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.

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.

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.

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.

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.

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.

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.

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.

Habitat-Based Radiomics for Predicting EGFR Mutations in Exon 19 and 21 From Brain Metastasis.

RATIONALE AND OBJECTIVES: To explore and externally validate habitat-based radiomics for preoperative prediction of epidermal growth factor receptor (EGFR) mutations in exon 19 and 21 from MRI imaging of non-small cell lung cancer (NSCLC)-originated brain metastasis (BM). METHODS: A total of 170, 62 and 61 patients from center 1, center 2 and center 3, respectively were included. All patients underwent contrast-enhanced T1-weighted (T1CE) and T2-weighted (T2W) MRI scans. Radiomics features were extracted from the tumor active (TA) and peritumoral edema (PE) regions in each MRI slice. The most important features were selected by the least absolute shrinkage and selection operator regression to develop radiomics signatures based on TA (RS-TA), PE (RS-PE) and their combination (RS-Com). Receiver operating characteristic (ROC) curve analysis was performed to access performance of radiomics models for both internal and external validation cohorts. RESULTS: 10, four and six most predictive features were identified to be strongly associated with the EGFR mutation status, exon 19 and exon 21, respectively. The RSs derived from the PE region outperformed those from the TA region for predicting the EGFR mutation, exon 19 and exon 21. The RS-Coms generated the highest performance in the primary training (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.955 vs. 0.946 vs. 0.928), internal validation (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.879 vs. 0.819 vs. 0.882), external validation 1 (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.830 vs. 0.825 vs. 0.822), and external validation 2 (AUCs, RS-EGFR-Com vs. RS-exon 19-Com vs. RS-exon 21-Com, 0.812 vs. 0.818 vs. 0.800) cohort. CONCLUSION: The developed habitat-based radiomics model can be used to accurately predict the EGFR mutation subtypes, which may potentially guide personalized treatments for NSCLC patients with BM.

SMEK1 ablation promotes glucose uptake and improves obesity-related metabolic dysfunction via AMPK signaling pathway.

Obesity has become a major risk of global public health. SMEK1 is also known as a regulatory subunit of protein phosphatase 4 (PP4). Both PP4 and SMEK1 have been clarified in many metabolic functions, including the regulation of hepatic gluconeogenesis and glucose transporter gene expression in yeast. Whether SMEK1 participates in obesity and the broader metabolic role in mammals is unknown. Thus, we investigated the function of SMEK1 in white adipose tissue and glucose uptake. GWAS/GEPIA/GEO database was used to analyze the correlation between SMEK1 and metabolic phenotypes/lipid metabolism-related genes/obesity. Smek1 KO mice were generated to identify the role of SMEK1 in obesity and glucose homeostasis. Cell culture and differentiation of stromal-vascular fractions (SVFs) and 3T3-L1 were used to determine the mechanism. 2-NBDG was used to measure the glucose uptake. Compound C was used to confirm the role of AMPK. We elucidated that SMEK1 was correlated with obesity and adipogenesis. Smek1 deletion enhanced adipogenesis in both SVFs and 3T3-L1. Smek1 KO protected mice from obesity and had protective effects on metabolic disorders, including insulin resistance and inflammation. Smek1 KO mice had lower levels of fasting serum glucose. We found that SMEK1 ablation promoted glucose uptake by increasing p-AMPKα(T172) and the transcription of Glut4 when the effect on AMPK-regulated glucose uptake was due to the PP4 catalytic subunits (PPP4C). Our findings reveal a novel role of SMEK1 in obesity and glucose homeostasis, providing a potential new therapeutic target for obesity and metabolic dysfunction.NEW & NOTEWORTHY Our study clarified the relationship between SMEK1 and obesity for the first time and validated the conclusion in multiple ways by combining available data from public databases, human samples, and animal models. In addition, we clarified the role of SMEK1 in glucose uptake, providing an in-depth interpretation for the study of its function in glucose metabolism.

Characteristics of the Hantaan virus complicated with SARS-CoV2 infection: A case series report.

Background: Coinfection poses a persistent threat to global public health due to its severe effect on individual-level infection risk and disease outcome. Coinfection of SARS-CoV2 with one or more pathogens has been documented. Nevertheless, this virus co-infected with the Hantaan virus (HTNV) is rarely reported. Case summary: Here, we presented three cases of HTNV complicated with SARS-CoV2 infection. Not only the conditions including general clinical manifestations, immune and inflammation parameters fluctuation presented in the single infection of HTNV or SARS-CoV2 can be found, but also the unexpected manifestations have attracted our attention that presented as more symptoms of HTNV infection including exudative changes in both lungs and an amount of bilateral pleural effusion as well as bilateral kidney enlargement rather than typical viral pneumonia in SARS-CoV2 infection. Fortunately, the conditions of patients gradually return to normal which is beneficial from the antiviral treatment, hemodialysis, and various supportive therapies including anti-inflammation, liver and gastric mucosa protection. Conclusion: Unexpected manifestations of coinfection patients present herein may be associated with multiple factors including virus load, competition or antagonism among antigens, and the susceptibility of target cells to the various pathogens, even though the pathogenesis of HTNV and SARS-CoV2 remains to be elucidated. Given that these two viruses have posed a profound influence on the socioeconomic, healthcare system worldwide, and the threat of coinfection to public health, it is warranted for clinicians, public health authorities, and infectious disease researchers to have a high index of consideration for patients co-infected with HTNV and SARS-CoV2.

PSMB2 plays an oncogenic role in glioma and correlates to the immune microenvironment.

There has been an upward trend in the incidence of glioma, with high recurrence and high mortality. The beta subunits of the 20S proteasome are encoded by the proteasome beta (PSMB) genes and may affect the proteasome's function in glioma, assembly and inhibitor binding. This study attempted to reveal the function of the proliferation and invasion of glioma cells, which is affected by proteasome 20S subunit beta 2 (PSMB2). We subjected the data downloaded from the TCGA database to ROC, survival, and enrichment analyses. After establishing the stable PSMB2 knockdown glioma cell line. We detect the changes in the proliferation, invasion and migration of glioma cells by plate colony formation assay, transwell assay, wound healing assay and flow cytometry and PSMB2 expression was verified by quantitative PCR and Western blotting to identify the mRNA and protein levels. PSMB2 expression was higher in glioma tissues, and its expression positively correlated with poor prognosis and high tumor grade and after PSMB2 knockdown, the proliferation, invasion and migration of glioma cells were weakened.

Improved Prediction of Epidermal Growth Factor Receptor Status by Combined Radiomics of Primary Nonsmall-Cell Lung Cancer and Distant Metastasis.

OBJECTIVES: This study aimed to investigate radiomics based on primary nonsmall-cell lung cancer (NSCLC) and distant metastases to predict epidermal growth factor receptor (EGFR) mutation status. METHODS: A total of 290 patients (mean age, 58.21 ± 9.28) diagnosed with brain (BM, n = 150) or spinal bone metastasis (SM, n = 140) from primary NSCLC were enrolled as a primary cohort. An external validation cohort, consisting of 69 patients (mean age, 59.87 ± 7.23; BM, n = 36; SM, n = 33), was enrolled from another center. Thoracic computed tomography-based features were extracted from the primary tumor and peritumoral area and selected using the least absolute shrinkage and selection operator regression to build a radiomic signature (RS-primary). Contrast-enhanced magnetic resonance imaging-based features were calculated and selected from the BM and SM to build RS-BM and RS-SM, respectively. The RS-BM-Com and RS-SM-Com were developed by integrating the most important features from the primary tumor, BM, and SM. RESULTS: Six computed tomography-based features showed high association with EGFR mutation status: 3 from intratumoral and 3 from peritumoral areas. By combination of features from primary tumor and metastases, the developed RS-BM-Com and RS-SM-Com performed well with areas under curve in the training (RS-BM-Com vs RS-BM, 0.936 vs 0.885, P = 0.177; RS-SM-Com vs RS-SM, 0.929 vs 0.843, P = 0.003), internal validation (RS-BM-Com vs RS-BM, 0.920 vs 0.858, P = 0.492; RS-SM-Com vs RS-SM, 0.896 vs 0.859, P = 0.379), and external validation (RS-BM-Com vs RS-BM, 0.882 vs 0.805, P = 0.263; RS-SM-Com vs RS-SM, 0.865 vs 0.816, P = 0.312) cohorts. CONCLUSIONS: This study indicates that the accuracy of detecting EGFR mutations significantly enhanced in the presence of metastases in primary NSCLC. The established radiomic signatures from this approach may be useful as new predictors for patients with distant metastases.

Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors.

The ubiquitous methyltransferases employing SAM as the methyl donor have emerged as potential targets in many disease treatments, especially in anticancer. Therefore, developing SAM-competitive inhibitors of methyltransferases is of great interest to the drug research. To explore this direction, herein, we rationally designed a series of nucleoside derivatives as potent PRMT5 inhibitors with novel scaffold. The representative compounds A2 and A8 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other PRMTs and PKMTs. Further cellular experiments revealed that compounds A2 and A8 potently reduced the level of sDMA and inhibited the proliferation of Z-138 and MOLM-13 cell lines by inducing apoptosis. Moreover, compounds A8 which had favorable pharmacokinetic properties exhibited potent antitumor efficacy without the loss of body weight in a subcutaneous MOLM-13 xenograft model. In summary, our efforts provided a series of novel nucleoside analogs as potent PRMT5 inhibitors and may also offer a new strategy to develop SAM analogs as other methyltransferases' inhibitors.

[Characterization and identification of chemical constituents from Schizonepetae Spica based on UHPLC-Q-TOF-MS/MS technique].

The chemical constituents of Schizonepetae Spica were qualitatively analyzed by UHPLC-Q-TOF-MS/MS. An Agilent poroshell 120 SB-C_(18) column(3.0 mm×100 mm, 2.7 µm) was used for gradient elution with 0.1% formic acid water(A)-acetonitrile(B) solution as mobile phase at the flow rate of 0.4 mL·min~(-1) and column temperature of 45 ℃. The data were collected by scanning in positive and negative ion modes, and the compounds were identified by comparison of reference materials and PeakView software. Ninety-seven compounds were identified from Schizonepetae Spica, including 28 flavonoids, 23 phenolic acids, 23 fatty acids, 15 terpenoids, and 8 other compounds. The UHPLC-Q-TOF-MS/MS method established in this study can identify the chemical components of Schizonepetae Spica rapidly, accurately, and comprehensively, and provide a basis for the basic study of pharmacodynamic substances of Schizonepetae Spica.

Epidemiology and risk factors of nosocomial infections in a Chinese tertiary-care hospital: a 10-year retrospective case-control study.

BACKGROUND: Nosocomial infections (NIs) are the most frequent adverse events among patients and cause a heavy burden on both health and economics. To investigate epidemiology of NIs and identify risk factors for NIs by integrating continuous long-term surveillance data. METHODS: We performed an observational study among inpatients at the Chinese People's Liberation Army General Hospital between January 1, 2010, and December 31, 2019. Infection rates, mortality rates and percentage of NIs were calculated. Trends of yearly infection rates by pathogens were assessed using Mann-Kendall trend test. Controls were matched to cases (2:1) by age (±2 years), sex, admission date (±1 year) and admission diagnosis, and conditional logistic regression was used to estimate odds ratios. RESULTS: A total of 1,534,713 inpatients were included among which 33,468 NIs cases occurred with an infection rate of 2.18%. The most common infections were respiratory system infection (52.22%), bloodstream infection (17.60%), and genitourinary system infection (15.62%). Acinetobacter. baumannii (9.6%), Klebsiella. pneumoniae (9.0%), Pseudomonas. aeruginosa (8.6%), Escherichia. coli (8.6%) and Enterococcus. faecium (5.0%) were the top five isolated pathogens. Infection rates of K. pneumoniae and carbapenems-resistant K. pneumoniae significantly increased. Prior ICU stay, surgery, any device placement (including central venous catheter, mechanical ventilation, urinary catheter, and tracheotomy), prior use of triple or more antibiotics combinations, carbapenem, and ß-Lactamase inhibitors were significantly associated with NIs. CONCLUSION: K. pneumoniae has the potential to cause a clinical crisis with increasing infection rates and carbapenem resistance. Clinical management of invasive operations and antibiotics use should be further strengthened.

Human Bocavirus 1 NP1 acts as an ssDNA-binding protein to help AAV2 DNA replication and cooperates with RPA to regulate AAV2 capsid expression.

Adeno-associated virus (AAV) requires co-infection with helper virus for efficient replication. We previously reported that Human Bocavirus 1 (HBoV1) genes, including NP1, NS2, and BocaSR, were critical for AAV2 replication. Here, we first demonstrate the essential roles of the NP1 protein in AAV2 DNA replication and protein expression. We show that NP1 binds to single-strand DNA (ssDNA) at least 30 nucleotides (nt) in length in a sequence-independent manner. Furthermore, NP1 colocalized with the BrdU-labeled AAV2 DNA replication center, and the loss of the ssDNA-binding ability of NP1 by site-directed mutation completely abolished AAV2 DNA replication. We used affinity-tagged NP1 protein to identify host cellular proteins associated with NP1 in cells cotransfected with the HBoV1 helper genes and AAV2 duplex genome. Of the identified proteins, we demonstrate that NP1 directly binds to the DBD-F domain of the RPA70 subunit with a high affinity through the residues 101-121. By reconstituting the heterotrimer protein RPA in vitro using gel filtration, we demonstrate that NP1 physically associates with RPA to form a heterologous complex characterized by typical fast-on/fast-off kinetics. Following a dominant-negative strategy, we found that NP1-RPA complex mainly plays a role in expressing AAV2 capsid protein by enhancing the transcriptional activity of the p40 promoter. Our study revealed a novel mechanism by which HBoV1 NP1 protein supports AAV2 DNA replication and capsid protein expression through its ssDNA-binding ability and direct interaction with RPA, respectively.IMPORTANCERecombinant adeno-associated virus (rAAV) vectors have been extensively used in clinical gene therapy strategies. However, a limitation of these gene therapy strategies is the efficient production of the required vectors, as AAV alone is replication-deficient in the host cells. HBoV1 provides the simplest AAV2 helper genes consisting of NP1, NS2, and BocaSR. An important question regarding the helper function of HBoV1 is whether it provides any direct function that supports AAV2 DNA replication and protein expression. Also of interest is how HBoV1 interplays with potential host factors to constitute a permissive environment for AAV2 replication. Our studies revealed that the multifunctional protein NP1 plays important roles in AAV2 DNA replication via its sequence-independent ssDNA-binding ability and in regulating AAV2 capsid protein expression by physically interacting with host protein RPA. Our findings present theoretical guidance for the future application of the HBoV1 helper genes in the rAAV vector production.

Increasing evolution, prevalence, and outbreaks for rift valley fever virus in the process of breaking geographical barriers.

BACKGROUND: Rift valley fever (RVF) is listed as one of prioritized diseases by WHO. This study aims to describe RVF virus' landscape distribution globally, and to insight dynamics change of its evolution, prevalence, and outbreaks in the process of breaking geographical barriers. METHODS: A systematic literature review and meta-analyses was conducted to estimate RVF prevalence by hosts using a random-effect model. Molecular clock-based phylogenetic analyses were performed to estimate RVF virus nucleotide substitution rates using nucleotide sequences in NCBI database. RVF virus prevalence, nucleotide substitution rates, and outbreaks were compared before and after breaking geographical barriers twice, respectively. RESULTS: RVF virus was reported from 26 kinds of hosts covering 48 countries from 1930 to 2022. Since RVF broke geographical barriers, (1) nucleotide substitution rates significantly increased after firstly spreading out of Africa in 2000, (2) prevalence in humans significantly increased from 1.92 % (95 % CI: 0.86-3.25 %) to 3.03 % (95 % CI: 2.09-4.12 %) after it broke Sahara Desert geographical barriers in 1977, and to 5.24 % (95 % CI: 3.81-6.82 %) after 2000, (3) RVF outbreaks in humans and the number of wildlife hosts presented increasing trends. RVF virus spillover may exist between bats and humans, and accelerate viral substitution rates in humans. During outbreaks, the RVF virus substitution rates accelerated in humans. 60.00 % RVF outbreaks occurred 0-2 months after floods and (or) heavy rainfall. CONCLUSION: RVF has the increasing risk to cause pandemics, and global collaboration on "One Health" is needed to prevent potential pandemics.