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Arachnoid cysts (ACs) are frequently encountered as incidental findings in the brain, with most cases being asymptomatic and not requiring intervention. However, severe brain malformations caused by ACs are rare. In this study, we describe the case of an 8-day-old female infant with a left mandibular mass that was diagnosed as an insular operculum, which has become disconnected and herniated into the parapharyngeal space through an incompletely ossified greater wing of the sphenoid, caused by a fetal Galassi Type III AC. The newborn also exhibited left hearing impairment, which did not improve at the 6-month follow-up after the cyst peritoneal shunt. This report highlights that ACs that manifest during the early fetal period may protrude from the cranial cavity through an unossified skull, potentially affecting the development of brain tissues.

ObjectiveThe aim of the study was to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP4i) on cardiac structure and function by cardiac magnetic resonance (CMR). Research Methods & Procedures: Database including PubMed, Cochrane library, Embase and SinoMed for clinical studies of DPP4i on cardiac structure and function by CMR were searched. Two authors extracted the data and evaluated study quality independently. Mean difference (MD) or standardized MD and 95% confidence intervals (CI) were used for continuous variables. Review Manager 5.3 was used to performed the analysis.ResultsTen references (nine studies) were included in this meta-analysis. Most of the studies were assessed as well quality by the assessment of methodological quality. For clinical control studies, the merged MD values of △LVEF by fixed-effect model and the pooled effect size in favor of DPP4i was 1.55 (95% CI 0.35 to 2.74, P=0.01). Compared with positive control drugs, DPP4i can significantly improve the LVEF (MD=4.69, 95%CI=2.70 to 6.69), but no such change compared to placebo (MD=-0.20, 95%CI=-1.69 to 1.29). For single-arm studies and partial clinical control studies that reported LVEF values before and after DPP4i treatment, random-effect model was used to combine effect size due to a large heterogeneity (Chi2 = 11.26, P=0.02, I2 = 64%), and the pooled effect size in favor of DPP4i was 2.31 (95% CI 0.01 to 4.62, P=0.05). DPP4i significantly increased the Peak filling rate (PFR) without heterogeneity when the effect sizes of two single-arm studies were combined (MD=31.98, 95% CI 13.69 to 50.27, P=0.0006; heterogeneity test: Chi2 = 0.56, P=0.46, I2 = 0%).ConclusionsIn summary, a possible benefit of DPP4i in cardiac function (as measured by CMR) was found, both including ventricular systolic function and diastolic function.

Abstract Background Atherosclerosis are well established risk factors for ischemic stroke, however the association between alcohol consumption and atherosclerosis is controversial. This study aims to explore the potential correlation between alcohol consumption and cerebral stenosis in patients with acute ischemic stroke and transient ischemic attack (TIA). Methods Nine hundreds and eighty-eight patients with first acute ischemic stroke attack or TIA were recruited retrospectively. Alcohol consumption was classified into five consumption categories (non-drinkers, occasional drinkers,

ObjectiveEvaluate the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) on cardiovascular and cerebrovascular diseases.MethodsArticles of SGLT2i on cardiovascular and cerebrovascular diseases were searched. Two authors independently screened the literature, extracted the data, assessed the quality of the study and performed statistical analyses using Review Manager 5.4.ResultsRandom-effect model was used to merge the OR values, and the pooled effect showed that SGLT2i had significant preventive effects on cardiovascular death (OR=0.76, 95%CI 0.64 to 0.89), myocardial infarction (OR=0.90, 95%CI 0.84 to 0.96), heart failure (OR=0.69, 95%CI 0.64 to 0.74) and all-cause mortality (OR=0.65, 95%CI 0.58 to 0.73). Empagliflozin, dapagliflozin and canagliflozin all reduced the incidence of heart failure (OR=0.72, 95%CI 0.64 to 0.82; OR=0.56, 95%CI 0.39 to 0.80; OR=0.62, 95%CI 0.53 to 0.73), but only dapagliflozin displayed a favorable effect on inhibiting stroke (OR=0.78, 95%CI 0.63 to 0.98). SGLT2i could prevent stroke (OR=0.86, 95%CI 0.75 to 0.99), heart failure (OR=0.63, 95%CI 0.56 to 0.70) and all-cause mortality (OR=0.64, 95%CI 0.57 to 0.72) compared to DPP-4i. Furthermore, SGLT2i could reduce the incidence of heart failure (OR=0.72, 95%CI 0.67 to 0.77) and cardiovascular death (OR=0.72, 95%CI 0.54 to 0.95) in patients with high-risk factors.ConclusionsSGLT2i affects cardiovascular death, myocardial infarction, heart failure and all-cause mortality. Only dapagliflozin displayed a favorable effect on inhibiting stroke. SGLT2i could prevent stroke, heart failure and all-cause mortality compared to DPP-4i. In addition, SGLT2i significantly reduced the development of heart failure and cardiovascular death in patients with high-risk factors.Systematic review registrationhttps://www.crd.york.ac.uk/prospero, identifier CRD42024532783.

Oil spill detection plays an important role in marine environment protection. The technique of global navigation satellite system-reflectometry (GNSS-R) has the advantage of a short revisit time, which could help with timely cleanup of marine oil pollution. The conventional GNSS-R oil spill detection algorithm can resolve only the dielectric constant of oil based on power ratio measurements, while that of water cannot be realized. This is because the dielectric constant of water is much larger than that of oil such that the range of the equation used in the conventional algorithm is inadequate. To resolve this problem, we proposed a new algorithm containing a new equation with a larger scope, which has never been applied previously to GNSS-R oil spill detection. We derived a lookup method to resolve the dielectric constant of both oil and water. To validate our method, a drone-borne GNSS-R experiment based on dual-frequency QZSS reflection signals was conducted on 17 July 2023 using experimental pools simulating oil spills. Raw IF data in the L1 and L5 bands, collected using dual antennas and a data recorder, were processed using a software-defined receiver to deduce the power ratios and SNR of the GNSS signals. Results showed that the proposed algorithm is capable of resolving the dielectric constants of the reflected surface. In addition, the L5 signal was found to provide more detail and better contrast than the L1 C/A signal.

Abstract The dual functions of TMEM16F as Ca2+-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug niclosamide to inhibit TMEM16F-dependent syncytia formation induced by SARS-CoV-2, we examined cryo-EM structures of TMEM16F with or without bound niclosamide or 1PBC, a known blocker of TMEM16A Ca2+-activated Cl- channel. Here, we report evidence for a lipid scrambling pathway along a groove harboring a lipid trail outside the ion permeation pore. This groove contains the binding pocket for niclosamide and 1PBC. Mutations of two residues in this groove specifically affect lipid scrambling. Whereas mutations of some residues in the binding pocket of niclosamide and 1PBC reduce their inhibition of TMEM16F-mediated Ca2+ influx and PS exposure, other mutations preferentially affect the ability of niclosamide and/or 1PBC to inhibit TMEM16F-mediated PS exposure, providing further support for separate pathways for ion permeation and lipid scrambling.

During cerebral ischemia/reperfusion (I/R) injury, oxidative stress and inflammation are major contributors to disability. Finding compounds that reduce oxidative stress, inflammation and strengthen the antioxidant defense system properties is one of the vital areas of research. Therefore, the present research aimed to evaluate the effects of resveratrol loaded in copolymer nanoparticles (RES.CP.NPs) on cerebral I/R injury in rats. After preparing and characterization RES.CP.NPs, these platforms were administered to cerebral I/R injured rats at a dose of 20 mg/kg after 2 h occlusion and the neurological disability scores were measured 24 h later. The content of malondialdehyde (MDA), glutathione (GSH), and catalase (CAT) activity as well as the expression levels of TNF-α, IL-10 and NF-κB-p65 in rat brain homogenates were measured. The RES.CP.NPs synthesized in the present study had a spherical structure with a zeta potential of −38 mV and a stable RES release for 72 h. Administration of RES.CP.NPs to I/R rats resulted in significant improvement in neurological disability score, decreased MDA levels, increased GSH content, increased CAT activity, decreased TNF-α expression, increased IL-10 expression, and decreased NF-κB-p65 expression (P

ABSTRACT Melioidosis is a severe and often fatal infectious disease caused by Burkholderia pseudomallei, which poses significant challenges due to its high mortality rate and frequent misdiagnosis. To effectively treat infected patients, especially in epidemic regions like Hainan with a high resistance rate to ceftazidime (CAZ), early diagnosis and resistance testing are critical. Here, we designed a strategy that combines RNase-HII-dependent PCR with lateral flow strip assay (LFSA) for simultaneous detection of B. pseudomallei and its CAZ resistance mutation. In this strategy, we utilized rhPCR technology to design specific primers with a C3-spacer modification. These primers target a 115-base pair region within the ORF2 of the B. pseudomallei type III secretion system gene cluster, as well as the P174L mutation in the penA gene, which is a major mutation associated with CAZ resistance in Hainan. The primers contain complementary RNA bases that can be hydrolyzed only in the presence of thermostable RNase-HII enzymes, facilitating subsequent PCR reactions. Additionally, we introduced two pairs of universal probes carrying fluorescein isothiocyanate (FITC) and biotin, as well as digoxin and biotin. The sequences of these universal probes align with specific regions of the primers, resulting in target products labeled with different tags. The resulting amplification products are then subjected to LFSA, where the presence of specific markers is visually interpreted based on color development. These markers flow to test line 1 (T1) and are captured by a fixed anti-FITC antibody, generating a red line that indicates the presence of B. pseudomallei. Similarly, the occurrence of a red line on test line 2 (T2), which is fixed with anti-digoxin antibodies, indicates the presence of the P174L mutation in B. pseudomallei. This protocol serves as an excellent tool for the rapid diagnosis of melioidosis and provides a basis for selecting appropriate antibiotic medication. It has the potential to revolutionize the diagnosis of melioidosis, particularly in resource-limited settings. Furthermore, this technique holds promise as a versatile tool for disease diagnosis in general. IMPORTANCE This study focused on the development of a reaction system using rhPCR to amplify a specific gene, ORF2, of B. pseudomallei and to identify the P174L mutation associated with increased drug resistance to ceftazidime (CAZ). The system incorporated universal primer probes and a simple temperature cycle reaction. The amplified products were then analyzed using lateral flow strip assay (LFSA) for strain identification and mutation interpretation. The developed system provides a reliable basis for diagnosing melioidosis and selecting appropriate drugs. Its potential impact is particularly significant in resource-limited settings where access to advanced diagnostic techniques is limited. This platform stands out for its simplicity, convenience, sensitivity, specificity, and portability. It shows promise as a point-of-care testing method for detecting single nucleotide polymorphism in genes associated with other diseases. By leveraging the advantages of this platform, researchers and healthcare professionals can potentially expand its use beyond melioidosis and apply it to the rapid detection of genetic variations in other disease-related genes.

Abstract Background Recently, several studies investigated the association between lactate dehydrogenase (LDH) level and the prognosis of urothelial carcinoma. However, no studies explored the role of serum LDH level in the survival of overall bladder cancer (BC). In this study, we intended to address the association of LDH level with the prognosis of BC. Methods 206 patients with BC were included in this study. The clinical data and blood samples of patients were collected. The overall survival and progression-free survival were used. Kaplan–Meier method and Log rank test were used to evaluate the effects of LDH level on the survival of BC. Univariate and multivariate Cox regression analyses were utilized to identify prognosis predictors of BC. Results Data indicated that serum LDH level in the BC patients was significantly higher than those in controls. In addition, this study suggested that serum LDH level was associated with T stage, N stage, tumor size, M stage, pathological type, and lymphovascular invasion. The Kaplan–Meier analysis found significant differences in the OS and PFS rate between lower and higher serum LDH level groups (LDH ≥ 225 U/L and

ObjectiveWe aimed to investigate the methodology, results, complications and stereotactic application accuracy of electrode implantation and its explanatory variables in stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-RFTC) for pediatric hypothalamic hamartoma.MethodsChildren with hypothalamic hamartoma who underwent robot-assisted SEEG-RFTC between December 2017 and November 2021 were retrospectively analyzed. The methodology, seizure outcome, complications, in vivo accuracy of electrode implantation and its explanatory variables were analyzed.ResultsA total of 161 electrodes were implanted in 28 patients with 30 surgeries. Nine electrodes not following the planned trajectories due to intraoperative replanning were excluded, and the entry point and target point errors of 152 electrodes were statistically analyzed. The median entry point error was 0.87 mm (interquartile range, 0.50–1.41 mm), and the median target point error was 2.74 mm (interquartile range, 2.01–3.63 mm). Multifactor analysis showed that whether the electrode was bent (b = 2.16, p

Abstract Background Alzheimer’s disease (AD), a type of neurodegeneration disease, is characterized by Aβ deposition and tangles of nerve fibers. Schisandrin is one of the main components of Fructus Schisandrae Chinensis. Researches showed that schisandrin can improve the cognitive impairment and memory of AD mice, but the specific mechanism has not been fully elucidated. Purpose The purpose of this study is to investigate the possible mechanism of schisandrin in improving AD pathology. Methods The Morris water maze test was executed to detect spatial learning and memory. Ultra performance liquid chromatography-Triple time of flight mass spectrometry (UPLC-Triple-TOF/MS)-based plasma lipidomics was used to study the changes of plasma lipids. Moreover, we measured the levels of protein and mRNA expression of APOE and ABCA1 in the rat brains and in BV2 microglia. Results Our study found that schisandrin could improve learning and memory, and reduce Aβ deposition in AD rats. Furthermore, we found that schisandrin can improve plasma lipid metabolism disorders. Therefore, we hypothesized schisandrin might act via LXR and the docking results showed that schisandrin interacts with LXRβ. Further, we found schisandrin increased the protein and mRNA expression of LXR target genes APOE and ABCA1 in the brain of AD rats and in BV2 microglia. Conclusion Our study reveals the neuroprotective effect and mechanism of schisandrin improves AD pathology by activating LXR to produce APOE and ABCA1.

The Drosha cleavage of a pri-miRNA defines mature microRNA sequence. Drosha cleavage at alternative positions generates 5’ isoforms (isomiRs) which have distinctive functions. To understand how pri-miRNA structures influence Drosha cleavage, we performed a systematic analysis of the maturation of endogenous pri-miRNAs and their variants both in vitro and in vivo. We show that in addition to previously known features, the overall structural flexibility of pri-miRNA impact Drosha cleavage fidelity. Internal loops and nearby G · U wobble pairs on the pri-miRNA stem induce the use of non-canonical cleavage sites by Drosha, resulting in 5’ isomiR production. By analysing patient data deposited in the Cancer Genome Atlas, we provide evidence that alternative Drosha cleavage of pri-miRNAs is a tunable process that responds to the level of pri-miRNA-associated RNA-binding proteins. Together, our findings reveal that Drosha cleavage fidelity can be modulated by altering pri-miRNA structure, a potential mechanism underlying 5’ isomiR biogenesis in tumours. Graphical Abstract

The authors reveal insights into miRNA tailing specificity of TENTs and their effect on miRNA levels by combinatory KOs of TENT2, TUT4 and TUT7. They show uridylation is linked to TENT2 and identify non-redundant functions between TUT4 and TUT7.

Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) protects vascular endothelium function through ameliorating autophagy in mesenteric arteries of metabolic syndrome (MS) rats. This study aimed to investigate the role of adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling in CIHH effect. Six-week-old male Sprague-Dawley rats were divided into control (CON), MS model, CIHH treatment (CIHH), and MS + CIHH groups. Serum pro-inflammatory cytokines were measured. The endothelium dependent relaxation (EDR), endothelial ultrastructure and autophagosomes were observed in mesenteric arteries. The expression of phosphor (p)-AMPKα, p-mTOR, autophagy-related and endoplasmic reticulum stress-related proteins, p-endothelial nitric oxide synthase, and cathepsin D were assayed. In MS rats, pro-inflammatory cytokines were increased, EDR was attenuated, and endothelial integrity was impaired. In addition, the expression level of p-AMPKα and cathepsin D was down-regulated, but the level of p-mTOR was up-regulated. While in MS + CIHH rats, all aforementioned abnormalities were ameliorated, and the beneficial effect of CIHH was cancelled by AMPKα inhibitor. In conclusion, AMPK-mTOR signaling pathway participates in the protection of CIHH on vascular endothelium of MS rats.

Summary: Canonical microRNA (miRNA) hairpins are processed by the RNase III enzymes Drosha and Dicer into ∼22 nt RNAs loaded into an Argonaute (Ago) effector. In addition, splicing generates numerous intronic hairpins that bypass Drosha (mirtrons) to yield mature miRNAs. Here, we identify hundreds of previously unannotated, splicing-derived hairpins in intermediate-length (∼50–100 nt) but not small (20–30 nt) RNA data. Since we originally defined mirtrons from small RNA duplexes, we term this larger set as structured splicing-derived RNAs (ssdRNAs). These associate with Dicer and/or Ago complexes, but generally accumulate modestly and are poorly conserved. We propose they contaminate the canonical miRNA pathway, which consequently requires defense against the siege of splicing-derived substrates. Accordingly, ssdRNAs/mirtrons comprise dominant hairpin substrates for 3′ tailing by multiple terminal nucleotidyltransferases, notably TUT4/7 and TENT2. Overall, the rampant proliferation of young mammalian mirtrons/ssdRNAs, coupled with an inhibitory molecular defense, comprises a Red Queen’s race of intragenomic conflict.

Alzheimer's disease (AD) is a latent and progressive neurodegenerative disease. Schisandra chinensis（Turcz.）Baill - Acorus tatarinowii Schott (Sc-At) are effective in treating neurological disorders.Purpose of this study is to explore the mechanism of Sc-At in AD treatment. First, untargeted ultra-performance liquid chromatography quadrupole-time of flight/mass spectrometer (UPLC-QTOF/MS) metabolomics was employed to detect the rat brain metabolism. Then, network pharmacology was used to determine the potential anti-AD targets. Bioinformatics, and molecular docking were conducted for further analysis. A MetScape study examined the association between differential metabolites and potential targets. Finally, the targeted ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) metabolomics and the potential protein activity studies were carried out to elucidate the mechanisms. The results showed that Sc-At improved the neuronal cell alignment disorder in hippocampal CA1 region of AD rats. In brain metabolomics, 30 differential metabolites were screened in the study model versus blank group. The network pharmacology analyzed 54 targets of Sc-At anti-AD where, 14 were correlated with amyloid β-protein (Aβ). Aromatase was selected as an important hub target having the best binding power in molecular docking simulation predictions and also correlated with Aβ. Further tests showed that the brain aromatase activity, and the downstream product 17β-Estradiol levels were elevated in AD rats treated with Sc-At. This work may provide new perspectives for the pharmacological effects and the action mechanisms of natural compounds extracts in treating AD progression.

Schisandrin is one of the main active compounds isolated from the fruit of Schisandrae chinensis Fructus, which is scientifically proven to have beneficial effects on Alzheimer’s disease (AD) treatment at the cellular and whole organism level. However, the oral availability of schisandrin is very low, thus implying that the underlying mechanism of therapeutic effect on AD treatment is yet to be clarified fully. Therefore, we speculated that the therapeutic effect of schisandrin on AD is mainly by regulating the imbalance of the gut microbiota (GM). In this study, behavioral experiments and H&E staining were used to confirm the pharmacological effects of schisandrin on rats with AD. 16S rDNA gene sequencing and feces, plasma, and brain metabolomics techniques were utilized to investigate the therapeutic effects and the underlying mechanisms of schisandrin on cognitive impairment in rats with AD. The results indicated that schisandrin improved cognitive impairment and hippocampal cell loss in rats. The UPLC-QTOF/MS-based metabolomics studies of the feces, plasma, and brain revealed that 44, 96, and 40 potential biomarkers, respectively, were involved in the treatment mechanism of schisandrin. Schisandrin improved the metabolic imbalance in rats with AD, and the metabolic changes mainly affected the primary bile acid biosynthesis, sphingolipid metabolism, glycerophospholipid metabolism, and unsaturated fatty acid biosynthesis. Schisandrin can improve the GM structure disorder and increase the abundance of beneficial bacteria in the gut of rats with AD. The predictive metagenomics analysis indicated that the altered GM was mainly involved in lipid metabolism, steroid hormone biosynthesis, arachidonic acid metabolism, biosynthesis of unsaturated fatty acids, and bacterial invasion of epithelial cells. Spearman’s correlation analysis showed a significant correlation between affected bacteria and metabolites in various metabolic pathways. Overall, the data underline that schisandrin improves the cognitive impairment in rats with AD by affecting the composition of the GM community, thus suggesting the potential therapeutic effect of schisandrin on the brain–gut axis in rats with AD at the metabolic level.

Alzheimer's disease is the most common form of dementia and affects human health. In this study, a classic prescription of Chinese Medicine Gan-Mai-Da-Zao decoction was used for treating Alzheimer's disease for the first time. Hence, firstly components of Gan-Mai-Da-Zao decoction in plasma were screened using UPLC-QTOF/MS. Then the MWM, HE and Metabolomics methods were used to examine the effect of Gan-Mai-Da-Zao decoction on Alzheimer's disease rats. The results showed 9 active components in ESI+ and 3 active components in ESI− of Gan-Mai-Da-Zao decoction in blood were identified, and Gan-Mai-Da-Zao decoction improved the learning and memory ability and pathological damage in Alzheimer's disease rats. 57 plasma metabolites and 21 urine metabolites were returned to normal in Alzheimer's disease model group after Gan-Mai-Da-Zao decoction treatment. 2-hydroxyestradiol, biotin, 4,6-dihydroxyquinoline, morphine-6-glucuronide, riboflavin can clearly distinguish between Gan-Mai-Da-Zao decoction-treated group and Alzheimer's disease model group involving steroid hormone biosynthesis, biotin metabolism, tryptophan metabolism, drug metabolism - cytochrome P450, and riboflavin metabolism pathway, which were the main pathways of Gan-Mai-Da-Zao decoction treatment on Alzheimer's disease. This study may bring a deeper understanding of the Alzheimer's disease-associated metabolic profile and the therapeutic mechanism of Gan-Mai-Da-Zao decoction on Alzheimer's disease.

Pediatric central nervous system (CNS) tumors are the second most common cancer diagnosis among children. Long noncoding RNAs (lncRNAs) emerge as critical regulators of gene expression, and they play fundamental roles in immune regulation. However, knowledge on epigenetic changes in lncRNAs in diverse types of pediatric CNS tumors is lacking. Here, we integrated the DNA methylation profiles of 2,257 pediatric CNS tumors across 61 subtypes with lncRNA annotations and presented the epigenetically regulated landscape of lncRNAs. We revealed the prevalent lncRNA methylation heterogeneity across pediatric pan-CNS tumors. Based on lncRNA methylation profiles, we refined 14 lncRNA methylation clusters with distinct immune microenvironment patterns. Moreover, we found that lncRNA methylations were significantly correlated with immune cell infiltrations in diverse tumor subtypes. Immune-related lncRNAs were further identified by investigating their correlation with immune cell infiltrations and potentially regulated target genes. LncRNA with methylation perturbations potentially regulate the genes in immune-related pathways. We finally identified several candidate immune-related lncRNA biomarkers (i.e., SSTR5-AS1, CNTN4-AS1, and OSTM1-AS1) in pediatric cancer for further functional validation. In summary, our study represents a comprehensive repertoire of epigenetically regulated immune-related lncRNAs in pediatric pan-CNS tumors, and will facilitate the development of immunotherapeutic targets.

3′ end of microRNAs binds to the PAZ domain of Argonaute (AGO) proteins. Here the authors show that terminal nucleotidyltransferases TUT4/7 and exonuclease DIS3L2 induce tailing and decay of 3’ end exposed-microRNAs in AGO PAZ mutant expressing- or cancer cells.

Background/Aims: Myocardial ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury is always characterized by Ca2+ overload, energy metabolism disorder and necrocytosis of cardiomyocytes. We showed previously that chronic intermittent hypobaric hypoxia (CIHH) improves cardiac function during I/R through improving cardiac glucose metabolism. However, the underlying cellular and molecular mechanisms of CIHH treatment improving energy metabolism in cardiomyocytes are still unclear. In this study, we determined whether and how CIHH protects cardiomyocytes from Ca2+ overload and necrocytosis through energy regulating pathway. Methods: Adult male Sprague-Dawley rats were randomly divided into two groups: control (CON) and CIHH group. CIHH rats received a hypobaric hypoxia simulating 5,000-m altitude for 28 days, 6 hours each day, in hypobaric chamber. Rat ventricular myocytes were obtained by enzymatic dissociation. The intracellular calcium concentration ([Ca2+]i) and cTnI protein expression were used to evaluate the degree of cardiomyocytes injury during and after H/R. The mRNA and protein expressions involved in cardiac energy metabolism were determined using quantitative PCR and Western blot techniques. PGC-1α siRNA adenovirus transfection was used to knock down PGC-1α gene expression of cardiomyocytes to determine the effect of PGC-1α in the energy regulating pathway. Results: H/R increased [Ca2+]i and cTnI protein expression in cardiomyocytes. CIHH treatment decreased [Ca2+]i (p< 0.01) and cTnI protein expression (p< 0.01) in cardiomyocytes after H/R. Both mRNA and protein expression of PGC-1α increased after CIHH treatment, which was reversed by PGC-1α siRNA adenovirus transfection. Furthermore, CIHH treatment increased the expression of HIF-1α, AMPK and p-AMPK in cardiomyocytes, and pretreatment with AMPK inhibitor dorsomorphin abolished the enhancement of PGC-1α protein expression in cardiomyocytes by CIHH (p< 0.01). In addition, PGC-1α knock down also abolished the increased protein level of GLUT4 (p< 0.01) and decreased the protein level of CPT-1b (p< 0.05) in cardiomyocytes by CIHH treatment. Conclusion: CIHH treatment could reduce the calcium overload and H/R injury in cardiomyocytes by up-regulating the expression of PGC-1α and regulating the energy metabolism of glucose and lipid. The HIF-1α-AMPK signaling pathway might be involved in the process.

Abstract The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer’s disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs—ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin—as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.

Summary: MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low-grade glioma patient samples indicate that the alternative-miR-9 has a potential role in tumor progression. Furthermore, we provide evidence that distortion of pri-miRNA stems induced by asymmetric internal loops correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing. : By studying the processing of pri-miR-9 family, Bofill-De Ros et al. demonstrate that the tertiary structure of pri-miRNA triggers alternative biogenesis. Drosha cleaves pri-miR-9-1 at an additional site because of its distorted and flexible lower stem, generating a 5′ isomiR that regulates a distinct set of genes in low-grade glioma. Keywords: primary miRNA, miR-9, isomiRs, Drosha, microprocessor, RNA structure, paralogs

As one of the major contemporary alternative medicines, traditional Chinese medicine (TCM) continues its influence in Chinese communities and has begun to attract the academic attention in the world of western medicine. This paper aims to examine Chinese herbal medicine (CHM), the essential branch of TCM, from both narrative and scientific perspectives. CHM is a traditional health practice originated from Chinese philosophy and religion, holding the belief of holism and balance in the body. With the development of orthodox medicine and science during the last centuries, CHM also seized the opportunity to change from traditional health practice to scientific drug discovery illustrated in the famous story of the herb-derived drug artemisinin. However, hindered by its culture and founding principles, CHM faces the questions of the research paradigm posed by the convention of science. To address these questions, we discussed two essential questions concerning the relationship of CHM and science, and then upheld the paradigm of methodological reductionism in scientific research. Finally, the contemporary narrative of CHM in the 21st century was discussed in the hope to preserve this medical tradition in tandem with scientific research.

Cells frequently simultaneously express RNAs and cognate antisense transcripts without necessarily leading to the formation of RNA duplexes. Here, we present a novel transcriptome-wide experimental approach to ascertain the presence of accessible double-stranded RNA structures based on sequencing of RNA fragments longer than 18 nucleotides that were not degraded by single-strand cutting nucleases. We applied this approach to four different cell lines with respect to three different treatments (native cell lysate, removal of proteins, and removal of ribosomal RNA and proteins). We found that long accessible RNA duplexes were largely absent in native cell lysates, while the number of RNA duplexes was dramatically higher when proteins were removed. The majority of RNA duplexes involved ribosomal transcripts. The duplex formation between different non-ribosomal transcripts appears to be largely of a stochastic nature. These results suggest that cells are—via RNA-binding proteins—mostly devoid of long RNA duplexes, leading to low “noise„ in the molecular patterns that are utilized by the innate immune system. These findings have implications for the design of RNA interference (RNAi)-based therapeutics by imposing structural constraints on designed RNA complexes that are intended to have specific properties with respect to Dicer cleavage and target gene downregulation.

The detailed lifestyle of microorganisms in deep-sea brine environments remains largely unexplored. Using a carefully calibrated genome binning approach, we reconstructed partial to nearly-complete genomes of 51 microorganisms in biofilms from the Thuwal cold seep brine pool of the Red Sea. The recovered metagenome-assembled genomes (MAGs) belong to six different phyla: Actinobacteria, Proteobacteria, Candidatus Cloacimonetes, Candidatus Marinimicrobia, Bathyarchaeota and Thaumarchaeota. By comparison with close relatives of these microorganisms, we identified a number of unique genes associated with organic carbon metabolism and energy generation. These genes included various glycoside hydrolases, nitrate and sulfate reductases, putative bacterial microcompartment biosynthetic clusters (BMC), and F420H2 dehydrogenases. Phylogenetic analysis suggested that the acquisition of these genes probably occurred through horizontal gene transfer (HGT). Metatranscriptomics illustrated that glycoside hydrolases are among the most highly expressed genes. Our results suggest that the microbial inhabitants are well adapted to this brine environment, and anaerobic carbohydrate consumption mediated by glycoside hydrolases and electron transport systems (ETSs) is a dominant process performed by microorganisms from various phyla within this ecosystem.

Protein-ligand recognition plays key roles in many biological processes. One of the most fascinating questions about protein-ligand recognition is to understand its underlying mechanism, which often results from a combination of induced fit and conformational selection. In this study, we have developed a three-pronged approach of Markov State Models, Molecular Dynamics simulations, and flux analysis to determine the contribution of each model. Using this approach, we have quantified the recognition mechanism of the choline binding protein (ChoX) to be ∼90% conformational selection dominant under experimental conditions. This is achieved by recovering all the necessary parameters for the flux analysis in combination with available experimental data. Our results also suggest that ChoX has several metastable conformational states, of which an apo-closed state is dominant, consistent with previous experimental findings. Our methodology holds great potential to be widely applied to understand recognition mechanisms underlining many fundamental biological processes.

Acute coronary artery diseases have been observed to be associated with some meteorological variables. But few of the previous studies considered autocorrelated outcomes. Electrocardiography is a widely used tool in the initial diagnosis of acute cardiovascular events, and emergency electrocardiography counts were shown to be highly correlated with acute myocardial infarction in our pilot study, hence a good index of prediction for acute cardiovascular events morbidity among the elderly. To indirectly assess the impact of temperature on the number of acute cardiovascular events, we studied the association between temperature and emergency electrocardiography counts while considering autocorrelated nature of the response variables.We collected daily emergency electrocardiography counts for elderly females and males in Shanghai from 2007 to middle 2012, and studied temperature and other effects on these data using Mixed Generalized Additive Modelling methods. Delayed temperature effect distribution was described as the weighted average of the temperatures within 3 days before the counts was recorded. Autoregressive random effects were used in the model to describe the autocorrelation of the response variables.Temperature effect was observed to be piecewise linearly associated with the logarithm of emergency electrocardiography counts. The optimal weights of the delayed temperature effect distribution were obtained from the model estimation. The weights of lag-1 were the maximums, significantly greater than the weights of lag-2 and lag-3 for both females and males. The model showed good fit with R2 values of 0.860 for females and 0.856 for males.From the mixed generalized additive model, we infer that during cold and mild days, the number of emergency electrocardiography counts increase as temperature effect decreases, while during hot days, counts increase as temperature effect increases. Similar properties could be inferred for the occurrence of cardiovascular events.

Objective: We aimed to investigate the methodology, results, complications and stereotactic application accuracy of electrode implantation and its explanatory variables in stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-RFTC) for pediatric hypothalamic hamartoma. Methods: Children with hypothalamic hamartoma who underwent robot-assisted SEEG-RFTC between December 2017 and November 2021 were retrospectively analyzed. The methodology, seizure outcome, complications, in vivo accuracy of electrode implantation and its explanatory variables were analyzed. Results: A total of 161 electrodes were implanted in 28 patients with 30 surgeries. Nine electrodes not following the planned trajectories due to intraoperative replanning were excluded, and the entry point and target point errors of 152 electrodes were statistically analyzed. The median entry point error was 0.87 mm (interquartile range, 0.50--1.41 mm), and the median target point error was 2.74 mm (interquartile range, 2.01--3.63 mm). Multifactor analysis showed that whether the electrode was bent (b = 2.16, p < 0.001), the length of the intracranial electrode (b = 0.02, p = 0.049), and the entry point error (b = 0.337, p = 0.017) had statistically significant effects on the target error. During follow-up (mean duration 31 months), 27 of 30 (90%) procedures were seizure-free. The implantationrelated complication rate was 2.6% (4/152), and the major complication rate in all procedures was 6.7% (2/30). Conclusion: Robot-assisted SEEG-RFTC is a safe, effective and accurate procedure for pediatric hypothalamic hamartoma. Explanatory variables significantly associated with the target point localization error at multivariate analysis include whether the intracranial electrode is bent, the intracranial electrode length and the entry point error. [ABSTRACT FROM AUTHOR]

Abstract Fluorinated or fluoroalkylated alcohols are common structural motifs in biologically active molecules, natural products, and pharmaceuticals. However, pentafluorosulfanyl (SF5) alcohols, a unique class of SF5 compounds that serve as synthetically valuable building blocks, are difficult to prepare with current methodologies. In this article, we present a single-step, metal-free, and photo-induced hydroxypentafluorosulfanylation of styrenes or α,β-unsaturated esters/amide, producing a series of structurally diverse pentafluorosulfanyl alcohols with up to 89% yields. This reaction is mild and operationally simple, using molecular oxygen as the hydroxy source. The protocol is suitable for a wide range of alkenes, including natural products and drug molecule derivatives. The formed SF5 alcohol units can be readily converted into diverse functionalized SF5 compounds, such as α-SF5 ketones, SF5 diols, and SF5 cyclic carbonates. The potential applications of these SF5 compounds in pharmaceutical and material sciences are vast, making this research a step forward in the field.