CT from 205 individuals (107 men and 98 women; mean ± SD age: 63 ± 8 years) from an outpatient clinic were analyzed for external validation and observer performance. Two radiologists independently reviewed the chest radiographs by referring to the paired chest CT and made reference standards. Two pulmonologists and two thoracic radiologists participated in observer performance tests, and the total amount of time taken during the test was measured. RESULTS: The performance of DLAD (area under the receiver operating characteristic curve [AUC] = 0.920) was significantly higher than that of pulmonologists (AUC = 0.756) and radiologists (AUC = 0.782) without assistance of DLAD. With help of DLAD, the AUCs were significantly higher for both groups (pulmonologists AUC = 0.853; radiologists AUC = 0.854). A greater than 50% decrease in mean interpretation time was observed in the pulmonologist group with assistance of DLAD compared to mean reading time without aid of DLAD (from 67 s per case to 30 s per case). No significant difference was observed in the radiologist group (from 61 s per case to 61 s per case). CONCLUSION: DLAD demonstrated good performance in interpreting chest radiographs of patients at an outpatient clinic, and was especially helpful for pulmonologists in improving performance.

Carbon-13 labeling of ibrutinib for human microdosing.

Ibrutinib is an oral medication for the treatment of B cell malignancies. During its clinical development, a stable isotopologue of ibrutinib was required for the assessment of the drug's absolute oral bioavailability via intravenous microdosing. The following work describes a 10-step, gram-scale production of carbon-13 labeled ibrutinib from [13 C6 ]phenol (13 C6 , 99%) in 31% overall yield with >99% chemical purity and >99% enantiomeric excess (ee), suitable for intravenous microdosing in humans.

Biochemical and mutational studies of an endonuclease V from the hyperthermophilic crenarchaeon Sulfolobus islandicus REY15A.

Endonuclease V (EndoV), which is widespread in bacteria, eukarya and Archaea, can cleave hypoxanthine (Hx)-containing DNA or RNA strand, and play an essential role in Hx repair. However, our understanding on archaeal EndoV's function remains incomplete. The model archaeon Sulfolobus islandicus REY15A encodes a putative EndoV protein (Sis-EndoV). Herein, we probed the biochemical characteristics of Sis-EndoV and dissected the roles of its seven conserved residues. Our biochemical data demonstrate that Sis-EndoV displays maximum cleavage efficiency at above 60 °C and at pH 7.0-9.0, and the enzyme activity is dependent on a divalent metal ion, among which Mg2+ is optimal. Importantly, we first measured the activation energy for cleaving Hx-containing ssDNA by Sis-EndoV to be 9.6 ± 0.8 kcal/mol by kinetic analyses, suggesting that chemical catalysis might be a rate-limiting step for catalysis. Mutational analyses show that residue D38 in Sis-EndoV is essential for catalysis, but has no role in DNA binding. Furthermore, we first revealed that residues Y41 and D189 in Sis-EndoV are involved in both DNA cleavage and DNA binding, but residues F77, H103, K156 and F161 are only responsible for DNA binding.

[Clinical observation of dapoxetine combined with percutaneous neuromuscular electrical stimulation in the treatment of primary premature ejaculation].

OBJECTIVE: To investigate the clinical efficacy of dapoxetine combined with transcutaneous neuromuscular electrical stimulation (TNES) in the treatment of primary premature ejaculation. METHODS: A total of 60 patients who met the diagnostic criteria for primary premature ejaculation were selected as study subjects and randomly divided into a dapoxetine group (control group) and a dapoxetine combined with percutaneous neuromuscular electrical stimulation group (observation group).30 patients in each group were treated for 4 weeks. Intravaginal ejaculatory latency time (IELT), the score of Premature Ejaculation Diagnostic Tool (PEDT), sympathetic skin response located in the penis (PSSR), Patient Health Questionnaire (PHQ-9), and Generalized Anxiety Disorder Questionnaire (GAD-7) before and after treatment were recorded in the two groups. Before and after treatment, the difference in observed indexes in the two groups and the comparison of effective rates between the two groups were analyzed. RESULTS: The latency of IELT and PSSR was prolonged and the PEDT score was decreased in both the observation group and the control group, the difference was statistically significant (P<0.01). Compared with the control group, the observation group had statistically significant differences in extending IELT and PSSR latency and reducing PEDT score (P<0.05). The effective rates of the observation group and control group were 90% and 63.33%, respectively, and the difference was statistically significant (P<0.05). There was no significant difference in the improvement of depression and anxiety levels between the two groups (P> 0.05). CONCLUSION: Dapoxetine combined with TNES has a better clinical effect than dapoxetine alone in the treatment of primary premature ejaculation, and can be used as an effective option for clinical treatment of primary premature ejaculation.

[Mechanism of astragaloside â £ in regulating autophagy of PC12 cells under oxygen-glucose deprivation by medicating Akt/mTOR/HIF-1α pathway].

This study explored the protective effect of astragaloside Ⅳ(AS-Ⅳ) on oxygen-glucose deprivation(OGD)-induced autophagic injury in PC12 cells and its underlying mechanism. An OGD-induced autophagic injury model in vitro was established in PC12 cells. The cells were divided into a normal group, an OGD group, low-, medium-, and high-dose AS-Ⅳ groups, and a positive drug dexmedetomidine(DEX) group. Cell viability was measured using the MTT assay. Transmission electron microscopy was used to observe autophagosomes and autolysosomes, and the MDC staining method was used to assess the fluorescence intensity of autophagosomes. Western blot was conducted to determine the relative expression levels of functional proteins LC3-Ⅱ/LC3-Ⅰ, Beclin1, p-Akt/Akt, p-mTOR/mTOR, and HIF-1α. Compared with the normal group, the OGD group exhibited a significant decrease in cell viability(P<0.01), an increase in autophagosomes(P<0.01), enhanced fluorescence intensity of autophagosomes(P<0.01), up-regulated Beclin1, LC3-Ⅱ/LC3-Ⅰ, and HIF-1α(P<0.05 or P<0.01), and down-regulated p-Akt/Akt and p-mTOR/mTOR(P<0.05 or P<0.01). Compared with the OGD group, the low-and medium-dose AS-Ⅳ groups and the DEX group showed a significant increase in cell viability(P<0.01), decreased autophagosomes(P<0.01), weakened fluorescence intensity of autophagosomes(P<0.01), down-regulated Beclin1, LC3-Ⅱ/LC3-Ⅰ, and HIF-1α(P<0.05 or P<0.01), and up-regulated p-Akt/Akt and p-mTOR/mTOR(P<0.01). AS-Ⅳ at low and medium doses exerted a protective effect against OGD-induced autophagic injury in PC12 cells by activating the Akt/mTOR pathway, subsequently influencing HIF-1α. The high-dose AS-Ⅳ group did not show a statistically significant difference compared with the OGD group. This study provides a certain target reference for the prevention and treatment of OGD-induced cellular autophagic injury by AS-Ⅳ and accumulates laboratory data for the secondary development of Astragali Radix and AS-Ⅳ.

A New Hybrid Lead-Free Metal Halide Piezoelectric for Energy Harvesting and Human Motion Sensing.

Hybrid organic-inorganic piezoelectrics have attracted attention due to their simple synthesis, mechanical flexibility, and designability, which have promising application potential in flexible sensing and self-powered energy harvesting devices. Although some hybrid piezoelectrics are discovered, most of their structures are limited by the perovskite-type and often contain lead. Herein, the synthesis, structure, and piezoelectric properties of a new hybrid lead-free metal halide, (BTMA)2 CoBr4 (BTMA = benzyltrimethylammonium) are reported. The experimental and theoretical results demonstrate that this material simply composed of [CoBr4 ]2- tetrahedra and BTMA+ cations exhibits significant piezoelectricity (d22 = 5.14, d25 = 12.40 pC N-1 ), low Young's and shear moduli (4.11-17.56 GPa; 1.86-7.91 GPa). Moreover, the (BTMA)2 CoBr4 /PDMS (PDMS = polydimethylsiloxane) composite thin films are fabricated and optimized. The 10% (BTMA)2 CoBr4 /PDMS-based flexible devices show attractive performance in energy harvesting with an open-circuit voltage of 19.70 V, short-circuit current of 4.24 µA, and powder density of 11.72 µW cm-2 , catching up with those of piezoelectric ceramic composites. Meanwhile, these film devices show excellent capability in accurately sensing human body motions, such as finger bending and tapping. This work demonstrates that (BTMA)2 CoBr4 and related piezoelectric lead-free halides can be promising molecular materials in modern energy and sensing applications.

Radiologic-pathologic correlation of interstitial lung abnormalities and predictors for progression and survival.

OBJECTIVES: To evaluate radiologic and histologic correlations for interstitial lung abnormalities (ILAs) and to investigate radiologic or pathologic features contributing to disease progression and mortality. METHODS: From 268 patients who underwent surgical lung biopsy between January 2004 and April 2019, 45 patients with incidentally detected ILA and normal pulmonary function were retrospectively included. CT features were classified as subpleural fibrotic or non-fibrotic, and changes in ILA over at least 2 years of follow-up were evaluated. Histologic findings were categorized as definite, probable, indeterminate, or alternative diagnosis for usual interstitial pneumonia (UIP) patterns. Overall and progression-free survival were calculated using the Kaplan-Meier method, and the Cox proportional hazard method was used to examine predictors for ILA progression and survival. RESULTS: Among 36 subpleural fibrotic ILA subjects, 25 (69%) showed definite or probable UIP patterns, and 89% (8/9) of subpleural non-fibrotic ILA subjects showed an indeterminate or alternative diagnosis for UIP pattern on histopathology. On the radiologic-pathologic correlation, reticular opacity of fibrotic ILA was correlated with patchy involvement of fibrosis, and ground-glass attenuation of non-fibrotic ILA corresponded to diffuse interstitial thickening. The median progression time of ILA was 54 months, and fibrotic ILA increased the likelihood of progression (hazard ratio, 2.42; p = 0.017). The median survival time of ILA subjects was 123 months, and fibrotic ILA was associated with an increased risk of death (hazard ratio, 9.22; p = 0.025). CONCLUSIONS: Subpleural fibrotic ILAs are associated with pathologic UIP patterns, and it is important to recognize subpleural fibrotic ILA on CT to predict disease progression and mortality. KEY POINTS: • In total, 69% of subpleural fibrotic ILA showed definite or probable UIP patterns, while 11% of subpleural non-fibrotic ILA showed definite or probable UIP patterns. • Subpleural fibrotic ILA was associated with an increased rate of progression (hazard ratio, 2.42; p = 0.017), and the median progression-free time was 40 months. • Subpleural fibrotic ILA had an increased risk of death (hazard ratio, 9.22; p = 0.025), and the median survival time was 86 months.

Association between serum uric acid to serum creatinine ratio and poor functional outcomes in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: The role of serum uric acid (SUA) in prognosis is controversial because SUA levels largely depend on renal clearance function. This study aimed to investigate the association between renal function-normalized SUA (SUA to serum creatinine [SCr] ratio [SUA/SCr ratio]) and poor functional outcomes in patients with acute ischemic stroke (AIS). METHODS: All patients were recruited from the Third China National Stroke Registry. Poor functional outcomes were defined by modified Rankin Scale (mRS) scores of 3-6 or 2-6 at 3 months and 1 year. RESULTS: Among 8169 enrolled patients, the median (interquartile range) SUA/SCr ratio was 4.19 (3.47-5.08). Compared with patients in the fourth quintile group, those in the first quintile group had higher proportions of mRS scores 3-6 (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.24-1.93) and mRS scores 2-6 (OR 1.28, 95% CI 1.08-1.53) at 3 months. The addition of SUA/SCr ratio to the conventional risk model had a greater incremental value than the addition of either SUA or SCr alone. Subgroup analysis showed that the association was only significant in patients with normal kidney function (p for interaction<0.05). Similar results were found for outcomes at 1 year. CONCLUSIONS: A lower SUA/SCr ratio was associated with poor functional outcomes in patients with AIS at 3 months and at 1 year, suggesting the potential use of SUA/SCr ratio in clinical practice as a preferable marker for stroke outcomes.

Nitro-Activated Nucleobase Exchange in the Synthesis of 2'-Fluoro-2'-Deoxyribonucleosides.

Functionalized nucleosides bearing pyrimidine or purine bases can be prepared by activation of accessible pyrimidine nucleosides and subsequent transglycosylation. Nitration of lumicitabine, a 2'-fluoro-2'-deoxycytidine class antiviral agent, and its 2'-fluoro-2'-deoxyuridine precursor produce the same 5-nitro-2'-fluoro-2'-deoxyuridine. Under Vorbrüggen conditions, 5-nitrouracil serves as the leaving nucleobase and enables exchange with pyrimidine and purine nucleobases to anomeric 2'-fluoro-2'-deoxyribonucleosides in favor of ß-anomers generally. The strategy is also applied in the isotopic labeling of 2'-fluoro-2'-deoxyuridines.