Physiological and genetic responses of the benthic dinoflagellate Prorocentrum lima to polystyrene microplastics.

Microplastics are well known as contaminants in marine environments. With the development of biofilms, most microplastics will eventually sink and deposit in benthic environment. However, little research has been done on benthic toxic dinoflagellates, and the effects of microplastics on benthic dinoflagellates are unknown. Prorocentrum lima is a cosmopolitan toxic benthic dinoflagellate, which can produce a range of polyether metabolites, such as diarrhetic shellfish poisoning (DSP) toxins. In order to explore the impact of microplastics on marine benthic dinoflagellates, in this paper, we studied the effects of polystyrene (PS) on the growth and toxin production of P. lima. The molecular response of P. lima to microplastic stress was analyzed by transcriptomics. We selected 100 nm, 10 µm and 100 µm PS, and set three concentrations of 1 mg L-1, 10 mg L-1 and 100 mg L-1. The results showed that PS exposure had limited effects on cell growth, but increased the OA and extracellular polysaccharide content at high concentrations. After exposure to PS MPs, genes associated with DSP toxins synthesis, carbohydrate synthesis and energy metabolism, such as glycolysis, TCA cycle and pyruvate metabolism, were significantly up-regulated. We speculated that after exposure to microplastics, P. lima may increase the synthesis of DSP toxins and extracellular polysaccharides, improve the level of energy metabolism and gene expression of ABC transporter, thereby protecting algal cells from damage. Our findings provide new insights into the effects of microplastics on toxic benthic dinoflagellates.

Phosphoric Acid-Catalyzed Alkene Difunctionalization of 2-Vinylpyridines via HOMO/LUMO Biactivated Diels-Alder Reaction.

The difunctionalization of vinylpyridines based on the cyclization strategy remains rare and underdeveloped, in contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO bifunctional activation model. This protocol features mild reaction conditions, high functional group tolerance, broad substrate compatibility, and high diastereoselectivity, enabling the efficient construction of various functionalized pyridine-substituted tetrahydrocarbazoles with prominent potential in drug discovery.

BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma.

Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.

MED1 IDR acetylation reorganizes the transcription preinitiation complex, rewires 3D chromatin interactions and reprograms gene expression.

With our current appreciation of the complexity of eukaryotic transcription, whose dysregulation drives diseases including cancer, it is becoming apparent that identification of key events coordinating multiple aspects of transcriptional regulation is of special importance. To elucidate how assembly of RNA polymerase II (Pol II) with Mediator complex preinitiation complexes (PICs) and formation of transcription-permissive 3D chromatin organization are coordinated, we studied MED1, a representative subunit of the Mediator complex that acts to establish functional preinitiation complexes (PICs) that forms biomolecular condensates through an intrinsically disordered region (IDR) to facilitate transcription, and is implicated in the function of estrogen receptor α (hereafter ER) in ER-positive breast cancer (ER+ BC) cells. We found that MED1 is acetylated at 6 lysines in its IDR and, further, that MCF7 ER+ BC cells in which endogenous MED1 is replaced by an ectopic 6KR (non-acetylatable) mutant (6KR cells) exhibit enhanced cell growth and elevated expression of MED1-dependent genes. These results indicate an enhanced function of 6KR MED1 that may be attributed to two mechanisms: (1) reorganized PIC assembly, as indicated by increased MED1 and Pol II, decreased MED17, and equivalent ERα occupancies on chromatin, particularly at active enhancers and promoters; (2) sub-TAD chromatin unfolding, as revealed by HiCAR (Hi-C on accessible regulatory DNA) analyses. Furthermore, in vitro assays demonstrate distinct physio-chemical properties of liquid-liquid phase separation (LLPS) for 6KR versus 6KQ MED1 IDRs, and for non-acetylated versus CBP-acetylated WT MED1 IDR fragments. Related, Pol II CTD heptads are sequestered in 6KR and control WT MED1 IDR condensates, but not 6KQ and CBP-acetylated WT MED1 IDR condensates. These findings, in conjunction with recent reports of PIC structures, indicate that MED1 coordinates reorganization of the PIC machinery and the rewiring of regional chromatin organization through acetylation of its IDR. This study leads to an understanding of how the transition in phase behavior of a transcription cofactor acts as a mechanistic hub integrating linear and spatial chromatin functions to support gene expression, and have potential therapeutic implications for diseases involving MED1/Mediator-mediated transcription control.

Exposure to microplastics renders immunity of the thick-shell mussel more vulnerable to diarrhetic shellfish toxin-producing harmful algae.

Despite both microplastics (MPs) and harmful algae blooms (HABs) may pose a severe threat to the immunity of marine bivalves, the toxification mechanism underlying is far from being fully understood. In addition, owing to the prevalence and sudden occurrence characteristics of MPs and HABs, respectively, bivalves with MP-exposure experience may face acute challenge of harmful algae under realistic scenarios. However, little is known about the impacts and underlying mechanisms of MP-exposure experience on the susceptibility of immunity to HABs in bivalve mollusks. Taking polystyrene MPs and diarrhetic shellfish toxin-producing Prorocentrum lima as representatives, the impacts of MP-exposure on immunity vulnerability to HABs were investigated in the thick-shell mussel, Mytilus coruscus. Our results revealed evident immunotoxicity of MPs and P. lima to the mussel, as evidenced by significantly impaired total count, phagocytic activity, and cell viability of haemocytes, which may result from the induction of oxidative stress, aggravation of haemocyte apoptosis, and shortage in cellular energy supply. Moreover, marked disruptions of immunity, antioxidant system, apoptosis regulation, and metabolism upon MPs and P. lima exposure were illustrated by gene expression and comparative metabolomic analyses. Furthermore, the mussels that experienced MP-exposure were shown to be more vulnerable to P. lima, indicated by greater degree of deleterious effects on abovementioned parameters detected. In general, our findings emphasize the threat of MPs and HABs to bivalve species, which deserves close attention and more investigation.

Application and effect of tension-reducing suture in surgical treatment of hypertrophic scar.

PURPOSE: To investigate the application and effectiveness of tension-reducing suture in the repair of hypertrophic scars. METHODS: A retrospective analysis of clinical data was conducted on 82 patients with hypertrophic scars treated at the Department of Burns and Plastic Surgery of Nanjing Drum Tower Hospital from September 2021 to December 2022. Patients were operated with combination of heart-shaped tension-reducing suturing technique and looped, broad, and deep buried (LBD) suturing technique or conventional suture method. Outcomes of surgical treatment were assessed before and 6 months after surgery using the Patient and Observer Scar Assessment Scale (POSAS) and the Vancouver Scar Scale (VSS). RESULTS: Improvements were achieved on scar quality compared to that preoperatively, with a reduction in scar width (1.7 ± 0.6 cm vs. 0.7 ± 0.2 cm, P < 0.001). Assessment using the POSAS and VSS scales showed significant improvements in each single parameter and total score compared to preoperative values (P < 0.05). The Combination method group achieved better score in total score of VSS scale, in color, stiffness, thickness and overall opinion of PSAS scale, and in vascularity, thickness, pliability and overall opinion of OSAS scale. CONCLUSION: The amalgamation of the heart-shaped tension-reducing suturing technique and the LBD suturing technique has shown promising outcomes, garnering notably high levels of patient satisfaction in the context of hypertrophic scar repair. Patients have exhibited favorable postoperative recoveries, underscoring the clinical merit and the prospective broader applicability of this approach in the realm of hypertrophic scar management.

Aluminum and polyanion-doping to improve structural and moisture stability of Ni-rich layered oxides for lithium-ion batteries.

Ni-rich layered materials LiNi0.8Co0.1Mn0.1O2 attracts extensive interest to build high-performance lithium-ion batteries, but ground challenges, e.g., unfavorable phase transfer and interfacial parasitic reactions during cycling, especially after being exposure to the air for a long time, greatly limit their practical utilization. Here, we prove that those issues of Ni-rich layered materials can be alleviated by concurrently incorporating the Al3+ and PO34-, and conduct corresponding comprehensive studies to explore mechanisms of the enhanced electrochemical performances. It is suggested that the phase transition (H2 to H3) that related to the lattice contraction can be suppressed after Al3+ and PO34- co-doping, leading to improved cycling stability. Additionally, the co-doping successfully mitigates the chemical reaction between the Ni-based oxides and the ambient air, significantly improving the reversibility of lithium intercalation and charge transfer kinetics against long-time storage. Specifically, the Al3+ and PO34- co-doped material maintains 94.1% capacity retention of 150 cycles before storage, and 73.6% capacity retention of 100 cycles after being stored in ambient air for 30 days, which is much better than that of the undoped one.

Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), and Eosinophil-to-Lymphocyte Ratio (ELR) as Biomarkers in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD).

Purpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Patients and Methods: Six hundred and nineteen patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics of the patients with AECOPD and the complete blood counts (CBCs) of the healthy volunteers were collected. The associations of PLR, NLR, MLR, BLR, and ELR with airflow limitation, hospital length of stay (LOS), C-reactive protein (CRP), and in-hospital mortality in patients with AECOPD were analyzed. Results: Compared with the healthy volunteers, PLR, NLR, MLR, BLR, and ELR were all elevated in COPD patients under stable condition. PLR, NLR, MLR, and BLR were further elevated while ELR was lowered during exacerbation. In the patients with AECOPD, PLR, NLR, and MLR were positively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more severe airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while elevated ELR was associated with decreased in-hospital mortality. Binary logistic regression analysis showed that smoking history, FEV1% predicted, pneumonia, pulmonary heart disease (PHD), uric acid (UA), albumin, and MLR were significant independent predictors ofin-hospital mortality. These predictors along with ELR were used to construct a nomogram for predicting in-hospital mortality in AECOPD. The nomogram had a C-index of 0.850 (95% CI: 0.799-0.901), and the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) further demonstrated its good predictive value and clinical applicability. Conclusion: In summary, PLR, NLR, MLR, and ELR served as useful biomarkers in patients with AECOPD.

A density functional theory study on the mechanism of toluene from dimethylcyclopentane catalyzed by the [GaH]2+ active site of Ga-ZSM-5.

The ONIOM (ωb97xd/6-31G(d,p):pm6) method was used to study the reaction mechanism of dimethylcyclopentane to toluene by the [GaH]2+ active site of Ga-ZSM-5. The results showed that the rate-determining step in the dimethylcyclopentane aromatization process is the ring expansion process. Compared to those of methylcyclopentane to benzene (D. D. Zhang, H. Y. Liu, L. X. Ling, H. R. Zhang, R. G. Zhang, P. Liu and B. J. Wang, Phys. Chem. Chem. Phys., 2021, 23, 10988-11003.), the free energy barriers of dimethylcyclopentane to toluene are significantly decreased, indicating that toluene is easier to produce than benzene, which confirmed the experimental results that a higher proportion of toluene than benzene is produced in the MTA process.

Enhancing the reversibility of the chemical evolution of the Ni-rich LiNi0.8Co0.1Mn0.1O2 cathode via a simple pre-oxidation process.

For developing commercially viable LiNi1-x-yMnxCoyO2 (NCM), it is necessary to alleviate the irreversible chemical process upon Li-ion insertion/extraction, which primarily accounts for prevailing capacity loss, impedance buildup as well as low columbic efficiency. To resolve this issue, we herein propose a simple but novel method to alter the chemical composition by a facile treatment of H2O2, which remarkably reduces the cation mixing of Li+/Ni2+ and residual lithium on the cathode. The tailored composition contributes great resistance to the structural reconstruction and enhancement in structural reversibility, as shown by in situ Raman and high-resolution transmission electron microscope (HRTEM) results. Thus, the modified sample outperforms the pristine one; it exhibits cyclability with 95.7% capacity retention over 300 cycles, high columbic efficiency and enhanced rate capability.

Potent inhibitors targeting cyclin-dependent kinase 9 discovered via virtual high-throughput screening and absolute binding free energy calculations.

Due to the crucial regulatory mechanism of cyclin-dependent kinase 9 (CDK9) in mRNA transcription, the development of kinase inhibitors targeting CDK9 holds promise as a potential treatment strategy for cancer. A structure-based virtual screening approach has been employed for the discovery of potential novel CDK9 inhibitors. First, compounds with kinase inhibitor characteristics were identified from the ZINC15 database via virtual high-throughput screening. Next, the predicted binding modes were optimized by molecular dynamics simulations, followed by precise estimation of binding affinities using absolute binding free energy calculations based on the free energy perturbation scheme. The binding mode of molecule 006 underwent an inward-to-outward flipping, and the new binding mode exhibited binding affinity comparable to the small molecule T6Q in the crystal structure (PDB ID: 4BCF), highlighting the essential role of molecular dynamics simulation in capturing a plausible binding pose bridging docking and absolute binding free energy calculations. Finally, structural modifications based on these findings further enhanced the binding affinity with CDK9. The results revealed that enhancing the molecule's rigidity through ring formation, while maintaining the major interactions, reduced the entropy loss during the binding process and, thus, enhanced binding affinities.

Single-cell RNA sequencing analysis of lung cells in COVID-19 patients with diabetes, hypertension, and comorbid diabetes-hypertension.

Background: There is growing evidence that the lung is a target organ for injury in diabetes and hypertension. There are no studies on the status of the lungs, especially cellular subpopulations, and related functions in patients with diabetes, hypertension, and hypertension-diabetes after combined SARS-CoV-2 infection. Method: Using single-cell meta-analysis in combination with bulk-RNA analysis, we identified three drug targets and potential receptors for SARS-CoV-2 infection in lung tissues from patients with diabetes, hypertension, and hypertension-diabetes, referred to as "co-morbid" patients. Using single-cell meta-analysis analysis in combination with bulk-RNA, we identified drug targets and potential receptors for SARS-CoV-2 infection in the three co-morbidities. Results: The single-cell meta-analysis of lung samples from SARS-CoV-2-infected individuals with diabetes, hypertension, and hypertension-diabetes comorbidity revealed an upregulation of fibroblast subpopulations in these disease conditions associated with a predictive decrease in lung function. To further investigate the response of fibroblasts to therapeutic targets in hypertension and diabetes, we analyzed 35 upregulated targets in both diabetes and hypertension. Interestingly, among these targets, five specific genes were upregulated in fibroblasts, suggesting their potential association with enhanced activation of endothelial cells. Furthermore, our investigation into the underlying mechanisms driving fibroblast upregulation indicated that KREMEN1, rather than ACE2, could be the receptor responsible for fibroblast activation. This finding adds novel insights into the molecular processes involved in fibroblast modulation in the context of SARS-CoV-2 infection within these comorbid conditions. Lastly, we compared the efficacy of Pirfenidone and Nintedanib as therapeutic interventions targeting fibroblasts prone to pulmonary fibrosis. Our findings suggest that Nintedanib may be a more suitable treatment option for COVID-19 patients with diabetes and hypertension who exhibit fibrotic lung lesions. Conclusion: In the context of SARS-CoV-2 infections, diabetes, hypertension, and their coexistence predominantly lead to myofibroblast proliferation. This phenomenon could be attributed to the upregulation of activated endothelial cells. Moreover, it is noteworthy that therapeutic interventions targeting hypertension-diabetes demonstrate superior efficacy. Regarding treating fibrotic lung conditions, Nintedanib is a more compelling therapeutic option.

A prediction model for neonatal necrotizing enterocolitis in preterm and very low birth weight infants.

Objectives: Neonatal necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that primarily affects preterm and very low birth weight infants, with high morbidity and mortality. We aim to build a reliable prediction model to predict the risk of NEC in preterm and very low birth weight infants. Methods: We conducted a retrospective analysis of medical data from infants (gestational age <32 weeks, birth weight <1,500 g) admitted to Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region. We collected clinical data, randomly dividing it into an 8:2 ratio for training and testing. Multivariate logistic regression was employed to identify significant predictors for NEC. Principal component analysis was used for dimensionality reduction of numerical variables. The prediction model was constructed through logistic regression, incorporating all relevant variables. Subsequently, we calculated performance evaluation metrics, including Receiver Operating Characteristic (ROC) curves and confusion matrices. Additionally, we conducted model performance comparisons with common machine learning models to establish its superiority. Results: A total of 292 infants were included, with 20% (n = 58) randomly selected for external validation. Multivariate logistic regression revealed the significance of four predictors for NEC in preterm and very low birth weight infants: temperature (P = 0.003), Apgar score at 5 min (P = 0.004), formula feeding (P = 0.007), and gestational diabetes mellitus (GDM, P = 0.033). The model achieved an accuracy of 82.46% in the test set with an F1 score of 0.90, outperforming other machine learning models (support vector machine, random forest). Conclusions: Our logistic regression model effectively predicts NEC risk in preterm and very low birth weight infants, as confirmed by external validation. Key predictors include temperature, Apgar score at 5 min, formula feeding, and GDM. This study provides a vital tool for NEC risk assessment in this population, potentially improving early interventions and child survival. However, clinical validation and further research are necessary for practical application.

Cytokines as drivers: Unraveling the mechanisms of epithelial-mesenchymal transition in COVID-19 lung fibrosis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), like other viruses, can induce proliferation of myofibroblasts and even lead to fibrosis in the lung. Epithelial-mesenchymal transition (EMT) is thought to play an essential role in the pathogenesis of Coronavirus disease 19 (COVID-19). EMT is originally a critical process that regulates the development of different tissues in the embryo, but in inflammatory situations, EMT tries to be activated again to control inflammation or even heal inflammatory damage. However, in pathological situations, such as chronic viral infections (e.g., COVID-19) or pulmonary fibrosis initiation, this benign healing transforms into sinister nature, pushing the lung into the fibrotic process. Notably, the cytokines released by inflammatory cells and the chronic inflammatory microenvironment shared by fibrotic cells promote each other as critical factors in the induction of pathological EMT. In the induction of SARS-CoV-2 virus, cytokines are an essential mediator of EMT transformation, and a summary of whether COVID-19 patients, during the infection phase, have many persistent inflammatory mediators (cytokines) that are a causative factor of EMT has not yet appeared. The following common signaling drivers, including Transforming growth factor beta (TGF-ß), cytokines, Notch signaling pathway, Wnt and hypoxia signaling pathways, drive the regulation of EMT. In this review, we will focus on 3 key EMT signaling pathways: TGF-ß, Leucine zipper transcription factor like 1 (LZTFL1) and the common interleukin family expressed in the lung. TGF-ß-induced SNAIL and LZTFL1 were identified as regulatory EMT in COVID-19. For cytokines, the interleukin family is a common inducer of EMT and plays an essential role in the formation of the microenvironment of fibrosis. We sought to demonstrate that cytokines act as "communicators" and build the "microenvironment" of fibrosis together with EMT as a "bridge" to induce EMT in fibrosis. The mechanisms utilized by these two pathways could serve as templates for other mesenchymal transformations and provide new potential therapeutic targets.

Evaluation and optimization of ecological landscape pattern for urban agglomeration in the Pearl River Delta, China.

The evaluation and optimization of landscape ecological pattern has important implications for the accurate improvement of forest quality and high-quality urban development in the Pearl River Delta urban agglomeration. Based on the "one map" data and digital elevation model data of forest resource management in 2021, we evaluated and optimized landscape ecological pattern of the Pearl River Delta urban agglomeration by morphological spatial pattern analysis and minimum cumulative resistance model. The results showed that there were 435861 patches in the Pearl River Delta urban agglomeration that could be used as ecological source area, covering an area of 7346.60 km2 and accounting for 13.4% of the Pearl River Delta area. Thirty patches were selected as the ecological source area of the study area by using the area and patch importance index, covering an area of 2792.59 km2 and accounting for 5.1% of the Pearl River Delta area. The overall natural environment of the Pearl River Delta urban agglomeration was excellent. The ecological resistance level was small. The peripheral ecological resistance was low. The core ecological resistance was high. There was still a large room for adjustment of stand types and landscape patterns, which should be optimized by adjusting the composition and spatial distribution of tree species. The ecological network of the Pearl River Delta urban agglomeration was optimized with 30 ecological sources, 103 key ecological corridors, and 95 ecological nodes. The improvement rates of the optimized probability of connectivity index and integral index of connectivity index were 297.5% and 695.1%, respectively. The optimization results could effectively connect the ecological sources and spread the ecological service functions of ecological sources.

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OBJECTIVES: To investigate the difference in intestinal microbiota between preterm infants with neurodevelopmental impairment (NDI) and those without NDI. METHODS: In this prospective cohort study, the preterm infants who were admitted to the neonatal intensive care unit of Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region from September 1, 2019 to September 30, 2021 were enrolled as subjects. According to the assessment results of Gesell Developmental Scale at the corrected gestational age of 1.5-2 years, they were divided into two groups: normal (n=115) and NDI (n=100). Fecal samples were collected one day before discharge, one day before introducing solid food, and at the corrected gestational age of 1 year. High-throughput sequencing was used to compare the composition of intestinal microbiota between groups. RESULTS: Compared with the normal group, the NDI group had a significantly higher Shannon diversity index at the corrected gestational age of 1 year (P<0.05). The principal coordinate analysis showed a significant difference in the composition of intestinal microbiota between the two groups one day before introducing solid food and at the corrected gestational age of 1 year (P<0.05). Compared with the normal group, the NDI group had a significantly higher abundance of Bifidobacterium in the intestine at all three time points, a significantly higher abundance of Enterococcus one day before introducing solid food and at the corrected gestational age of 1 year, and a significantly lower abundance of Akkermansia one day before introducing solid food (P<0.05). CONCLUSIONS: There are significant differences in the composition of intestinal microbiota between preterm infants with NDI and those without NDI. This study enriches the data on the characteristics of intestinal microbiota in preterm infants with NDI and provides reference for the microbiota therapy and intervention for NDI in preterm infants.

Impacts of the COVID-19 pandemic on life expectancy at birth in Asia.

OBJECTIVE: To investigate the impact of the COVID-19 pandemic on life expectancy at birth (e0) for 51 Asian countries and territories from January 1, 2020 to December 31, 2021. METHOD: Based on age-sex-specific mortality used for estimating the changes in e0 for years 2019, 2020, and 2021 from the 2022 revision of the World Population Prospects, we employed Arriaga's discrete method to decompose changes in e0 into both absolute and relative contributions of changes in age-specific death rate, and further obtained the age-sex-specific contribution to changes in e0 by country/territory and period (i.e., 2019-2020 and 2020-2021) for Asia. FINDINGS: The COVID-19 pandemic reduced 1.66 years in e0 of the Asian population from 2019 to 2021, slightly lower than the world average of 1.74 years. South Asia had a high loss of 3.01 years, whereas Eastern Asia had almost no changes. Oman, Lebanon, India, Armenia, Azerbaijan, Indonesia, and the Philippines experienced a high loss of above 2.5 years in e0. Despite significant national and territorial variations, the decline of e0 in Asia was mostly from the age group of 60-79 years, followed by age groups of 80 + and 45-59 years; and age groups of children contributed little (i.e., 0-4 and 5-14 years old). Males suffered more losses than females in this pandemic. Asian nations saw less loss in e0 in the second year of the pandemic, i.e., 2020-2021, than in the first year, i.e., 2019-2020, but this recovery trend was not observed in Southern Asia and South-Eastern Asia. Countries from Central Asia and Western Asia, such as Kazakhstan, Armenia, Azerbaijan, Lebanon, and Oman, had extraordinarily more losses in e0 in the first year at ages around 70. CONCLUSION: The COVID-19 pandemic had significantly affected e0 of Asian populations, and most contribution to the reduction of e0 came from the three older age groups, 60-79 years, 80 + years, and 45-59 years, with great variations across countries/territories. Our findings could have important implications for development of more resilient public health systems in Asian societies with better policy interventions for vulnerable demographic groups.

Inhibition of ERK downregulates autophagy via mitigating mitochondrial fragmentation to protect SH-SY5Y cells from OGD/R injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is the main cause leading to high mortality and neurological disability in patients with cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Our previous study found that extracellular signal-regulated kinase (ERK) activation, dynamin-related protein1 (Drp1)/Mitofusin2 (Mfn2)-dependent mitochondrial dynamics imbalance, and excessive autophagy were involved in the mechanism of nerve injury after CA/CPR. However, the specific pathological signaling pathway is still unknown. This study aimed to explore the molecular function changes of ERK-Drp1/Mfn2-autophagy signaling pathway in SH-SY5Y cell oxygen-glucose deprivation/reoxygenation (OGD/R) model, to further clarify the pathophysiological mechanism of CIRI, and to provide a new strategy for cerebral protection after CIRI. METHODS: SH-SY5Y cells were pretreated with drugs 24 h before OGD/R. The Drp1 and Mfn2 knockdown were adopted small interfering RNAs. The overexpression of p-Drp1S616 and Mfn2 were used recombinant plasmids. The expression levels of mitochondrial dynamics proteins (p-Drp1, Drp1, Mfn2, Mfn1 and Opa1) and autophagy markers (LC3, Beclin1 and p62) were measured with the Western blotting. The mRNA levels after transfection were determined by PCR. Cell injury and viability were evaluated with released LDH activity and CCK8 assay kits. Mitochondria morphology and autophagosome were observed under transmission electron microscopy. Mitochondrial function was detected by the mitochondrial permeability transition pore assay kit. The co-expression of p-ERK, p-Drp1 and LC3 was assessed with multiple immunofluorescences. One-way analysis of variance followed by least significance difference post hoc analysis (for equal homogeneity) or Dunnett's T3 test (for unequal homogeneity) were used for statistical tests. RESULTS: ERK inhibitor-PD98059 (PD) protects SH-SY5Y cells from OGD/R-induced injury; while ERK activator-TPA had the opposite effect. Similar to autophagy inhibitor 3-MA, PD downregulated autophagy to improve cell viability; while autophagy activator-rapamycin further aggravated cell death. PD and Drp1-knockdown synergistically attenuated OGD/R-induced Drp1 activation, mPTP opening and cell injury; overexpression of Drp1S616E or ablating Mfn2 partly abolished the protective effects of PD. Multiple immunofluorescences showed that p-ERK, p-Drp1 and LC3 were co-expressed. CONCLUSION: Inhibition of ERK downregulates autophagy via reducing Drp1/Mfn2-dependent mitochondrial fragmentation to antagonize mitochondrial dysfunction and promotes cell survival in the SH-SY5Y cells OGD/R model. Video Abstract.

Use of narcotics and sedatives among very preterm infants in neonatal intensive care units in China: an observational cohort study.

Background: Narcotics and sedatives are widely used in neonatal intensive care units for very preterm infants. This study aimed to describe the current use of narcotics and/or sedatives among very preterm infants in Chinese neonatal intensive care units, with an emphasis on infants on invasive mechanical ventilation, and to investigate the association of exposure to narcotics and/or sedatives with neonatal outcomes. Methods: This was a retrospective observational cohort study that enrolled all infants born at 24+0-31+6 weeks and admitted to 57 tertiary neonatal intensive care units in the Chinese Neonatal Network in 2019. A multivariate logistic regression model was used to assess the association between narcotics and/or sedatives exposure and major neonatal outcomes. Results: Among 9,442 very preterm infants enrolled, 1,566 (16.6%) received at least one dose of narcotics or sedatives, 111 (1.2%) received only narcotics, 1,301 (13.8%) received sedatives solely, and 154 (1.6%) received both narcotics and sedatives during their hospital stay. Of 4,172 very preterm infants who underwent invasive mechanical ventilation, 1,117 (26.8%) received at least one dose of narcotics or sedatives, with 883 (21.2%) only received sedatives. Significant site variation of narcotics/sedatives use existed among hospitals, with the application rate ranging from 0-72.5% in individual hospital. The narcotics and/or sedatives use by very preterm infants was independently associated with increased risks for periventricular leukomalacia, severe retinopathy of prematurity, and bronchopulmonary dysplasia. Conclusions: Narcotic and/or sedative administration is relatively conservative for very preterm infants in Chinese neonatal intensive care units, with significant variation among hospitals. Since narcotic and sedative use might be related to adverse neonatal outcomes, a pressing and developing need for national quality improvement initiatives is seen with respect to pain/stress management for very preterm infants.