Peripheral Control of the Assembly and Chirality of Anion-Based Octanuclear Cubes by Cation-π Networks.

Self-assembly of sophisticated polyhedral cages has drawn much attention because of their elaborate structures and potential applications. Herein, we report the anion-coordination-driven assembly of the first A8L12 (A = anion, L = ligand) octanuclear cubic structures from phosphate anion and p-xylylene-spaced bis-bis(urea) ligands via peripheral templating of countercations (TEA+ or TPA+). By attaching terminal aryl rings (phenyl or naphthyl) to the ligand through a flexible (methylene) linker, these aryls actively participate in the formation of plenty of "aromatic pockets" for guest cation binding. As a result, multiple peripheral guests (up to 22) of suitable size are bound on the faces and vertices of the cube, forming a network of cation-π interactions to stabilize the cube structure. More interestingly, when chiral ligands were used, either diastereomers of mixed Λ- and Δ-configurations (with TEA+ countercation) for the phosphate coordination centers or enantiopure cubes (with TPA+) were formed. Thus, the assembly and chirality of the cube can be modulated by remote terminal groups and peripheral templating tetraalkylammonium cations.

Observation of Chiral Channels in Helical Covalent Organic Frameworks.

Unraveling the mechanism of chirality transfer across length scales is crucial to the rational development of functional materials with hierarchical chirality. The key obstacle is the lack of structural information, especially at the mesoscopic level. We report herein the structural identification of helical covalent organic frameworks (heliCOFs) with hierarchical chirality, which integrate molecular chirality, channel chirality, and morphology chirality into one crystalline entity. Specifically, benefiting from the highly ordered structure of heliCOFs, the existence of chiral channels at the mesoscopic level has been confirmed by electron crystallography, and the handedness of these chiral channels has been directly determined through the stereopair imaging technique. Accordingly, the chirality transfer in heliCOFs from microscopic to macroscopic levels could be rationalized with a layer-rotating model that has been supported by both crystal structure analysis and theoretical calculations. Observation of chiral channels in heliCOFs not only provides unprecedented data for the understanding of the chirality transfer process but also sheds new light on the rational construction of highly ordered polymeric materials with hierarchical chirality.

SARS-CoV-2 NSP12 utilizes various host splicing factors for replication and splicing regulation.

The RNA-dependent RNA polymerase (RdRp) is a crucial element in the replication and transcription of RNA viruses. Although the RdRps of lethal human coronaviruses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) have been extensively studied, the molecular mechanism of the catalytic subunit NSP12, which is involved in pathogenesis, remains unclear. In this study, the biochemical and cell biological results demonstrate the interactions between SARS-CoV-2 NSP12 and seven host proteins, including three splicing factors (SLU7, PPIL3, and AKAP8). The entry efficacy of SARS-CoV-2 considerably decreased when SLU7 or PPIL3 was knocked out, indicating that abnormal splicing of the host genome was responsible for this occurrence. Furthermore, the polymerase activity and stability of SARS-CoV-2 RdRp were affected by the three splicing factors to varying degrees. In addition, NSP12 and its homologues from SARS-CoV and MERS-CoV suppressed the alternative splicing of cellular genes, which were influenced by the three splicing factors. Overall, our research illustrates that SARS-CoV-2 NSP12 can engage with various splicing factors, thereby impacting virus entry, replication, and gene splicing. This not only improves our understanding of how viruses cause diseases but also lays the foundation for the development of antiviral therapies.

Ras-Targeting Stabilized Peptide Increases Radiation Sensitivity of Cancer Cells.

Radiation therapy is one of the most common treatments for cancer. However, enhancing tumors' radiation sensitivity and overcoming tolerance remain a challenge. Previous studies have shown that the Ras signaling pathway directly influences tumor radiation sensitivity. Herein, we designed a series of Ras-targeting stabilized peptides, with satisfactory binding affinity (KD = 0.13 µM with HRas) and good cellular uptake. Peptide H5 inhibited downstream phosphorylation of ERK and increased radio-sensitivity in HeLa cells, resulting in significantly reduced clonogenic survival. The stabilized peptides, designed with an N-terminal nucleation strategy, acted as potential radio-sensitizers and broadened the applications of this kind of molecule. This is the first report of using stabilized peptides as radio-sensitizers, broadening the applications of this kind of molecule.

Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

Bottom-Up Construction of Ni(II)-Incorporated Covalent Organic Framework for Metallaphotoredox Catalysis.

The construction of an all-in-one catalyst, in which the photosensitizer and the transition metal site are close to each other, is important for improving the efficiency of metallaphotoredox catalysis. However, the development of convenient synthetic strategies for the precise construction of an all-in-one catalyst remains a challenging task due to the requirement of precise installation of the catalytic sites. Herein, we have successfully established a facile bottom-up strategy for the direct synthesis of Ni(II)-incorporated covalent organic framework (COF), named LZU-713@Ni, as a versatile all-in-one metallaphotoredox catalyst. LZU-713@Ni showed excellent activity and recyclability in the photoredox/nickel-catalyzed C-O, C-S, and C-P cross-coupling reactions. Notably, this catalyst displayed a better catalytic activity than its homogeneous analogues, physically mixed dual catalyst system, and, especially, LZU-713/Ni which was prepared through post-synthetic modification. The improved catalytic efficiency of LZU-713@Ni should be attributed to the implementation of bottom-up strategy, which incorporated the fixed, ordered, and abundant catalytic sites into its framework. This work sheds new light on the exploration of concise and effective strategies for the construction of multifunctional COF-based photocatalysts.

POSS and PEG Contained Copolymer for Antibioadhesive Rigid Contact Lenses Materials Application.

Myopia is a global public health issue. Rigid contact lenses (RCLs) are an effective way to correct or control myopia. However, bioadhesion issues remain one of the significant obstacles limiting its clinical application. Although enhancing hydrophilicity through various surface treatments can mitigate this problem, the duration of effectiveness is short-lived and the processing involved is complex and costly. Herein, an antiadhesive RCLs material was designed via 8-armed methacrylate-POSS (8MA-POSS), and poly(ethylene glycol) methacrylate (PEGMA) copolymerization with 3-[tris(trimethylsiloxy)silyl] propyl methacrylate (TRIS). The POSS and PEG segments incorporated P(TRIS-co-PEGMA-co-8MA-POSS) (PTPM) material was obtained and their optical transparency, refractive index, resolution, hardness, surface charge, thermal features, and wettability were tested and optimized. The antibioadhesion activities, including protein, lipid, and bacteria, were evaluated as well. In vitro and in vivo results indicated that the optimized antibioadhesive PTPM materials present good biocompatibility and biosafety. Thus, such POSS and PEG segments containing material were a potential antibioadhesive RCL material option.

Analysis of the Brucella melitensis epidemic in Xinjiang: genotyping, polymorphism, antibiotic resistance and tracing.

Brucella spp. are facultative intracellular pathogens that cause zoonosis- brucellosis worldwide. There has been a trend of the re-emergence of brucellosis worldwide in recent years. The epidemic situation of brucellosis is serious in Xinjiang. To analyze the epidemic situation of Brucella spp. in Xinjiang among humans and animals, this study identified 144 Brucella isolates from Xinjiang using classical identification and 16 S rRNA sequencing. MLVA, drug resistance testing, and wgSNP detection were also performed. At the same time, analysis was conducted based on the published data of Brucella isolates worldwide. The results showed that the dominant species was B. melitensis biovar 3, which belonged to GT42 (MLVA-8 typing) and the East Mediterranean lineage. The correlation among isolates was high both in humans or animals. The isolates in Xinjiang exhibited higher polymorphism compared to other locations in China, with polymorphism increasing each year since 2010. No amikacin/kanamycin-resistant strains were detected, but six rifampicin-intermediate isolates were identified without rpoB gene variation. The NJ tree of the wgSNP results indicated that there were three main complexes of the B. melitensis epidemic in Xinjiang. Based on the results of this study, the prevention and control of brucellosis in Xinjiang should focus on B. melitensis, particularly strains belonging to B. melitensis bv.3 GT42 (MLVA-8 typing) and East Mediterranean lineage. Additionally, the rifampicin- and trimethoprim-sulfamethoxazole- resistance of isolates in Xinjiang should be closely monitored to avoid compromising the therapeutic efficacy and causing greater losses. These results provide essential data for the prevention and control of brucellosis in Xinjiang and China. Although the isolates from Xinjiang have significant characteristics among Chinese isolates and can reflect the epidemiological situation of brucellosis in China to some extent, this study cannot represent the characteristics of isolates from other regions.

ABRO1 arrests cardiomyocyte proliferation and myocardial repair by suppressing PSPH.

The role of Abraxas 2 (ABRO1 or KIAA0157), a component of the lysine63-linked deubiquitinating system, in the cardiomyocyte proliferation and myocardial regeneration is unknown. Here, we found that ABRO1 regulates cardiomyocyte proliferation and cardiac regeneration in the postnatal heart by targeting METTL3-mediated m6A methylation of Psph mRNA. The deletion of ABRO1 increased cardiomyocyte proliferation in hearts and restored the heart function after myocardial injury. On the contrary, ABRO1 overexpression significantly inhibited the neonatal cardiomyocyte proliferation and cardiac regeneration in mouse hearts. The mechanism by which ABRO1 regulates cardiomyocyte proliferation mainly involved METTL3-mediated Psph mRNA methylation and CDK2 phosphorylation. In the early postnatal period, METTL3-dependent m6A methylation promotes cardiomyocyte proliferation by hypermethylation of Psph mRNA and upregulating PSPH expression. PSPH dephosphorylates cyclin-dependent kinase 2 (CDK2), a positive regulator of cell cycle, at Thr14/Tyr15 and increases its activity. Upregulation of ABRO1 restricts METTL3 activity and halts the cardiomyocyte proliferation in the postnatal hearts. Thus, our study reveals that ABRO1 is an essential contributor in the cell cycle withdrawal and attenuation of proliferative response in the postnatal cardiomyocytes and could act as a potential target to accelerate cardiomyocyte proliferation and cardiac repair in the adult heart.

Upconversion nanoparticles doped optical lens: let's see the near-infrared light.

The human cannot detect light with a wavelength exceeding 700 nm, primarily due to limitations in the physiological structure of the human eye. However, in certain specific scenarios, the ability to detect near-infrared (NIR) light proves to be extremely valuable. To attain this desired capability, NIR up conversion nanoparticles (UCNPs) were prepared and doped in the optical lens materials, aiming to obtain a NIR light "visible" optical lens. It is demonstrated that the doping of UCNPs in the optical lens materials does not significantly impact on their mechanical properties, optical properties, surface properties and it exhibits excellent biocompatibility in cell and animal experiments. More importantly, the UCNPs doping can convert NIR light into visible light within the material effectively and stably. The eyes can "see" the NIR light after wearing such UCNPs doped optical lens. Such NIR light visible optical lens could have great potential in actual applications.

The regulatory relationship between transcription factor STAT3 and noncoding RNA.

Signal transducer and activator of transcription 3 (STAT3), as a key node in numerous carcinogenic signaling pathways, is activated in various tumor tissues and plays important roles in tumor formation, metastasis, and drug resistance. STAT3 is considered a potential subtarget for tumor therapy. Noncoding RNA (ncRNA) is a special type of RNA transcript. Transforming from "junk" transcripts into key molecules involved in cell apoptosis, growth, and functional regulation, ncRNA has been proven to be closely related to various epithelial-mesenchymal transition and drug resistance processes in tumor cells over the past few decades. Research on the relationship between transcription factor STAT3 and ncRNAs has attracted increased attention. To date, existing reviews have mainly focused on the regulation by ncRNAs on the transcription factor STAT3; there has been no review of the regulation by STAT3 on ncRNAs. However, understanding the regulation of ncRNAs by STAT3 and its mechanism is important to comprehensively understand the mutual regulatory relationship between STAT3 and ncRNAs. Therefore, in this review, we summarize the regulation by transcription factor STAT3 on long noncoding RNA, microRNA, and circular RNA and its possible mechanisms. In addition, we provide an update on research progress on the regulation of STAT3 by ncRNAs. This will provide a new perspective to comprehensively understand the regulatory relationship between transcription factor STAT3 and ncRNAs, as well as targeting STAT3 or ncRNAs to treat diseases such as tumors.

Spongia Sponges: Unabated Sources of Novel Secondary Metabolites.

Marine sponges of the genus Spongia have proven to be unabated sources of novel secondary metabolites with remarkable scaffold diversities and significant bioactivities. The discovery of chemical substances from Spongia sponges has continued to increase over the last few years. The current work provides an up-to-date literature survey and comprehensive insight into the reported metabolites from the members of the genus Spongia, as well as their structural features, biological activities, and structure-activity relationships when available. In this review, 222 metabolites are discussed based on published data from the period from mid-2015 to the beginning of 2024. The compounds are categorized into sesquiterpenes, diterpenes, sesterterpenes, meroterpenes, linear furanoterpenes, steroids, alkaloids, and other miscellaneous substances. The biological effects of these chemical compositions on a vast array of pharmacological assays including cytotoxic, anti-inflammatory, antibacterial, neuroprotective, protein tyrosine phosphatase 1B (PTP1B)-inhibitory, and phytoregulating activities are also presented.

Early cartilage lesion and 5-year incident joint surgery in knee osteoarthritis patients: a retrospective cohort study.

OBJECTIVE: to investigate the association between cartilage lesion-related features observed in knee osteoarthritis (OA) patients' first MRI examination and incident knee surgery within 5 years. Additionally, to assess the predictive value of these features for the incident knee surgery. METHODS: We identified patients diagnosed with knee OA and treated at our institution between January 2015 and January 2018, and retrieved their baseline clinical data and first MRI examination films from the information system. Next, we proceeded to determine joint space narrowing grade, cartilage lesion size grade, cartilage full-thickness loss grade and cartilage lesion sum score for the medial and lateral compartments, respectively. Generalized linear regression models examined the association of these features with 5-year incident knee surgery. Positive and negative predictive values (PPVs and NPVs) were determined referring to 5-year incident knee surgery. RESULTS: Totally, 878 participants (knees) were found eligible to form the study population. Within the 5 years, surgery was performed on 61 knees. None of the cartilage-related features had been found significantly associated with incident surgery. The results were similar for medial and lateral compartments. The PPVs were low for all the features. CONCLUSIONS: Among symptomatic clinically diagnosed OA knees, cartilage lesions observed in the first MRI examinations were not found to be associated with the occurrence of joint surgery within a 5-year period. All these cartilage-related features appear to have no additional value in predicting 5-year incident joint surgery.

Identification of inducible CYP3 and CYP4 genes associated with abamectin tolerance in the fat body and Malpighian tubules of Spodoptera litura.

Abamectin, as a broad-spectrum bioinsecticide, has been widely used for the control of Lepidoptera insects, resulting in different levels of resistance to abamectin in Spodoptera litura. Cytochrome P450 monooxygenases (P450s) are known for their important roles in insecticide detoxification. In this study, the expression of SlCYP6B40, SlCYP4L12 and SlCYP9A32 in the fat body, and SlCYP4S9, SlCYP6AB12, SlCYP6AB58, SlCYP9A75a and SlCYP9A75b in Malpighian tubules was found to be significantly upregulated after abamectin exposure. SlCYP6AE44 and SlCYP6AN4 were simultaneously upregulated in these two tissues after abamectin exposure. Ectopically overexpressed SlCYP6AE44, SlCYP9A32 and SlCYP4S9 in transgenic Drosophila conferred tolerance to abamectin. In addition, homology modeling and molecular docking results suggested that SlCYP6AE44, SlCYP9A32 and SlCYP4S9 may be capable of binding with abamectin. These results demonstrate that upregulation of CYP3 and CYP4 genes may contribute to abamectin detoxification in S. litura and provide information for evidence-based insecticide resistance management strategies.

Crestal strain of two-implant mandibular overdentures with implants placed at different positions: An in vitro 3D printed simulation study.

STATEMENT OF PROBLEM: The 2-implant mandibular overdenture (2IMO) is a popular treatment for patients with mandibular edentulism. However, information on the influence of implant positions on crestal strain is lacking. PURPOSE: The purpose of this in vitro study was to evaluate the crestal strain around 2 implants to support mandibular overdentures when placed at different positions. MATERIAL AND METHODS: Edentulous mandibles were 3-dimensionally (3D) designed separately with 2 holes for implant placement at similar distances of 5, 10, 15, and 20 mm from the midline, resulting in 4 study conditions. The complete denture models were 3D designed and printed from digital imaging and communications in medicine (DICOM) images after scanning the patient's denture. Two 4.3×12-mm dummy implants were placed in the preplanned holes. Two linear strain gauges were attached on the crest of the mesial and distal side of each implant (CH1, CH2, CH3, and CH4) and connected to a computer to record the electrical signals. Male LOCATOR attachments were attached, the mucosal layer simulated, and the denture picked up with pink female nylon caps. A unilateral and bilateral force of 100 N was maintained for 10 seconds for each model in a universal testing machine while recording the maximum strains in the DCS-100A KYOWA computer software program. Data were analyzed by using 1-way analysis of variance, the Tukey post hoc test, and the paired t test (α=.05). RESULTS: Under bilateral loading, the strain values indicated a trend with increasing distance between the implants with both right and left distal strain gauges (CH4 and CH1). The negative (-ve) values indicated the compressive force, and the positive (+ve) values indicated the tensile force being applied on the strain gauges. The strain values for CH4 ranged between -166.08 for the 5-mm and -251.58 for the 20-mm position; and for CH1 between -168.08 for the 5-mm and -297.83 for the 20-mm position. The remaining 2 mesial strain gauges for all 4 implant positions remained lower than for CH4 and CH1. Under unilateral-right loading, only the right-side distal strain gauge CH4 indicated the increasing trend in the strain values with -147.5 for the 5-mm, -157.17 for the 10-mm, -209.33 for the 15-mm, and -234.75 for the 20 mm position. The remaining 3 strain gauges CH3, CH2, and CH1 ranged between -28.33 and -107.17. For each position for both implants, significantly higher (P<.05) strain values were observed on the distal strain gauge channels CH4 and CH1 than on the mesial channels CH3 and CH2 under bilateral loading and on the right side under unilateral loading. CONCLUSIONS: Peri-implant crestal strains in the 2IMO increased by increasing the distance of the implants from the midline. The stress values progressively increased from 5 to 10 mm to 15 to 20 mm from midline, represented as lateral incisor, canine, and premolar positions. The distal side of the implants exhibits higher strains than the mesial side of the implants.

Anion-Coordination-Driven Assembly.

The assembly of discrete architectures has been an important subject in supramolecular chemistry because of their elegant structures and fascinating properties. During the last several decades, supramolecular chemists have developed manifold strategies for hierarchical assembly, which are normally classified by two main types of driving force: covalent and noncovalent interactions. Typical noncovalent interactions include metal coordination, hydrogen bonding, and other weak forces. These approaches have achieved great progress in the construction of various supramolecular structures, such as macrocycles, cages, polyhedra, and interlocked systems. Among these methods, metal-coordination-driven assembly is attractive due to the well-defined coordination properties of metal ions. Indeed, in terms of supramolecular chemistry, the concept of "coordination" has been expanded beyond transition metals. In particular, anion coordination chemistry, which was first proposed by Lehn in 1978 [ Acc. Chem. Res. 1978, 11, 49] and then elucidated in detail by Bowman-James two decades later [ Acc. Chem. Res. 2005, 38, 671], has grown up to a subfield of supramolecular chemistry. It is noticeable that anions also show "dual valencies" like transition metals, wherein the "primary valence" is the charge balance for anions by countercations while the "secondary valence", i.e., the coordination, refers to hydrogen bonding interactions where the electron flow is from the electron-rich anion (the coordination center) to hydrogen bonding donors (the ligands). Thus, anions also display certain coordination numbers and specific coordination geometries. Although such features are far less regular than those of transition metals, they are sufficient to allow anion coordination to serve as the driving force for assembling discrete supramolecular architectures. In this Account, the anion-coordination-driven assembly (ACDA), a new assembling strategy established by us during the past decade, will be presented. We summarize our work in the construction of a series of "aniono" supramolecular structures, especially triple helicates and tetrahedral cages, based on the coordination between oligourea ligands and anions (mostly phosphate). In particular, we will detail the considerations in the design of ligands, the assembling process including structural transformation, and functionalization of the systems toward guest inclusion, supramolecular catalysis, photoswitches, and molecular devices. These results demonstrate the great potential of ACDA in fabricating novel anion-based systems. Although the design concept was originally loaned from traditional coordination chemistry of transition metals, and structures of anion complexes bear some resemblance to metal complexes, there are significant differences of the aniono supramolecular assemblies from the metallo analogues. For example, these metal-free systems are held together by multiple hydrogen bonds (dozens to nearly 100), thus facilitating assembly/disassembly under mild conditions and relatively flexible structures for adaptive guest inclusion. To this end, intriguing applications (supramolecular chirality, catalysis, energy storage, etc.) may be expected for aniono systems. We hope the current Account will attract more attention from researchers in supramolecular assembly and inspire more efforts in this fascinating area.

Serum Potassium Levels and Mortality in Hospitalized Heart Failure Patients.

Background: To assess the link between serum potassium ( K + ) and all-cause mortality in hospitalized heart failure (HF) patients. Methods: Hospitalized HF patients (n = 3114) were analyzed at the Fuwai Hospital Heart Failure Center. Before discharge, HF patients were divided into four groups according to the K + level quartiles: K + ≤ 3.96 mmol/L (Q1), 3.96 < K + ≤ 4.22 mmol/L (Q2), 4.22 < K + ≤ 4.52 mmol/L (Q3), and K + > 4.52 mmol/L (Q4). At 90 days, 2 years, and maximal follow-up, all-cause mortality was the primary outcome. Results: Patients with HF in the Q4 group had worse cardiac function, higher N-terminal pro-B-type natriuretic peptide levels, lower left ventricular ejection fractions and lower estimated glomerular filtration rates than patients in the Q2 group. In the multivariate-adjusted Cox analysis, the mortality assessed during the 90-day, 2-year, and maximal follow-up examinations increased in the Q4 group of HF patients but not in the Q1 and Q3 groups. The Q4 group had a 28% (hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 1.09-1.49, p = 0.002) higher risk of all-cause mortality at maximum follow-up. Hypokalemia and hyperkalemia were linked to increased HF mortality risk at the 90-day, 2-year, and maximal follow-up periods. Conclusions: Serum K + levels had a J-shaped association with all-cause mortality in HF patients. Both hypokalemia and a K + level of > 4.52 mmol/L were associated with increased all-cause mortality in the short term and long term, suggesting a narrow target K + range in HF patients. Clinical Trial Registration: Unique Identifier: NCT02664818; URL: clinicaltrials.gov.

Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.

BACKGROUND: Emerging research has reported that circular RNAs (circRNAs) play important roles in cardiac cell death after myocardial ischemia and reperfusion (I/R). Ferroptosis, a new form of cell death discovered in recent years, has been proven to participate in the regulation of myocardial I/R. This study used circRNA sequencing to explore the key circRNA in the regulation of cardiac ferroptosis after I/R and study the mechanisms of potential circRNA function. METHODS: We performed circRNA sequencing to explore circRNAs differentially expressed after myocardial I/R. We used quantitative polymerase chain reactions to determine the circRNA expression in different tissues and detect the circRNA subcellular localization in the cardiomyocyte. Gain- and loss-of-function experiments were aimed to examine the function of circRNAs in cardiomyocyte ferroptosis and cardiac tissue damage after myocardial I/R. RNA pull-down was applied to explore proteins interacting with circRNA. RESULTS: Here, we identified a ferroptosis-associated circRNA (FEACR) that has an underlying regulatory role in cardiomyocyte ferroptosis. FEACR overexpression suppressed I/R-induced myocardial infarction and ameliorated cardiac function. FEACR inhibition induces ferroptosis in cardiomyocytes and FEACR overexpression inhibits hypoxia and reoxygenation-induced ferroptosis. Mechanistically, FEACR directly bound to nicotinamide phosphoribosyltransferase (NAMPT) and enhanced the protein stability of NAMPT, which increased NAMPT-dependent Sirtuin1 (Sirt1) expression, which promoted the transcriptional activity of forkhead box protein O1 (FOXO1) by reducing FOXO1 acetylation levels. FOXO1 further upregulated the transcription of ferritin heavy chain 1 (Fth1), a ferroptosis suppressor, which resulted in the inhibition of cardiomyocyte ferroptosis. CONCLUSIONS: Our finding reveals that the circRNA FEACR-mediated NAMPT-Sirt1-FOXO1-FTH1 signaling axis participates in the regulation of cardiomyocyte ferroptosis and protects the heart function against I/R injury. Thus, FEACR and its downstream factors could be novel targets for alleviating ferroptosis-related myocardial injury in ischemic heart diseases.

Prevalence and prognostic importance of malnutrition, as assessed by four different scoring systems, in elder patients with heart failure.

BACKGROUND AND AIMS: The lack of standard diagnostic criteria in elder patients with heart failure (HF) makes it challenging to diagnose and manage malnutrition. We aimed to explore the prevalence of malnutrition, its associations and prognostic significance among elder patients with HF using four different nutritional scoring systems. METHODS AND RESULTS: Consecutively presenting patients aged ⩾65 years, diagnosed with HF, and admitted to HF care unit of Fuwai Hospital CAMS&PUMC (Beijing, China) were assessed for nutritional indices. In total, 1371 patients were enrolled (59.4% men; mean age 72 years; median NT-proBNP 2343 ng/L). Using scores for the prognostic nutritional index (PNI) ≤38, controlling nutritional status (CONUT) score >4, geriatric nutritional risk index (GNRI) ≤91, and triglycerides, total cholesterol, and body weight index (TCBI) ≤1109, 10.4%, 18.3%, 9.2%, and 50.0% of patients had moderate or severe malnutrition, respectively. There was a strong association between worse scores and lower body mass index, more severe symptoms, atrial fibrillation, and anemia. The mortality over a median follow-up of 962 days (interquartile range (IQR): 903-1029 days) was 28.3% (n = 388). For those with moderate or severe condition, 1-year mortality was 35.2% for PNI, 28.3% for CONUT, 28.0% for GNRI, and 19.1% for TCBI. Malnutrition, defined by any of the included indices, showed added prognostic value when incorporated into a model and included preexisting prognostic factors (C-statistic: 0.711). However, defining malnutrition by the CONUT score yielded the most significant improvement in the prognostic predictive value (C-statistic: 0.721; p < 0.001). CONCLUSION: Malnutrition is prevalent among elder patients with HF and confers increased mortality risk. Among the nutritional scores studied, the CONUT score was most effective in predicting the mortality risk. CLINICAL TRIAL REGISTRATION: URL: ClinicalTrials.gov; Unique Identifier: NCT02664818.

Trophoblast retrieval from the cervical canal to predict abnormal pregnancy early in gestation: a pilot study.

BACKGROUND: The current detection of fetal chromosomal abnormalities by non-invasive prenatal testing (NIPT) mainly relies on the cell free DNA(cfDNA) in the maternal blood. However, a gestational age of less than 12 weeks or a high maternal BMI affects cfDNA fetal fraction and further the detection by NIPT negatively. In this study, we aim to retrieve the trophoblast cells from the maternal cervix to develop a new sampling method for NIPT enabling an earlier use of NIPT. METHODS: We enrolled three patients who wanted to undergo induced abortion at Beijing Hospital between January 2022 and March 2022. Peripheral blood, cervix specimen, and the abortion tissue were collected and processed for each patient. Allele frequencies of the mutated gene loci of the maternal blood and the cervix sample were compared and the Sex Determining Region Y (SRY) gene was tested. RESULTS: The allele frequencies of the mutated gene loci showed no significant difference between the maternal blood and the cervix sample. But we successfully detected signal of the SRY gene in the cervix sample of the only patient carrying a male fetus. CONCLUSIONS: The detection of the SRY gene in a cervix sample indicated a successful retrieval of trophoblast cells from the cervix canal. Further study needs to be conducted to verify our finding before its application to the clinical settings.