Broad-Spectrum Engineered Multivalent Nanobodies Against SARS-CoV-1/2.

SARS-CoV-2 Omicron sublineages escape most preclinical/clinical neutralizing antibodies in development, suggesting that previously employed antibody screening strategies are not well suited to counteract the rapid mutation of SARS-CoV-2. Therefore, there is an urgent need to screen better broad-spectrum neutralizing antibody. In this study, a comprehensive approach to design broad-spectrum inhibitors against both SARS-CoV-1 and SARS-CoV-2 by leveraging the structural diversity of nanobodies is proposed. This includes the de novo design of a fully human nanobody library and the camel immunization-based nanobody library, both targeting conserved epitopes, as well as the development of multivalent nanobodies that bind nonoverlapping epitopes. The results show that trivale B11-E8-F3, three nanobodies joined tandemly in trivalent form, have the broadest spectrum and efficient neutralization activity, which spans from SARS-CoV-1 to SARS-CoV-2 variants. It is also demonstrated that B11-E8-F3 has a very prominent preventive and some therapeutic effect in animal models of three authentic viruses. Therefore, B11-E8-F3 has an outstanding advantage in preventing SARS-CoV-1/SARS-CoV-2 infections, especially in immunocompromised populations or elderly people with high-risk comorbidities.

Discovery of CZL-046 with an (S)-3-Fluoropyrrolidin-2-one Scaffold as a p300 Bromodomain Inhibitor for the Treatment of Multiple Myeloma.

E1A binding protein (p300) is a promising therapeutic target for the treatment of cancer. Herein, we report the discovery of a series of novel inhibitors with an (S)-3-fluoropyrrolidin-2-one scaffold targeting p300 bromodomain. The best compound 29 (CZL-046) shows potent inhibitory activity of p300 bromodomain (IC50 = 3.3 nM) and antiproliferative activity in the multiple myeloma (MM) cell line (OPM-2 IC50 = 51.5 nM). 29 suppressed the mRNA levels of c-Myc and IRF4 and downregulated the expression of c-Myc and H3K27Ac. Compared to the lead compound 5, 29 exhibits significantly improved in vitro and in vivo metabolic properties. Oral administration of 29 with 30 mg/kg achieved a TGI value of 44% in the OPM-2 xenograft model, accompanied by good tolerability. The cocrystal structure of CREB binding protein bromodomain with 29 provides an insight into the precise binding mode. The results demonstrate that 29 is a promising p300 bromodomain inhibitor for the treatment of MM.

Robust non-fragile hybrid control for delayed uncertain singular impulsive jump systems based on improved impulse instant-dependent auxiliary functions method.

This article researches the issue of robust non-fragile hybrid control for delayed uncertain singular impulsive jump systems (USIMJSs). The key aim is to design non-fragile hybrid state feedback controllers (including a non-fragile normal state feedback controller and a non-fragile impulsive state feedback controller), which are insensitive to the uncertainties of gains of controllers and can provide sufficient tuning margins. The non-fragile normal state feedback controller can eliminate the internal impulses and overcome the external disturbances; the non-fragile impulsive state feedback controller can suppress the interference of external unstable impulses and restrain the instantaneous jumps caused by Markovian modes switching. By introducing impulse instant-dependent auxiliary functions, the improved impulse-time-dependent Lyapunov-Krasovskii functional is constructed, which can capture the information of the impulse instants and Markovian jump modes. Novel criteria of robust admissibilization for delayed USIMJSs are acquired under linear matrix inequalities framework. Lastly, the effectiveness of the derived algorithm and designed method is confirmed by simulation examples including a direct current motor-controlled inverted pendulum device and a Quarter-Car active suspension model.

The therapeutic effect of Yinqiaosan decoction against influenza A virus infection by regulating T cell receptor signaling pathway.

Background: Yinqiaosan decoction (YQSD), a traditional Chinese medicinal recipe, has been employed to treat influenza in China for approximately 300 years. Objective: Our study aimed to explore the mechanisms of YQSD against influenza via in vivo and in vitro experimental studies. Study design: and methods UHPLC-Q-TOF-MS/MS was utilized to examine the substances of the YQSD. The chemical components of YQSD detected by UHPLC-Q-TOF-MS/MS were used for network pharmacology analysis. The antiviral effect of YQSD in vivo was investigated. The potential mechanisms of YQSD in combating influenza, which were predicted from network pharmacology analysis, were validated in vitro. Results: By use of UHPLC-Q-TOF-MS/MS, 97 compounds were identified from YQSD. Network pharmacology analysis revealed that the therapeutic effect of YQSD against influenza may be associated with the regulation of T cell receptors (TCR) and Phosphoinositide 3-Kinase (PI3K)- protein kinase B (Akt) signaling pathways. Treatment with YQSD significantly prolonged the mean survival time of the mice and reduced lung injury due to the influenza A virus in vivo. It was discovered that YQSD efficiently inhibited the expression of inflammation-related cytokines. Moreover, YQSD has been found to significantly reduce the expression levels of cluster of differentiation 3 (CD3), monocyte chemoattractant protein-1 (MCP-1), and H1N1 virus nucleoprotein (NP), and prevent the decrease of epithelial cadherin (E-cadherin) protein. In addition, YQSD can inhibit the phosphorylation of the zeta chain of T cell receptor-associated protein kinase 70 (ZAP70) and PI3K proteins in vitro. Conclusion: The capacity of YQSD to suppress viral multiplication and inflammatory response by modulating T cell immunity may explain its effect against influenza viral pneumonia, which may involve the regulation of TCR and PI3K signaling pathways.

Corrigendum to "Global epidemiology of severe fever with thrombocytopenia syndrome virus in human and animals: a systematic review and meta-analysis" [The Lancet Regional Health - Western Pacific, Volume: 48 (2024) 101133].

[This corrects the article DOI: 10.1016/j.lanwpc.2024.101133.].

Components of dissolved organic carbon in relation to environmental factors in lakes along an altitudinal gradient in central China.

Dissolved organic carbon (DOC) is an important organic substance that affects biogeochemical processes and underwater light conditions in aquatic ecosystems. To explore altitudinal variations in DOC components and water quality, 66 surface water samples were collected along an altitudinal gradient (10-1857 m) in three regions of central China, including a montane region (Enshi Prefecture) and two floodplain regions (Dongting Lake Basin and Wuhan City). DOC components were measured using a three-dimensional excitation-emission matrix (3D-EEM) fluorescence spectroscopy, in conjunction with fluorescence regional integration (FRI) and fluorescence indices. Generally, lakes at high elevations (Enshi Prefecture) had higher DOC concentrations (a mean value of 6.43 mg L-1) than floodplain lakes in Dongting Basin (4.51 mg L-1) and Wuhan City (3.89 mg L-1). Fluorescence index (FI, a range of 1.37-1.92) and biological index (BIX, a range of 0.47-0.74) indicated that DOC mainly originated from allochthonous sources in the three regions. Enshi Prefecture had relatively lower FI and BIX values, suggestive of a larger contribution of allochthonous carbon in this montane region in comparison with the floodplain regions. Humic-like substances were more abundant than other four fluorescent components, including tyrosine-like, tryptophan-like, fulvic acid-like, microbial-like substances. Spearman rank correlation analyses showed that tryptophane-like substances were positively correlated with K+, Mg2+, and Na+, while humic-like substances were negatively correlated with these cations. Taken together, the results can improve our understanding on altitudinal variations in DOC components and potential driving forces.

High Current Efficiency Red Perovskite Light-Emitting Diodes Meeting Rec. 2020 Standard.

Cesium lead iodide light-emitting diodes (LEDs) are attractive for displays due to their Rec. 2020 red standard compliance. However, achieving high current efficiencies (CEs), which is important for displays, is challenging because their emission spectrum is near the tail of the photopic luminosity function. Substituting some iodine with bromine can improve CEs by enlarging the bandgap, but defects easily form in iodine-bromine mixed perovskites. Here, we successfully reduced defect formation by adding organic ammonium salts and zwitterions. The organic ammonium salts do not form low-dimensional perovskites under the hydrogen bonding interaction of zwitterions. Instead, they passivate the cesium vacancy by forming new hydrogen bonds after perovskite crystallization. This approach leads to a red perovskite LED with a high CE of 12.8 cd A-1 and a peak external quantum efficiency of 20.3%, meeting the Rec. 2020 standard. It can be extended to large-area devices (2500 mm2) without a significant efficiency loss.

SMEK1 promotes clear cell renal cell carcinoma progression via EGFR tyrosine-kinase dependent pathway.

Studying the mechanisms underlying clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, may address an unmet need in ccRCC-targeted drug research. Growing evidences indicate that protein phosphatase 4 (PP4) plays an important role in cancer biology. Here, we characterized the upregulation of PP4 core component SMEK1 in ccRCC using tissue microarrays and revealed that its high expression is closely associated with reduced patient survival. We then conducted cell function experiments and animal experiments to prove the tumor-promoting effect of SMEK1. Next, RNA-seq was performed to explore its underlying mechanism, and the results revealed that SMEK1-regulated genes were extensively involved in cell motility, and the canonical tyrosine kinase receptor EGFR was one of its targets. Moreover, we verified the regulatory effect of SMEK1 on EGFR and its downstream MAPK and AKT pathway through molecular experiments, in which erlotinib, a tyrosine kinase inhibitor, can partially block this regulation, demonstrating that SMEK1 mediates its effects dependent on the tyrosine kinase activity of EGFR. Mechanistically, SMEK1 bond to PRMT5 and facilitated PRMT5-mediated histone methylation to promote the transcription of EGFR. Furthermore, we studied the upstream regulators of SMEK1 and demonstrated that the transcription factor E2F1 could directly bind to the SMEK1 promoter by chromatin immunoprecipitation. Functionally, E2F1 could also induce ccRCC progression by manipulating the expression of SMEK1. Collectively, our findings demonstrate the overexpression of SMEK1 in ccRCC, and reveal a novel E2F1/SMEK1/PRMT5/EGFR-tyrosine-kinase-dependent pathway for ccRCC progression.

CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation-Mediated c-Myc Deubiquitylation to Facilitate Mutant TP53 Transcription.

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%-80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c-Myc, further promoting the stability of c-Myc via deacetylation-mediated inhibition of K48-linked ubiquitylation. Stably expressed c-Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p-AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD-L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c-Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

Global epidemiology of severe fever with thrombocytopenia syndrome virus in human and animals: a systematic review and meta-analysis.

Background: Since the initial identification of the Severe Fever with Thrombocytopenia Syndrome (SFTS) in ticks in rural areas of China in 2009, the virus has been increasingly isolated from a diverse array of hosts globally, exhibiting a rising trend in incidence. This study aims to conduct a systematic analysis of the temporal and spatial distribution of SFTS cases, alongside an examination of the infection rates across various hosts, with the objective of addressing public concerns regarding the spread and impact of the disease. Methods: In this systematic review and meta-analysis, an exhaustive search was conducted across multiple databases, including PubMed, Web of Science, Embase, and Medline, CNKI, WanFang, and CQVIP. The literature search was confined to publications released between January 1, 2009, and May 29, 2023. The study focused on collating data pertaining to animal infections under natural conditions and human infection cases reported. Additionally, species names were unified using the National Center for Biotechnology Information (NCBI) database. The notification rate, notification death rate, case fatality rate, and infection rates (or MIR) were assessed for each study with available data. The proportions were pooled using a generalized linear mixed-effects model (GLMM). Meta-regressions were conducted for subgroup analysis. This research has been duly registered with PROSPERO, bearing the registration number CRD42023431010. Findings: We identified 5492 studies from database searches and assessed 238 full-text studies for eligibility, of which 234 studies were included in the meta-analysis. For human infection data, the overall pooled notification rate was 18.93 (95% CI 17.02-21.05) per ten million people, the overall pooled notification deaths rate was 3.49 (95% CI 2.97-4.10) per ten million people, and the overall pooled case fatality rate was 7.80% (95% CI 7.01%-8.69%). There was an increasing trend in notification rate and deaths rate, while the case fatality rate showed a significant decrease globally. Regarding animal infection data, among 94 species tested, 48 species were found to carry positive nucleic acid or antibodies. Out of these, 14 species were classified under Arthropoda, while 34 species fell under Chordata, comprising 27 Mammalia and 7 Aves. Interpretation: This systematic review and meta-analysis present the latest global report on SFTS. In terms of human infections, notification rates and notification deaths rates are on the rise, while the case fatality rate has significantly decreased. More SFTSV animal hosts have been discovered than before, particularly among birds, indicating a potentially broader transmission range for SFTSV. These findings provide crucial insights for the prevention and control of SFTS on a global scale. Funding: None.

Endovascular thrombectomy with or without intravenous alteplase in large-core ischemic stroke: a systematic review and meta-analysis.

The role of bridging intravenous thrombolysis (IVT) with alteplase before endovascular thrombectomy (EVT) in treating large core ischemic stroke remains uncertain. We aimed to compare clinical outcomes and safety of EVT with or without bridging IVT in patients with anterior circulation large vessel occlusion (ACLVO) and baseline Alberta Stroke Program Early CT Score (ASPECTS) ≤ 5. We systematically searched PubMed, Web of Science, Cochrane Library, and Embase from inception until November 2023. The primary outcome was 90-day functional independence (modified Rankin Scale [mRS] 0-2). Secondary outcomes included 90-day independent ambulation (mRS 0-3), successful recanalization, any intracranial hemorrhage (ICH), symptomatic ICH (sICH) and 90-day mortality. A random-effects model was used for data pooling. Five high-quality studies, incorporating 2124 patients (41% treated with bridging IVT), were included. Across both unadjusted and adjusted analyses, no significant differences were found between the bridging IVT and EVT-alone groups in terms of functional independence (odds ratios [OR] = 1.36, 95% confidence interval [CI]: 0.90-2.07, P = 0.14; adjusted OR [aOR] = 1.19, 95% CI: 0.68-2.09, P = 0.53) or independent ambulation (OR = 1.14, 95% CI: 0.80-1.62, P = 0.47; aOR = 1.18, 95% CI: 1.00-1.39, P = 0.05) at 90 days. Furthermore, no differences were observed in successful recanalization, any ICH, sICH, and 90-day mortality between the two treatment groups. Bridging IVT exhibits similar functional and safety outcomes compared to EVT alone in ACLVO patients with baseline ASPECTS ≤ 5. Further research is warranted to confirm these findings.

Zoonotic spillover and extreme weather events drive the global outbreaks of airborne viral emerging infectious diseases.

Outbreaks of airborne viral emerging infectious diseases (EIDs) cause an increasing burden on global public health, particularly with a backdrop of intensified climate change. However, infection sources and drivers for outbreaks of airborne viral EIDs remain unknown. Here, we aim to explore the driving mechanisms of outbreaks based on the one health perspective. Outbreak information for 20 types of airborne viral EIDs was collected from the Global Infectious Disease and Epidemiology Network database and a systematic literature review. Four statistically significant and high-risk spatiotemporal clusters for airborne viral EID outbreaks were identified globally using multivariate scan statistic tests. There were 112 outbreaks with clear infection sources, and zoonotic spillover was the most common source (95.54%, 107/112). Since 1970, the majority of outbreaks occurred in healthcare facilities (24.82%), followed by schools (17.93%) and animal-related settings (15.93%). Significant associations were detected between the number of earthquakes, storms, duration of floods, and airborne viral EIDs' outbreaks using a case-crossover study design and multivariable conditional logistic regression. These findings implied that zoonotic spillover and extreme weather events are driving global outbreaks of airborne viral EIDs, and targeted prevention and control measures should be made to reduce the airborne viral EIDs burden.

Elevating Charge Transport Layer for Stable Perovskite Light-Emitting Diodes.

Ion migration is a major factor affecting the long term stability of perovskite light-emitting diodes (LEDs), which limits their commercialization potential. The accumulation of excess halide ions at the grain boundaries of perovskite films is a primary cause of ion migration in these devices. Here, it is demonstrated that the channels of ion migrations can be effectively impeded by elevating the hole transport layer between the perovskite grain boundaries, resulting in highly stable perovskite LEDs. The unique structure is achieved by reducing the wettability of the perovskites, which prevents infiltration of the upper hole-transporting layer into the spaces of perovskite grain boundaries. Consequently, nanosized gaps are formed between the excess halide ions and the hole transport layer, effectively suppressing ion migration. With this structure, perovskite LEDs with operational half-lifetimes of 256 and 1774 h under current densities of 100 and 20 mA cm-2 respectively are achieved. These lifetimes surpass those of organic LEDs at high brightness. It is further found that this approach can be extended to various perovskite LEDs, showing great promise for promoting perovskite LEDs toward commercial applications.

CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation.

Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.

CBF Profile in Computed Tomography Perfusion-Based AutoMIStar Software Predicts Futile Recanalization After Basilar Artery Thrombectomy.

Background: Futile recanalization (FR) remains a significant challenge in patients with acute basilar artery occlusion (BAO) following successful endovascular treatment (EVT). This study aimed to investigate the predictive value of computed tomography perfusion (CTP)-based software (AutoMIStar; Apollo) for FR among BAO patients undergoing EVT. Methods: We analyzed a prospectively maintained database to identify consecutive BAO patients who achieved successful recanalization (modified Thrombolysis in Cerebral Infarction grade ≥ 2b) after EVT between January 2020 and September 2022. Clinical characteristics and imaging parameters from non-contrast CT, CT angiography, and CTP-AutoMIStar were collected for analysis. FR was defined as an unfavorable outcome (modified Rankin Scale score > 3) at 90 days despite successful recanalization. Multivariable stepwise logistic regression analysis was performed to identify independent predictors of FR. Results: Of the 54 patients included in this study, 24 (44.4%) experienced FR. In the univariate analysis, admission National Institutes of Health Stroke Scale score, posterior circulation Acute Stroke Prognosis Early CT Score, Basilar Artery on Computed Tomography Angiography (BATMAN) score, hypoperfusion intensity ratio, and perfusion deficit volume in delay time (DT) > 4 s, DT > 6 s, DT > 8 s, and all cerebral blood flow (CBF) thresholds were associated with FR (all P < 0.05). In the multivariate analysis, perfusion deficit volume in CBF < 35% (adjusted odds ratio [aOR] = 1.105, 95% confidence interval [CI]: 1.004-1.215; P = 0.040) and BATMAN score (aOR = 0.662, 95% CI: 0.455-0.964; P = 0.031) remained independent predictors of FR. Conclusion: Perfusion deficit volume in CBF < 35% on CTP-AutoMIStar imaging maps and BATMAN score are independent predictors of FR after EVT in BAO patients. There is a significant positive correlation between perfusion deficit volume in CBF < 35% and the occurrence of FR.

Polyethyleneimine surface-modified silver-selenium nanocomposites for anti-infective treatment of wounds by disrupting biofilms.

Bacterial biofilm formation is associated with the pathogenicity of pathogens and poses a serious threat to human health and clinical therapy. Complex biofilm structures provide physical barriers that inhibit antibiotic penetration and inactivate antibiotics via enzymatic breakdown. The development of biofilm-disrupting nanoparticles offers a promising strategy for combating biofilm infections. Hence, polyethyleneimine surface-modified silver-selenium nanocomposites, Ag@Se@PEI (ASP NCs), were designed for synergistic antibacterial effects by destroying bacterial biofilms to promote wound healing. The results ofin vitroantimicrobial experiments showed that, ASP NCs achieved efficient antibacterial effects againstStaphylococcus aureus (S. aureus)andEscherichia coli (E. coli)by disrupting the formation of the bacterial biofilm, stimulating the outbreak of reactive oxygen species and destroying the integrity of bacterial cell membranes. Thein-vivobacterial infection in mice model showed that, ASP NCs further promoted wound healing and new tissue formation by reducing inflammatory factors and promoting collagen fiber formation which efficiently enhanced the antibacterial effect. Overall, ASP NCs possess low toxicity and minimal side effects, coupled with biocompatibility and efficient antibacterial properties. By disrupting biofilms and bacterial cell membranes, ASP NCs reduced inflammatory responses and accelerated the healing of infected wounds. This nanocomposite-based study offers new insights into antibacterial therapeutic strategies as potential alternatives to antibiotics for wound healing.

Patient with suspected co-infection of hemorrhagic fever with renal syndrome and malaria: a case report.

Background: Hemorrhagic fever with renal syndrome (HFRS) is a natural epidemic disease that can be caused by the Hantaan virus (HTNV). Malaria is caused by plasmodium and can be transmitted by a mosquito bite. The similar manifestations shared by these disorders pose a challenge for clinicians in differential diagnosis, in particular, coupled with a false-positive serological test. Case presentation: A 46-year-old man was admitted for fever and chills for over 10 days and was suspected of being co-infected with HFRS and malaria due to a history of travel to malaria-endemic areas and a positive HTNV-immunoglobulin M (IgM) test. Although leukocytosis, thrombocytopenia, renal injury, lymphocytosis, overexpression of interleukin-6, and procalcitonin were observed during the hospitalization, the hypotensive, oliguria, and polyuria phases of the HFRS course were not observed. Instead, typical symptoms of malaria were found, including a progressive decrease in erythrocytes and hemoglobin levels with signs of anemia. Furthermore, because the patient had no history of exposure to HFRS endemic areas, exposure to an HTNV-infected rodent, or a positive HTNV-IgG test, and false serological tests of IgM can be caused by various factors, the HFRS coinfection with malaria was ruled out. Conclusion: Misdiagnosis can be easily induced by a false serological test, in particular the IgM test which can be influenced by various factors. A combination of health history, epidemiology, physical examination, precise application of specific examinations involving tests of conventional laboratory parameters as well as well-accepted methods such as the immunochromatographic (ICG) test, real-time reverse transcription-polymerase chain reaction (PCR), and Western blot (WB), and acquaintance with disorders with similar manifestations will contribute to the precise diagnosis in clinical treatment.

Boron modification promoting electrochemical surface reconstruction of NiFe-LDH for efficient and stable freshwater/seawater oxidation catalysis.

Transition metal-based electrocatalysts generally take place surface reconstruction in alkaline conditions, but little is known about how to improve the reconstruction to a highly active oxyhydroxide surface for an efficient and stable oxygen evolution reaction (OER). Herein, we develop a strategy to accelerate surface reconstruction by combining boron modification and cyclic voltammetry (CV) activation. Density functional theory calculations and in-situ/ex-situ characterizations indicate that both B-doping and electrochemical activation can reduce the energy barrier and contribute to the surface evolution into highly active oxyhydroxides. The formed oxyhydroxide active phase can tune the electronic configuration and boost the OER process. The reconstructed catalyst of CV-B-NiFe-LDH displays excellent alkaline OER performance in freshwater, simulated seawater, and natural seawater with low overpotentials at 100 mA cm-2 (η100: 219, 236, and 255 mV, respectively) and good durability. This catalyst also presents outstanding Cl- corrosion resistance in alkalized seawater electrolytes. The CV-B-NiFe-LDH||Pt/C electrolyzer reveals prominent performance for alkalized freshwater/seawater splitting. This study provides a guideline for developing advanced OER electrocatalysts by promoting surface reconstruction.

The lactate-to-albumin ratio relationship with all-cause mortality in cerebral infarction patients: analysis from the MIMIC-IV database.

Objective: To examine the association of lactate-to-albumin ratio (LAR) with 30-day and 90-day mortality in patients with cerebral infarction admitted to the intensive care unit (ICU). Methods: In this retrospective observational study, 1,089 patients with cerebral infarction were recruited. The concentration of blood lactate and serum albumin on the first day of ICU admission were recorded. The relationship between LAR levels and mortality was evaluated through univariate and multivariate Cox regression analyses, four-knot multivariate restricted cubic spline regression, and Kaplan-Meier (KM) curves. Results: The overall 30-day and 90-day mortality rates in the entire cohort were 27.3 and 35.8%, respectively. KM analysis revealed a significant relationship between high LAR index and the risk of all-cause mortality (log-rank p < 0.001). Furthermore, multivariate Cox proportional risk analysis showed that the LAR index independently predicted the risk of 30-day mortality (HR: 1.38, 95% CI 1.15-1.64, p = 0.004) and 90-day mortality (HR: 1.53, 95% CI 1.32-1.77, p < 0.001) in the study population. Furthermore, a higher LAR exceeding 0.53 was positively correlated with the risk of 30-day and 90-day mortalities. Subsequent subgroup analyses demonstrated that LAR could predict the primary outcome. Conclusion: In summary, the LAR index is a reliable and independent predictor of increased mortality among critically ill patients suffering from cerebral infarction. Nonetheless, there is a need for additional comprehensive prospective studies to validate these findings.

A comprehensive study on the regulation of Compound Zaoren Granules on cAMP/CREB signaling pathway and metabolic disorder in CUMS-PCPA induced insomnia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood. AIM OF THE STUDY: The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles. METHODS: The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated. RESULTS: The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted. CONCLUSION: These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.