Advances in the synthesis and applications of macrocyclic polyamines.

Macrocyclic polyamines constitute a significant class of macrocyclic compounds that play a pivotal role in the realm of supramolecular chemistry. They find extensive applications across diverse domains including industrial and agricultural production, clinical diagnostics, environmental protection and other multidisciplinary fields. Macrocyclic polyamines possess a distinctive cavity structure with varying sizes, depths, electron-richness degrees and flexibilities. This unique feature enables them to form specific supramolecular structures through complexation with diverse objects, thereby attracting considerable attention from chemists, biologists and materials scientists alike. However, there is currently a lack of comprehensive summaries on the synthesis methods for macrocyclic polyamines. In this review article, we provide an in-depth introduction to the synthesis of macrocyclic polyamines while analysing their respective advantages and disadvantages. Furthermore, we also present an overview of the recent 5-year advancements in using macrocyclic polyamines as non-viral gene vectors, fluorescent probes, diagnostic and therapeutic reagents as well as catalysts. Looking ahead to future research directions on the synthesis and application of macrocyclic polyamines across various fields will hopefully inspire new ideas for their synthesis and use.

Nonlinear relationship of red blood cell indices (MCH, MCHC, and MCV) with all-cause and cardiovascular mortality: A cohort study in U.S. adults.

BACKGROUND: In recent years, increasing attention has been focused on the impact of red blood cell indices (RCIs) on disease prognosis. We aimed to investigate the association of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular volume (MCV) with mortality. METHODS: The study used cohort data from U.S. adults who participated in the 1999-2008 National Health and Nutrition Examination Survey. All-cause mortality was the primary outcome during follow-up, with secondary cardiovascular mortality outcomes. COX regression was applied to analyze the connection between RCIs and mortality. We adopted three models to minimize potential bias. Smooth-fit curves and threshold effect analyses were utilized to observe the dose-response relationship between RCIs and all-cause and cardiovascular mortality. In addition, we performed sensitivity analyses. RESULTS: 21,203 individuals were enrolled in our research. During an average 166.2 ± 54.4 months follow-up, 24.4% of the population died. Curve fitting indicated a U-shaped relationship between MCV and MCH with all-cause mortality, and the relationship of MCHC to all-cause mortality is L-shaped. We identified inflection points in the relationship between MCV, MCH, and MCHC and all-cause mortality as 88.56732 fl, 30.22054 pg, 34.34624 g/dl (MCV <88.56732 fl, adjusted HR 0.99, 95 CI% 0.97-1.00; MCV >88.56732 fl, adjusted HR 1.05, 95 CI% 1.04-1.06. MCH <30.22054 pg, adjusted HR 0.95, 95 CI% 0.92-0.98; MCH >30.22054 pg, adjusted HR 1.08, 95 CI% 1.04-1.12. MCHC <34.34624 g/dl, adjusted HR 0.88, 95 CI% 0.83-0.93). Besides, the MCV curve was U-shaped in cardiovascular mortality (MCV <88.56732 fl, adjusted HR 0.97, 95 CI% 0.94-1.00; MCV >88.56732 fl, adjusted HR 1.04, 95 CI% 1.01-1.06). CONCLUSION: This cohort study demonstrated that RCIs (MCH, MCHC, and MCV) were correlated with mortality in the general population. Three RCIs were nonlinearly correlated with all-cause mortality. In addition, there were nonlinear relationships between MCH and MCV and cardiovascular mortality.

TAVR for Severe Aortic Valve Stenosis with LVOT Stenosis: A Case Report.

Transcatheter aortic valve replacement (TAVR) has been recently indicated for the treatment of patients with severe aortic stenosis in all risk profiles. At present, TAVR has become mature at home and abroad, but the relevant experience is deficient in the treatment of aortic valve stenosis with outflow tract stenosis. One case of a high-risk surgical patient was included in this paper who suffered from severe aortic valve stenosis with left ventricular outflow tract (LVOT) stenosis. In this case, TAVR was performed with deep implantation of a new valve and both aortic valve stenosis and LVOT stenosis were treated through a single TAVR procedure. This case highlights the vital role of such treatment in dealing with both aortic valve stenosis and LVOT stenosis through a single TAVR procedure, thus providing valuable information for similar cases.

RAB42 overexpression correlates with poor prognosis, immune cell infiltration and chemoresistance.

Background: RAB42 (Ras-related protein 42) is a new small GTPase that controls the vesicular trafficking from endosomes to trans-Golgi network in mammalian cells. However, the role of RAB42 in multiple cancers, especially in liver hepatocellular carcinoma (LIHC), has not been well investigated. Methods: A variety of cancer-related databases and online tools, including TCGA, GTEx, TARGET, QUANTISEQ, EPIC, RNAactDrug, CTR-DB, TIMER algorithms and Sangerbox, were applied to explore the correlation of RAB42 expression with prognosis, immune microenvironment, immune regulatory network, RNA modification, pathway activation and drug sensitivity in pan-cancer. The prognostic, immunomodulatory and tumor-promoting effects of RAB42 were verified in various malignancies and determined by a series of in vitro cellular experiments. Results: RAB42 is significantly overexpressed in most cancers with advanced pathological stages. Its overexpression is correlated with poor survival in pan-cancer. RAB42 overexpression has a high diagnostic accuracy of various cancers (AUC > 0.80). RAB42 overexpression not only correlates with distinct stromal immune infiltration and level of immune checkpoint molecules, but also associates with weak immune cell infiltration, immunomodulatory genes expression, and immunotherapeutic response to immune checkpoint inhibitors (ICIs). Additionally, RAB42 overexpression correlates with enhanced expression of m6A RNA methylation-related genes (MRGs) and its interactors. Moreover, overexpression of RAB42 serves as a drug-resistant marker to certain chemotherapies and acts as a potential biomarker for LIHC. Notably, RAB42 overexpression or activation promotes the cellular proliferation, migration and invasion of LIHC. Conclusion: Overexpressed RAB42 serves as a potential prognostic biomarker and therapeutic target in pan-cancer, especially in LIHC.

Clinical and endoscopic characteristics of colorectal sessile serrated lesions with or without dysplasia/carcinoma: A systematic review and meta-analysis.

OBJECTIVE: We aimed to compare the clinical and endoscopic characteristics of sessile serrated lesions (SSLs) with dysplasia/carcinoma (SSLD/Cs) and SSLs without dysplasia in this systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, and Cochrane Library databases and Clinicaltrials.gov were searched for relevant studies published up to August 28, 2023. The primary outcome was lesion size in SSLD/Cs and SSLs without dysplasia. The secondary outcomes included risk of dysplasia/carcinoma, morphology (classified based on the Paris classification), and lesion features such as mucus cap and nodules/protrusions in the two groups. RESULTS: Thirteen studies with 14 381 patients were included. The proportion of SSLD/Cs ≥10 mm was significantly higher than that of SSLs without dysplasia (odds ratio [OR] 3.82, 95% confidence interval [CI] 1.21-12.02, p = 0.02). There was no significant difference in the risk of dysplasia/carcinoma between the proximal (OR 0.80, 95% CI 0.57-1.14) and distal colon (OR 1.25, 95% CI 0.88-1.77, p = 0.21). The 0-Ip (OR 2.47, 95% CI 1.50-4.09) and 0-IIa + Is (OR 10.38, 95% CI 3.08-34.98) morphologies were more prevalent among SSLD/Cs, whereas the 0-IIa morphology (OR 0.38, 95% CI 0.22-0.65) was more prevalent among SSLs without dysplasia (all p < 0.001). Furthermore, mucus cap (OR 0.61, 95% CI 0.42-0.89, p = 0.01) was more common among SSLs without dysplasia, whereas nodules/protrusions (OR 7.80, 95% CI 3.07-19.85, p < 0.001) were more common in SSLD/Cs. CONCLUSION: SSLs >10 mm, 0-Ip or 0-IIa + Is morphologies, and those with nodules/protrusions are significantly associated with dysplasia/carcinoma.

Orthogonal Geometry Enhancing the Intersystem Crossing and Photosensitive Efficiency of Spiro Organoboron Compounds.

Based on the reported spiro organoboron compounds (PS1 and PS2 as potent 1O2 sensitizers), several new organoboron molecules (PS4-PS9) were constructed through structural modification, and their low-lying excited states and photophysical properties have been explored by density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. The predicted effective intersystem crossing (ISC) processes arise from the S1→T2 transition for PS4-PS6 and the S1→T4 transition for PS1, and corresponding KISC rate constants reach the order of magnitude of 109 (s-1). The organoboron compounds with a (N, N) chelate acceptor are predicted to exhibit relatively higher ISC efficiency than those bearing a (N, O) acceptor, and the planar C3NBN ring and the orthogonal configuration between the donor and acceptor moieties are responsible for the ISC rate enhancement. Importantly, the geometric features of the lowest singlet excited state (S1) for these compounds play a decisive role in their photosensitive efficiency. The present results provide a basis for better understanding of the photosensitivity of these spiro organoboron compounds and the structural modification effect.

Single-cell RNA sequencing reveals the CRTAC1+ population actively contributes to the pathogenesis of spinal ligament degeneration by SPP1+ macrophage.

Degenerative spinal stenosis is a chronic disease that affects the spinal ligaments and associated bones, resulting in back pain and disorders of the limbs among the elderly population. There are few preventive strategies for such ligament degeneration. We here aimed to establish a comprehensive transcriptomic atlas of ligament tissues to identify high-priority targets for pharmaceutical treatment of ligament degeneration. Here, single-cell RNA sequencing was performed on six degenerative ligaments and three traumatic ligaments to understand tissue heterogeneity. After stringent quality control, high-quality data were obtained from 32,014 cells. Distinct cell clusters comprising stromal and immune cells were identified in ligament tissues. Among them, we noted that collagen degradation associated with CTHRC1+ fibroblast-like cells and calcification linked to CRTAC1+ chondrocyte-like cells were key features of ligament degeneration. SCENIC analysis and further experiments identified ATF3 as a key transcription factor regulating the pathogenesis of CRTAC1+ chondrocyte-like cells. Typically, immune cells infiltrate localized organs, causing tissue damage. In our study, myeloid cells were found to be inflammatory-activated, and SPP1+ macrophages were notably enriched in degenerative ligaments. Further exploration via CellChat analysis demonstrated a robust interaction between SPP1+ macrophages and CRTAC1+ chondrocyte-like cells. Activated by SPP1, ATF3 propels the CRTAC1/MGP/CLU axis, fostering ligament calcification. Our unique resource provides novel insights into possible mechanisms underlying ligament degeneration, the target cell types, and molecules that are expected to mitigate degenerative spinal ligament. We also highlight the role of immune regulation in ligament degeneration and calcification, enhancing our understanding of this disease.

A long term outcomes analysis of severe haemophilia A boys receiving 4 years prophylaxis on the Chinese Haemophilia Individualized escalating low dose Prophylaxis (CHIPS).

BACKGROUND: The Chinese Haemophilia Individualized Prophylaxis Study (CHIPS), which was launched in 2016, reported a significant reduction in haemarthrosis over a one-year study. However, its long-term efficacy requires verification. This paper summarizes the clinical outcomes of 18 severe haemophilia A (SHA) patients who completed one year on the CHIPS and 3 more years of follow-up. METHODS: Clinical follow-up was based on the CHIPS protocol (from July 2018 to July 2021). Escalation was based on index joint bleeding, and serial ultrasound (greyscale and colour Doppler) examinations of the index joints (both sides of the ankles, knees and elbows) were conducted every 6 months via a scoring system. RESULTS: A total of 18 SHA patients completed the 3-year study. Fifteen patients dropped out due to the financial crisis during the COVID-19 pandemic in China. The median age was 5.4 (range 4.3-6.9) years. A significant reduction in haemarthrosis was achieved, with mean annual bleeding rates reduced from 18.9 ± 2.8 to 1.7 ± 0.4 (p < 0.001), annual joint bleeding rates from 3.1 ± 0.7 to1.2 ± 0.3 (p < 0.028). 5 out of 8 target joint resolved. Sixteen doses were escalated. At study exit, the heterogeneous treatment outcomes of the SHA boys were 5 at step 4 (20-25 lU/kg, every other day), 10 at step 3 (15-20 IU/kg, 3×/week), 2 at step 2 (10-15 lU/kg, 3×/week) and 1 at step 1 (10-15 lU/kg, 2×/week). The mean FVIII consumption was 2964 IU/kg/year, with savings. The quality of life improved, with Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT, Chinese Version 2.0) scores ranging from 68.8 to 78.8. There was no change in the ultrasound score. CONCLUSION: Our follow-up data on the 18 SHA boys after completing one year on the CHIPS verify the long-term efficacy of the CHIPS for haemarthrosis reduction, joint health preservation, improvement in the quality of life of the boys and cost savings.

Corrigendum: Phylogenetic analysis of the viral proteins VP4/VP7 of circulating human rotavirus strains in China from 2016 to 2019 and comparison of their antigenic epitopes with those of vaccine strains.

[This corrects the article DOI: 10.3389/fcimb.2022.927490.].

Highly Thermally Conductive and Flexible Thermal Interface Materials with Aligned Graphene Lamella Frameworks.

Highly thermally conductive and flexible thermal interface materials (TIMs) are desirable for heat dissipation in modern electronic devices. Here, we fabricated a high-crystalline aligned graphene lamella framework (AGLF) with precisely controlled lamella thickness, pore structure, and excellent intergraphene contact by manipulating the thermal expansion behavior of scanning centrifugal casted graphene oxide films. The rational design of the AGLF balances the trade-off between the thermal conductivity and flexibility of TIMs. The AGLF-based TIM (AGLF-TIM) shows a record thermal conductivity of 196.3 W m-1 K-1 with a graphene loading of only 9.4 vol %, which is about 4 times higher than those of reported TIMs at a similar graphene loading. Meanwhile, good flexibility remains comparable to that of commercial TIMs. As a result, an LED device achieves an additional temperature decrease of ∼8 °C with the use of AGLF-TIM compared to high-performance commercial TIMs. This work offers a strategy for the controlled fabrication of graphene macrostructures, showing the potential use of graphene as filler frameworks in thermal management.

Dual Modification for Low-Strain Ni-Rich Cathodes Toward Superior Cyclability in Pouch Full Cells.

Rapid capacity fading, interfacial instability, and thermal runaway due to oxygen loss are critical obstacles hindering the practical application and commercialization of Ni-rich cathodes (LiNi0.8Co0.1Mn0.1O2, NCM811). Herein, a Sn4+/F- codoping and LiF-coated Ni-rich cathode, denoted as NCM811-SF, is structurally fabricated that demonstrates very high cyclic and thermal stabilities. The introduction of Sn4+ regulates the local electronic structure and facilitates the conversion of the layered structure into a spinel phase; F- captures lithium impurities to form LiF coatings and forms TM-F bonds to reduce Ni/Li disordering. The compositionally complex codoping strategy reduces the internal structure strain, inhibits the Li+/Ni2+ intermixing during cycling and degradation of the nanoscale structure, and further improves the thermal stability and the crystal structure. The cathodic electrode showed a little volume shift at 2.8-4.5 V, which significantly decreased lattice flaws and fractures generated by local strain, based on detailed analyses performed using COMSOL simulations, X-ray diffraction, and scanning transmission electron microscopy. Benefiting from this, after 300 cycles, our as-prepared NCM811-SF cathode maintains 85.4% of its initial capacity at 4.5 V and has an excellent reversible capacity equal to 169 mAh·g-1 at 1 C. In addition, the NCM811-SF/graphite cell in a pouch-type complete cell retained 94.8% of its starting capacity following 500 cycles. These findings underscore the effectiveness of introducing the Sn-O and TM-F bonds in improving the durability and electrochemical efficiency of the cathode material, which makes it a good choice for high-efficiency Li-ion batteries.

Lipid synthesis, triggered by PPARγ T166 dephosphorylation, sustains reparative function of macrophages during tissue repair.

Macrophages may acquire a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements underpinning this process are incompletely understood. Here, we show that posttranslational modification (PTM) of PPARγ regulates lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrates function of reparative macrophages. In injured tissues, repair signaling leads to decreased macrophage PPARγ threonine 166 (T166) phosphorylation, which results in a partially active PPARγ transcriptional program comprised of increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby increased lipogenesis. The accumulated lipids serve as signaling molecules, triggering STAT3-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for protein secretion. Genetic or pharmacological inhibition of PPARγ T166 phosphorylation promotes the reparative function of macrophages and facilitates tissue regeneration. In summary, our work identifies PPARγ T166-regulated lipid biosynthesis as an essential pathway for meeting the anabolic demands of the activation and function of macrophages and provides a rationale for potential therapeutic targeting of tissue repair.

Associations of the EAT-Lancet reference diet with metabolic dysfunction-associated steatotic liver disease and its severity: A multicohort study.

BACKGROUND AND AIMS: The EAT-Lancet Commission devised a globally sustainable dietary pattern to jointly promote human health and sustainability. However, the extent to which this diet supports metabolic dysfunction-associated steatotic liver disease (MASLD) has not yet been assessed. This study aimed to investigate the association between the EAT-Lancet diet and the risk of MASLD and its severity. APPROACH AND RESULTS: This prospective multicohort study included 15,263 adults from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) cohort, 1137 adults from the Guangzhou Nutrition and Health Study (GNHS) cohort, and 175,078 adults from the UK Biobank. In addition, 228 Chinese adults from the Prospective Epidemic Research Specifically of Non-alcoholic Steatohepatitis (PERSONS) with biopsy-proven MASLD were included. An EAT-Lancet diet index was created to reflect adherence to the EAT-Lancet reference diet. The TCLSIH cohort recorded 3010 MASLD cases during 53,575 person-years of follow-up, the GNHS cohort documented 624 MASLD cases during 6454 person-years of follow-up, and the UK Biobank developed 1350 MASLD cases during 1,745,432 person-years of follow-up. In multivariable models, participants in the highest tertiles of the EAT-Lancet diet index had a lower risk of MASLD compared with those in the lowest tertiles (TCLSIH: HR = 0.87, 95% CI: 0.78, 0.96; GNHS: HR = 0.79, 95% CI: 0.64, 0.98; UK Biobank: HR = 0.73, 95% CI: 0.63, 0.85). Moreover, liver-controlled attenuation parameter decreased with increasing the diet index in individuals with biopsy-proven MASLD (ß = -5.895; 95% CI: -10.014, -1.775). CONCLUSIONS: Adherence to the EAT-Lancet reference diet was inversely associated with the risk of MASLD as well as its severity.

Umpolung Strategy for the One-Pot Synthesis of Highly Steric Bispirooxindoles via the l-Amino Acid Ester-Promoted In Situ Reduction/Nucleophilic Addition/Cyclization Cascade Reaction.

On the basis of a novel umpolung strategy, an efficient l-amino acid ester-mediated in situ reduction of 2-(2-oxoindolin-3-ylidene)malononitrile and sequential nucleophilic addition/cyclization cascade reaction is reported. Various densely substituted cyclopentene bispirooxindoles and dihydrofuran bispirooxindoles with two quaternary spirocenters were constructed in high yields (≤93%) with excellent diastereoselectivities (>20:1 dr). The method has advantages of readily available starting materials, mild reaction conditions, a one-pot process, a metal-free biomimetic reducing agent, a wide substrate scope, and operational simplicity (single filtration without column chromatography).

Prediction of laser printers and cartridges based on three-dimensional profiles via discrimination analysis.

Printer source prediction is an important task when examining questioned documents. While some research has provided methods to predict the source printer of documents, with the advent of compatible consumables, printer prediction could become more complex and difficult. Predicting the source printer after replacing cartridges and identifying the source of printer cartridges are unresolved issues that are rarely addressed in current research. Herein, we introduce a novel technique to predict the manufacturer, model, and cartridges of laser printers (i.e., compatible, and original cartridges) used to produce a given document. Document samples produced using eight laser printers and 247 cartridges were collected to establish a dataset. Common manufacturers included HP, Canon, Lenovo, and Epson. After obtaining white-light images and three-dimensional profile images of printed characters, a morphological analysis was conducted by questioned document examiners (QDEs) using microscopy. Microscopic image features across a series of images were also extracted and analyzed using algorithms. Then, six high-dimensional reduction algorithms were used to obtain between- and within-printer variations as well as between- and within-cartridge variations. Finally, we conducted principal component analysis (PCA) and discriminant analysis. For 40 % of the samples, mixed discrimination analysis (MDA) and fixed discrimination analysis (FDA) were employed to predict the manufacturer, model and cartridge of laser printers used to produce the questioned printed document; the remaining 60 % samples comprised the training dataset. In the prediction of manufacturer, model and cartridge, our method achieved mean accuracies of 95.5 %, 97.5 %, and 90.2 %, respectively. Hence, this technique could reasonably aid in predicting the manufacturer, model, and cartridge of a laser printer, even if different cartridges are loaded into printers.

Red blood cell distribution width to albumin ratio associates with prevalence and long-term diabetes mellitus prognosis: an overview of NHANES 1999-2020 data.

Background: Erythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality. Methods: Data analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999-2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of long-term prognosis. Results: Among non-DM (n=30,404) and DM (n=10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead (n=2,411) and surviving (n=6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P<0.0001). The multivariable hazard ratio (HR) for RAR was 1.80 (95% CI 1.57, 2.05). Considering Q1 as a foundation, the Q4 HR was 2.59 (95% CI 2.18, 3.09) after adjusting for confounding factors. Sensitivity analysis revealed the HR of male DM patients to be 2.27 (95% CI 1.95, 2.64), higher than females 1.56 (95% CI 1.31, 1.85). DM patients who were 60 years of age or younger had a higher HR of 2.08 (95% CI1.61, 2.70) as compared to those older than 60 years, who had an HR of 1.69 (95% CI 1.47, 1.94). The HR of RAR in DM patients was optimized by a restricted cubic spline (RCS) model; 3.22 was determined to be the inflection point of an inverse L-curve. DM patients with a RAR >3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width. Conclusions: The predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients.

OGG1: An emerging multifunctional therapeutic target for the treatment of diseases caused by oxidative DNA damage.

Oxidative DNA damage-related diseases, such as incurable inflammation, malignant tumors, and age-related disorders, present significant challenges in modern medicine due to their complex molecular mechanisms and limitations in identifying effective treatment targets. Recently, 8-oxoguanine DNA glycosylase 1 (OGG1) has emerged as a promising multifunctional therapeutic target for the treatment of these challenging diseases. In this review, we systematically summarize the multiple functions and mechanisms of OGG1, including pro-inflammatory, tumorigenic, and aging regulatory mechanisms. We also highlight the potential of OGG1 inhibitors and activators as potent therapeutic agents for the aforementioned life-limiting diseases. We conclude that OGG1 serves as a multifunctional hub; the inhibition of OGG1 may provide a novel approach for preventing and treating inflammation and cancer, and the activation of OGG1 could be a strategy for preventing age-related disorders. Furthermore, we provide an extensive overview of successful applications of OGG1 regulation in treating inflammatory, cancerous, and aging-related diseases. Finally, we discuss the current challenges and future directions of OGG1 as an emerging multifunctional therapeutic marker for the aforementioned challenging diseases. The aim of this review is to provide a robust reference for scientific researchers and clinical drug developers in the development of novel clinical targeted drugs for life-limiting diseases, especially for incurable inflammation, malignant tumors, and age-related disorders.

Amitriptyline protects afferent synapses in the cochlea against excitotoxic trauma in vitro.

Afferent synapses between inner hair cells (IHCs) and the type I spiral ganglion neurons (SGNs) in the cochlea provide over 95% of sensory signals for auditory perception in the brain. However, these afferent synapses are particularly vulnerable to damage, for example from excitotoxicity, and exposure to noise in the environment which often leads to noise-induced cochlear synaptopathy (NICS). In this study, we simulated excitotoxic trauma by incubating kainic acid, a non-desensitizing agonist for AMPA type glutamate receptors on cultured cochleae. The possible protective effects of amitriptyline against NICS were examined. We found that, in IHCs, amitriptyline reversed the decrease of Ca2+ current and exocytosis caused by excitotoxic trauma. In SGNs, amitriptyline promoted the recovery of neurite loss caused by excitotoxic trauma. Furthermore, we found that the protective effects of amitriptyline are likely mediated by suppressing apoptosis factors that were upregulated during excitotoxic trauma. In conclusion, our results suggest that amitriptyline could protect afferent synapses in the cochlea from NICS, making it a potential drug candidate for hearing protection.

Association of proton-density fat fraction with osteoporosis: a systematic review and meta-analysis.

This study aimed to evaluate the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, assessing its effectiveness as a biomarker for osteoporosis. A systematic review was conducted by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a mean difference of 11.04 (95% CI: 9.17 to 12.92, Z=11.52, P < 0.00001). Measuring PDFF via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care. OBJECTIVE: This study aims to assess the correlation between measuring proton-density fat fraction (PDFF) in bone marrow using multi-echo chemical shift-encoded MRI and osteoporosis, evaluating its effectiveness as a biomarker for osteoporosis. MATERIALS AND METHODS: This systematic review was carried out by two independent researchers using Cochrane, PubMed, EMBASE, and Web of Science databases up to December 2023. Quality assessments were evaluated using the Cochrane risk of bias tool and the Agency for Healthcare Research and Quality (AHRQ) checklist. RESULTS: Fourteen studies involving 1495 patients were analyzed. The meta-analysis revealed a significant difference in PDFF values between the osteoporosis/osteopenia group and the normal control group, with a (MD = 11.04, 95% CI: 9.17 to 12.92, Z = 11.52, P < 0.00001). Subgroup analyses indicated that diagnostic methods, gender, and echo length did not significantly impact the PDFF-osteoporosis association. CONCLUSION: PDFF measurement via MRI shows potential as an osteoporosis biomarker and may serve as a risk factor for osteoporosis. This insight opens new avenues for future diagnostic and therapeutic strategies, potentially improving osteoporosis management and patient care.

N-Heterocyclic Carbene Enabled Copper Catalyzed Asymmetric Synthesis of Pyrimidinyl Phosphine with both Axial and P- Stereogenicity.

P-stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu-catalyzed asymmetric C-P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96% ee, and good diastereoselectivity, with up to 14:1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.