Cellular senescence in acute kidney injury: Target and opportunity.

Acute kidney injury (AKI) is a common clinical disease with a high incidence and mortality rate. It typically arises from hemodynamic alterations, sepsis, contrast agents, and toxic drugs, instigating a series of events that culminate in tissue and renal damage. This sequence of processes often leads to acute renal impairment, prompting the initiation of a repair response. Cellular senescence is an irreversible arrest of the cell cycle. Studies have shown that renal cellular senescence is closely associated with AKI through several mechanisms, including the promotion of oxidative stress and inflammatory response, telomere shortening, and the down-regulation of klotho expression. Exploring the role of cellular senescence in AKI provides innovative therapeutic ideas for both the prevention and treatment of AKI. Furthermore, it has been observed that targeted removal of senescent cells in vivo can efficiently postpone senescence, resulting in an enhanced prognosis for diseases associated with senescence. This article explores the effects of common anti-senescence drugs senolytics and senostatic and lifestyle interventions on renal diseases, and mentions the rapid development of mesenchymal stem cells (MSCs). These studies have taken senescence-related research to a new level. Overall, this article comprehensively summarizes the studies on cellular senescence in AKI, aiming is to elucidate the relationship between cellular senescence and AKI, and explore treatment strategies to improve the prognosis of AKI.

Association between IL-2 Receptor and Severe Coronary Artery Calcification in Patients with Coronary Artery Disease.

Background: Coronary artery calcification (CAC) is a crucial marker for coronary atherosclerosis, and the extent of CAC is closely linked to the incidence and progression of cardiovascular diseases. The interleukin-2 (IL-2) receptor (IL-2R), which plays a critical role in mediating the proliferation and differentiation of immune cells, may also be involved in the development of CAC. The study aimed to investigate the relationship between IL-2R and CAC, with the goal of providing new insights into cardiovascular diseases. Methods: In this study, we enrolled 606 patients diagnosed with coronary artery disease to assess CAC. Based on coronary artery calcification score (CACS), patients were divided into two groups: the non-severe CAC group (CACS ≤ 400 Agatston units, AU) and the severe CAC group (CACS > 400 AU). Results: The results showed that IL-2R levels were significantly higher in patients with severe CAC compared to those with non-severe CAC (383 vs. 352 pg/mL, p = 0.002). Moreover, the level of IL-2R was positively correlated with the severity of CAC, independent of other clinical risk factors. According to Receiver Operating Characteristic (ROC) curve, the IL-2R prediction model demonstrated a good capability in distinguishing severe CAC with the Area Under the Curve (AUC) value of 0.726. Conclusions: Our study suggests that IL-2R is independently associated with the occurrence of severe CAC in coronary artery disease (CAD) patients. Additionally, IL-2R may play a crucial role in the development of advanced atherosclerosis. Consequently, therapeutic strategies targeting the IL-2/IL-2R pathway may be effective in preventing or treating CAD.

A fluorescent terbium-metal-organic framework material for high-sensitivity detection of vomitoxin and oxytetracycline hydrochloride in water.

A unique luminescent lanthanide metal-organic framework (LnMOF)-based fluorescence detection platform was utilized to achieve sensitive detection of vomitoxin (VT) and oxytetracycline hydrochloride (OTC-HCL) without the use of antibodies or biomolecular modifications. The sensor had a fluorescence quenching constant of 9.74 × 106 M-1 and a low detection limit of 0.68 nM for vomitoxin. Notably, this is the first example of a Tb-MOF sensor for fluorescence detection of vomitoxin. We further investigated its response to two mycotoxins, aflatoxin B1 and ochratoxin A, and found that their Stern-Volmer fluorescence quenching constants were lower than those of VT. In addition, the fluorescence sensor realized sensitive detection of OTC-HCL with a detection limit of 0.039 µM. In conclusion, the method has great potential as a sensitive and simple technique to detect VT and OTC-HCL in water.

In vitro antioxidant activity evaluation of pine nut peptides (Pinus koraiensis) fermented by Bacillus subtilis LS-45.

In this study, we utilized the remarkable capabilities of Bacillus subtilis ls-45 during the fermentation process to generate pine nut peptide. Through gene sequencing, we confirmed the proficiency of Bacillus subtilis ls-45 in producing protease, thereby serving as a valuable enzymatic source for protein hydrolysis. Our investigation focused on examining the variations in amino acid types and quantities between enzymatic pine nut protein peptide (EPP) and fermented pine nut protein polypeptide (FPP). Furthermore, we conducted a comprehensive assessment of the in vitro antioxidant activities of EPP and FPP, encompassing measurements of their Hydroxyl radical scavenging rate, Total reducing capacity, Superoxide anion scavenging rate, and ABTS+ radical scavenging rate. Notably, FPP exhibited superior antioxidant capacity compared to EPP. By employing semi-inhibitory mass concentration (IC50) analysis, we determined that FPP displayed enhanced efficacy in neutralizing hazardous free radicals when compared to EPP.

Comparative analysis of sipeimine content, metabolome and chloroplast genome in cultivated and wild varieties of Fritillaria taipaiensis.

BACKGROUND: The wild variety Fritillaria taipaiensis E.B (EB) is known for its superior therapeutic effects, but its limited production cannot meet demand. As a result, the cultivated variety F. taipaiensis P. Y. Li (PY) has been widely grown. In this study, we conducted a comprehensive analysis comparing EB and PY in terms of external features, sipeimine content, metabolome and chloroplast genome to differentiate these two varieties. RESULTS: Our research revealed that the petals and pods of EB are green, while those of PY have purple markings. The bulbs of EB contain significantly higher levels of sipeimine compared to those of PY. Metabolomic analysis identified 56 differentially expressed metabolites (DMs), with 23 upregulated and 33 downregulated in EB bulbs. Particularly, 3-hydroxycinnamic acid and secoxyloganin may serve as distinctive DMs. These DMs were associated with 17 KEGG pathways, including pyrimidine metabolism, alanine, aspartate and glutamate metabolism, and galactose metabolism. Differences in the length of the chloroplast genome were primarily observed in the large single-copy (LSC) region, with the largest variation in the trnH-GUC-psbA region. The placement of the trnH gene and the rps gene in proximity to the LSC/IRb boundary differs between EB and PY. CONCLUSION: The results of this study provide valuable insights for the introduction and comprehensive development of wild F. taipaiensis from a scientific perspective. © 2024 Society of Chemical Industry.

ATF5 regulates tubulointerstitial injury in diabetic kidney disease via mitochondrial unfolded protein response.

BACKGROUND: Mitochondrial quality control (MQC) plays a critical role in the progression of tubulointerstitial injury in diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt), which is an important MQC process, is activated to maintain mitochondrial protein homeostasis in response to mitochondrial stress. Activating transcription factor 5 (ATF5) is critical in the mammalian UPRmt via mitochondria-nuclear translocation. However, the role of ATF5 and UPRmt in tubular injury under DKD conditions is unknown. METHODS: ATF5 and UPRmt-related proteins including heat shock protein 60 (HSP60) and Lon peptidase 1 (LONP1), in DKD patients and db/db mice were examined by immunohistochemistry (IHC) and western blot analysis. Eight-week-old db/db mice were injected with ATF5-shRNA lentiviruses via the tail vein, and a negative lentivirus was used as a control. The mice were euthanized at 12 weeks, and dihydroethidium (DHE) and TdT-mediated dUTP nick end labeling (TUNEL) assays were performed to evaluate reactive oxygen species (ROS) production and apoptosis in kidney sections, respectively. In vitro, ATF5-siRNA, ATF5 overexpression plasmids or HSP60-siRNA were transfected into HK-2 cells to evaluate the effect of ATF5 and HSP60 on tubular injury under ambient hyperglycemic conditions. Mitochondrial superoxide (MitoSOX) staining was used to gauge mitochondrial oxidative stress levels, and the early stage of cell apoptosis was examined by Annexin V-FITC kits. RESULTS: Increased ATF5, HSP60 and LONP1 expression was observed in the kidney tissue of DKD patients and db/db mice and was tightly correlated with tubular damage. The inhibition of HSP60 and LONP1, improvements in serum creatinine, tubulointerstitial fibrosis and apoptosis were observed in db/db mice treated with lentiviruses carrying ATF5 shRNA. In vitro, the expression of ATF5 was increased in HK-2 cells exposed to high glucose (HG) in a time-dependent manner, which was accompanied by the overexpression of HSP60, fibronectin (FN) and cleaved-caspase3 (C-CAS3). ATF5-siRNA transfection inhibited the expression of HSP60 and LONP1, which was accompanied by reduced oxidative stress and apoptosis in HK-2 cells exposed to sustained exogenous high glucose. ATF5 overexpression exacerbated these impairments. HSP60-siRNA transfection blocked the effect of ATF5 on HK-2 cells exposed to continuous HG treatment. Interestingly, ATF5 inhibition exacerbated mitochondrial ROS levels and apoptosis in HK-2 cells in the early period of HG intervention (6 h). CONCLUSIONS: ATF5 could exert a protective effect in a very early stage but promoted tubulointerstitial injury by regulating HSP60 and the UPRmt pathway under DKD conditions, providing a potential target for the prevention of DKD progression.

27-hydroxycholesterol causes cognitive deficits by disturbing Th17/Treg balance and the related immune responses in mild cognitive impairment patients and C57BL/6J mice.

BACKGROUND: Cognitive impairment is associated with dysregulated immune responses. Emerging evidence indicates that Th17 cells and their characteristic cytokine-IL-17 are receiving growing interest in the pathogenesis of cognitive decline. Here, we focus on the involvement of Th17 cells in mild cognitive impairment (MCI) and the possible mechanism of cholesterol metabolite-27-hydroxycholesterol (27-OHC). METHODS: 100 individuals were recruited into the nested case-control study who completed cognition assessment and the detection of oxysterols and Th17-related cytokines in serum. In addition, mice were treated with 27-OHC and inhibitors of RORγt and Foxp3 (Th17 and Treg transcription factors), and the factors involved in Th17/Treg balance and amyloidosis were detected. RESULTS: Our results showed there was enhanced 27-OHC level in serum of MCI individuals. The Th17-related cytokines homeostasis was altered, manifested as increased IL-17A, IL-12p70, IL-23, GM-CSF, MIP-3α and TNF-α but decreased IL-13, IL-28A and TGF-ß1. Further, in vivo experiments showed that 27-OHC induced higher immunogenicity, which increased Th17 proportion but decreased Treg cells in peripheral blood mononuclear cells (PBMCs); Th17 proportions in hippocampus, and IL-17A level in serum and brain were also higher than control mice. The fluorescence intensity of amyloid-ß (Aß) and the precursor of amyloid A amyloidosis-serum amyloid A (SAA) was increased in the brain of 27-OHC-treated mice, and worse learning and memory performance was supported by water maze test results. While by inhibiting RORγt in 27-OHC-loaded mice, Th17 proportions in both PBMCs and hippocampus were reduced, and expressions of IL-17A and TGF-ß1 were down- and up-regulated, respectively, along with a decreased amyloidosis in brain and improved learning and memory decline. CONCLUSIONS: Altogether, our results demonstrate that excessive 27-OHC aggravates the amyloidosis and leads to cognitive deficits by regulating RORγt and disturbing Th17/Treg balance.

Development of On-DNA Cyclic Imide Synthesis for DNA Encoded Library Construction.

Here, we describe a novel method for the on-DNA synthesis of cyclic imides, an important class of molecules that includes several well-known medications. Significantly, the new method enabled on-DNA synthesis under mild conditions with high conversions and a broad functional group tolerance, utilizing ubiquitous bifunctional amines and bis-carboxylic acid, or alkyl halides, and therefore served as the linchpin for DNA encoded library (DEL) synthesis. The mechanism study of off-DNA and on-DNA chemical transformations revealed unique insights in contrast to conventional chemical transformation.

On-DNA Morita-Baylis-Hillman Reaction: Accessing Targeted Covalent Inhibitor Motifs in DNA-Encoded Libraries.

We herein present the first application of the on-DNA Morita-Baylis-Hillman (MBH) reaction for the creation of pharmaceutically relevant targeted covalent inhibitors (TCIs) with an α-hydroxyl Michael acceptor motif. Adapting a DNA-compatible organocatalytic process, this MBH reaction for covalent selection-capable DNA encoded library (DEL) synthesis grants access to densely functionalized and versatile precursors to explore novel chemical space for molecule recognition in drug discovery. Most importantly, this methodology sheds light on potentially unexpected reaction outcomes of the MBH reaction.

Streptomyces fuscus sp. nov., a brown-black pigment producing actinomycete isolated from dry mudflat sand.

A novel Gram-stain-positive, aerobic actinobacterial strain, designated GXMU-J15T, was isolated from dry mudflat sand. A polyphasic approach was employed for its taxonomic characterization. The strain developed extensively branched yellowish white to light yellow substrate mycelia and white aerial mycelia, and produced smooth cylindrical spores in a loose straight spore chain on International Streptomyces Project 2-7 agar media. Strain GXMU-J15T grew at 20-50 °C (optimum, 35 °C), at pH 5.0-8.0 (optimum, pH 7.0) and in the presence of 0-8 % (w/v) NaCl. Analysis of 16S rRNA gene sequences indicated that strain GXMU-J15T represents a member of the genus Streptomyces. Strain GXMU-J15T showed the highest 16S rRNA gene sequence similarity to Streptomyces lusitanus CGMCC 4.1745T (99.1 %) and Streptomyces thermocarboxydus CGMCC 4.1883T (98.8 %). Phylogenetic tree analysis based on multilocus sequence analysis (MLSA) and whole genome sequence construction revealed that strain GXMU-J15T was most closely related to Streptomyces cupreus PSKA01T, Streptomyces cinnabarinus DSM 40467T and Streptomyces davaonensis JCM 4913T. The MLSA and genome-to-genome distances between strain GXMU-J15T and its relatives were 0.0418, 0.0443 and 0.0485 and 0.1237, 0.1188 and 0.1179, respectively. The results of orthologous average nucleotide identity and digital DNA-DNA hybridization analysis corroborated the results of the MLSA and whole genome sequence evolution analysis, indicating that the novel isolate represents a distinct species of the genus Streptomyces. The whole-cell sugars of strain GXMU-J15T were xylose, glucose and galactose. The characteristic diamino acid in the cell-wall hydrolysate was ll-diaminopimelic acid. The lipids contained diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidylglycerides, phosphatidylcholine, two phospholipids of an unknown structure containing glucosamine, one unknown phospholipid and two unknown lipids. The major cellular fatty acid components were iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0 and anteiso-C17 : 0. The main respiratory quinone types were MK-9(H6) and MK-9(H8). The whole genome size of strain GXMU-J15T was 8.68 Mbp, with 71.23 mol% G+C content. Genomic analysis indicated that strain GXMU-J15T has the potential to synthesize polyketides, terpenes and a series of important antibiotics besides the gene cluster for melanin synthesis. Based on these genotypic and phenotypic data, strain GXMU-J15T is proposed to represent a new species of the genus Streptomyces named Streptomyces fuscus sp. nov. The type strain is GXMU-J15T (=MCCC 1K08211T=JCM 35917T).

A Combined Synthetic, Magnetic, and Theoretical Study on Enhancing Ligand-Field Axiality for Dy(III) Single-Molecule Magnets Supported by Ferrocene Diamide Ligands.

Molecular design is crucial for improving the performance of single-molecule magnets (SMMs). For dysprosium(III) SMMs, enhancing ligand-field axiality is a well-suited strategy to achieve high-performance SMMs. We synthesized a series of dysprosium(III) complexes, (NNTIPS)DyBr(THF)2 (1, NNTIPS = fc(NSiiPr3)2; fc = 1,1'-ferrocenediyl, THF = tetrahydrofuran), [(NNTIPS)Dy(THF)3][BPh4] (2), (NNTIPS)DyI(THF)2 (3), and [(NNTBS)Dy(THF)3][BPh4] (4, NNTBS = fc(NSitBuMe2)2), supported by ferrocene diamide ligands. X-ray crystallography shows that the rigid ferrocene backbone enforces a nearly axial ligand field with weakly coordinating equatorial ligands. Dysprosium(III) complexes 1-4 all exhibit slow magnetic relaxation under zero fields and possess high effective barriers (Ueff) around 1000 K, comparable to previously reported (NNTBS)DyI(THF)2 (5). We probed the influences of structural variations on SMM behaviors by theoretical calculations and found that the distribution of negative charges defined by rq, i.e., the ratio of the charges on the axial ligands to the charges on the equatorial ligands, plays a decisive role. Moreover, theoretical calculations on a series of model complexes 1'-5' without equatorial ligands unveil that the axial crystal-field parameters B20 are directly proportional to the N-Dy-N angles and support the hypothesis that enhancing the ligand-field axiality could improve SMM performance.

143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models.

The KRASG12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRASG12C-mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRASG12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRASG12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRASG12C mutation. 143D selectively inhibited cell proliferation and induced G1-phase cell cycle arrest and apoptosis by downregulating KRASG12C-dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (Cmax) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRASG12C-mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRASG12C mutation.

Roll Eccentricity Detection and Application Based on SFT and Regional DFT.

Roll eccentricity disturbance is a high-frequency periodic change signal caused by the irregular shape of the roll and roll bearing, which is difficult to identify and affects the periodic deviation of the exit thickness of the strip. To achieve rapid identification of the source and a mathematical model of roll eccentricity signals, a sparse Fourier transform (SFT) and regional DFT method for roll eccentricity signal recognition and detection was proposed. This method utilizes SFT to calculate the signal FFT more quickly based on the sparsity of the signal frequency domain. Under the premise of knowing the roll diameter, the signal frequency spectrum is identified online, the amplitude and phase are identified through regional DFT, and the eccentricity disturbance is compensated on site. The simulation results show that this method can accurately identify the source of roll disturbance, quickly update and replace the problematic rolls, and improve the online recognition efficiency by more than 3000 times. This method has good results in online detection and recognition of roll eccentricity signals, greatly improving engineering application efficiency, and ultimately achieving the goal of improving the accuracy of strip outlet thickness.

Environment-Aware Adaptive Reinforcement Learning-Based Routing for Vehicular Ad Hoc Networks.

With the rapid development of the intelligent transportation system (ITS), routing in vehicular ad hoc networks (VANETs) has become a popular research topic. The high mobility of vehicles in urban streets poses serious challenges to routing protocols and has a significant impact on network performance. Existing topology-based routing is not suitable for highly dynamic VANETs, thereby making location-based routing protocols the preferred choice due to their scalability. However, the working environment of VANETs is complex and interference-prone. In wireless-network communication, the channel contention introduced by the high density of vehicles, coupled with urban structures, significantly increases the difficulty of designing high-quality communication protocols. In this context, compared to topology-based routing protocols, location-based geographic routing is widely employed in VANETs due to its avoidance of the route construction and maintenance phases. Considering the characteristics of VANETs, this paper proposes a novel environment-aware adaptive reinforcement routing (EARR) protocol aimed at establishing reliable connections between source and destination nodes. The protocol adopts periodic beacons to perceive and explore the surrounding environment, thereby constructing a local topology. By applying reinforcement learning to the vehicle network's route selection, it adaptively adjusts the Q table through the perception of multiple metrics from beacons, including vehicle speed, available bandwidth, signal-reception strength, etc., thereby assisting the selection of relay vehicles and alleviating the challenges posed by the high dynamics, shadow fading, and limited bandwidth in VANETs. The combination of reinforcement learning and beacons accelerates the establishment of end-to-end routes, thereby guiding each vehicle to choose the optimal next hop and forming suboptimal routes throughout the entire communication process. The adaptive adjustment feature of the protocol enables it to address sudden link interruptions, thereby enhancing communication reliability. In experiments, the EARR protocol demonstrates significant improvements across various performance metrics compared to existing routing protocols. Throughout the simulation process, the EARR protocol maintains a consistently high packet-delivery rate and throughput compared to other protocols, as well as demonstrates stable performance across various scenarios. Finally, the proposed protocol demonstrates relatively consistent standardized latency and low overhead in all experiments.

DNA Compatible Oxidization and Amidation of Terminal Alkynes.

Through a modified Kinugasa reaction, a novel method of amidation on terminal oligo alkyne conjugates by copper-promoted oxidation with nitrones has been developed. Unprotected bifunctional carboxylic acid-amine reagents can be transformed directly to the respective amide products under these edited Kinugasa reaction conditions. 3-Cycle DNA-encoded libraries (DELs) can be built in three steps of chemical conversion.

On-DNA Alkyne Iodination and Acetylenic Coupling as a Useful Tool for DEL Synthesis.

1-Iodoalkynes and 1,3-diynes are versatile chemical intermediates and pharmaceutically valuable ingredients. In this study, copper mediated on-DNA alkyne iodination and Cadiot-Chodkiewicz coupling are developed for the first time. This generates diverse, systematic, and unprecedented topographic structural features, which could be invaluable as molecular recognition agents for drug discovery in DEL screening.

Single polymeric microfiber waveguide platform for sensitive detection and discrimination of DNA methylation.

The development of a rapid and sensitive detection platform for DNA and DNA methylation in complex biological environments has attracted considerable attention. Herein, we describe a detection platform for p16 and p16 methylation in buffer and serum based on a single polymeric fluorescent microfiber waveguide with sandwich-structured hybridization designs. The target p16 could be captured by oligonucleotides conjugated on the surface of polymeric microfibers and oligonucleotides conjugated with gold nanoparticles, resulting in quenching the out-coupled tip emission of the microfiber waveguide. Then the restriction digestion enzyme HpaII was applied to specifically recognize the unmethylated 5'-CCGG-3' site and cut the formed sandwich structure. The gold nanoparticles could be removed from the surface of chitosan fiber so that the out-coupled tip emission of the polymeric fluorescent microfiber would be partially recovered. It is noteworthy that the proposed polymeric microfiber waveguide platform exhibited selective and sensitive detection of p16 with a low limit of 2 pM and excellent analytical performance of methylation as low as 5% difference. This strategy avoids the use of traditional PCR-based amplification and tedious operative processes, and we envisage that this technique could be extended to various DNA methylation analyses, which is meaningful for early clinical diagnosis of diseases.

Quantifying human mixing patterns in Chinese provinces outside Hubei after the 2020 lockdown was lifted.

BACKGROUND: Contact patterns play a key role in the spread of respiratory infectious diseases in human populations. During the COVID-19 pandemic, the regular contact patterns of the population have been disrupted due to social distancing both imposed by the authorities and individual choices. Many studies have focused on age-mixing patterns before the COVID-19 pandemic, but they provide very little information about the mixing patterns in the COVID-19 era. In this study, we aim at quantifying human heterogeneous mixing patterns immediately after lockdowns implemented to contain COVID-19 spread in China were lifted. We also provide an illustrative example of how the collected mixing patterns can be used in a simulation study of SARS-CoV-2 transmission. METHODS AND RESULTS: In this work, a contact survey was conducted in Chinese provinces outside Hubei in March 2020, right after lockdowns were lifted. We then leveraged the estimated mixing patterns to calibrate a mathematical model of SARS-CoV-2 transmission. Study participants reported 2.3 contacts per day (IQR: 1.0-3.0) and the mean per-contact duration was 7.0 h (IQR: 1.0-10.0). No significant differences in average contact number and contact duration were observed between provinces, the number of recorded contacts did not show a clear trend by age, and most of the recorded contacts occurred with family members (about 78%). The simulation study highlights the importance of considering age-specific contact patterns to estimate the COVID-19 burden. CONCLUSIONS: Our findings suggest that, despite lockdowns were no longer in place at the time of the survey, people were still heavily limiting their contacts as compared to the pre-pandemic situation.

Takostubo syndrome combined with ventricular septal perforation: a case report.

BACKGROUND: The precise clinical features and etiologic basis of Takotsubo syndrome remain unclear, although an association with emotional or stressful triggers has been recognized. Ventricular septal perforation is a very rare life-threatening complication. CASE PRESENTATION: A 77-year-old female patient presented to the hospital with unrelieved chest tightness and shortness of breath. Three months ago, the patient's electrocardiogram revealed ischemic T wave inversion of the anterior wall, along with an increase in myocardial injury markers. There was no evidence of a ventricular septal defect on echocardiography. The patient was admitted to the respiratory department to treat lung lesions. The electrocardiogram demonstrated dynamic changes following admission, and the myocardial markers returned to normal, but the echocardiography revealed a ventricular septal defect. The initial diagnosis was ventricular septal perforation because of myocardial infarction with acute anterior ST-segment elevation. Coronary angiography revealed no abnormalities, but left ventricular angiography revealed an enlarged apex and VSD, with a right ventricular shunt bundle. Later, cardiac MRI revealed an apical ventricular septal defect. Further inquiry of the patient's medical history revealed that her husband died unexpectedly three months ago, and her daughter was seriously injured in a car accident, causing the patient severe emotional distress. Takotsubo syndrome was then determined in conjunction with the patient's medical history, symptoms, signs, and pertinent examinations. Without using a catheter or a surgical procedure, we managed the patient's medical condition. Two weeks later, the patient was discharged with symptoms improved. CONCLUSIONS: Takotsubo syndrome is comparable to an acute myocardial infarction on clinical and electrocardiographic examination in the absence of significant coronary disease. Although ventricular septal perforation is most commonly associated with acute myocardial infarction, it can also happen following Takotsubo syndrome. Takotsubo syndrome complicated by ventricular septal perforation is easily misdiagnosed. The early recognition and management of this condition can avoid or reduce morbidity and mortality.

Design, synthesis, and evaluation of novel pyridone derivatives as potent BRD4 inhibitors for the potential treatment of prostate cancer.

Since androgen receptor (AR) can bind to BRD4 protein and this binding can be blocked by BRD4 inhibitors, targeting BRD4 has emerged as a promising approach for the treatment of prostate cancer (PC). Herein, we designed and synthesized a series of 5-(1-benzyl-1H-indazol-6-yl)-4-ethoxy-1-methylpyridin-2(1H)-one derivatives as novel BRD4 inhibitors for prostate cancer. Among them, compound 13 displayed the most robust BRD4 inhibitory activity with an IC50 value of 18 nM. Furthermore, 13 showed potent anti-proliferative activity against enzalutamide-resistant 22RV1 cells. The mechanism of action studies demonstrated that 13 induced cell apoptosis by regulating Bcl-2/Bax proteins and activating caspase-3 signaling pathway. In addition, the c-Myc level was significantly reduced in 22RV1 cells on the western blot assay. These findings collectively suggested that compound 13 might find potential use for the treatment of prostate cancer.