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.

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

BACKGROUND 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 risk of MASLD and its severity. APPROACH RESULTS: This prospective multi-cohort study included 15,263 adults from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) cohort, 1,137 adults from the Guangzhou Nutrition and Health Study (GNHS) cohort, and 175,078 adults from the UK Biobank. Additionally, 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 3,010 MASLD cases during 53,575 person-years of follow-up, the GNHS cohort documented 624 MASLD cases during 6,454 person-years of follow-up, and the UK Biobank 1,350 developed 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 risk of MASLD as well as its severity.

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.

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.

ASA VI controls osteoarthritis in mice by maintaining mitochondrial homeostasis through Sirtuin 3.

OBJECTIVE: The aim of this study was to investigate whether ASA VI controls osteoarthritis (OA) by regulating mitochondrial function. METHODS: Primary chondrocytes were isolated and cultured from rat knee joints. The chondrocytes were treated with ASA VI and interleukin-1ß (IL-1ß) to simulate the inflammatory environment of OA. Cell viability, apoptosis, inflammatory cytokine levels, and extracellular matrix (ECM) component levels were assessed. Mitochondrial function, including ATP levels, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and mitochondrial DNA content, was evaluated. The expression of Sirtuin 3 (Sirt3), a key regulator of mitochondrial homeostasis, was examined. Additionally, a rat OA model was established by destabilizing the medial meniscus, and the effects of ASA VI on cartilage degeneration were assessed. RESULTS: ASA VI treatment improved cell viability, reduced apoptosis, and decreased IL-6 and TNF-α levels in IL-1ß-induced chondrocytes. ASA VI also upregulated Collagen II and Aggrecan expression, while downregulating ADAMTS5 and MMP-13 expression. Furthermore, ASA VI mitigated IL-1ß-induced mitochondrial dysfunction by increasing ATP levels, restoring mitochondrial membrane potential, reducing ROS production, and preserving mitochondrial DNA content. These effects were accompanied by the activation of Sirt3. In the rat OA model, ASA VI treatment increased Sirt3 expression and alleviated cartilage degeneration. CONCLUSION: ASA VI exerts chondroprotective and anti-inflammatory effects on IL-1ß-induced chondrocytes by improving mitochondrial function through Sirt3 activation. ASA VI also attenuates cartilage degeneration in a rat OA model. These findings suggest that ASA VI may be a potential therapeutic agent for the treatment of osteoarthritis by targeting mitochondrial dysfunction.

Lactate dehydrogenase A (LDHA)-mediated lactate generation promotes pulmonary vascular remodeling in pulmonary hypertension.

BACKGROUND: High levels of lactate are positively associated with prognosis and mortality in pulmonary hypertension (PH). Lactate dehydrogenase A (LDHA) is a key enzyme for the production of lactate. This study is undertaken to investigate the role and molecular mechanisms of lactate and LDHA in PH. METHODS: Lactate levels were measured by a lactate assay kit. LDHA expression and localization were detected by western blot and Immunofluorescence. Proliferation and migration were determined by CCK8, western blot, EdU assay and scratch-wound assay. The right heart catheterization and right heart ultrasound were measured to evaluate cardiopulmonary function. RESULTS: In vitro, we found that lactate promoted proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in an LDHA-dependent manner. In vivo, we found that LDHA knockdown reduced lactate overaccumulation in the lungs of mice exposed to hypoxia. Furthermore, LDHA knockdown ameliorated hypoxia-induced vascular remodeling and right ventricular dysfunction. In addition, the activation of Akt signaling by hypoxia was suppressed by LDHA knockdown both in vivo and in vitro. The overexpression of Akt reversed the inhibitory effect of LDHA knockdown on proliferation in PASMCs under hypoxia. Finally, LDHA inhibitor attenuated vascular remodeling and right ventricular dysfunction in Sugen/hypoxia mouse PH model, Monocrotaline (MCT)-induced rat PH model and chronic hypoxia-induced mouse PH model. CONCLUSIONS: Thus, LDHA-mediated lactate production promotes pulmonary vascular remodeling in PH by activating Akt signaling pathway, suggesting the potential role of LDHA in regulating the metabolic reprogramming and vascular remodeling in PH.

Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer.

BACKGROUND: Cervical cancer has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors such as programmed cell death protein 1 (PD-1) blockade are promising therapeutic agents, but their efficacy when combined with neoadjuvant chemotherapy (NACT) has not been fully tested, and how they alter the tumor microenvironment has not been comprehensively elucidated. METHODS: In this study, we conducted single-cell RNA sequencing using 46,950 cells from nine human cervical cancer tissues representing sequential different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and identified the crucial factors involved in combination therapy. Cell-cell communication analysis was performed between tumor and immune cells. In addition, THP-1-derived and primary monocyte-derived macrophages were cocultured with cervical cancer cells and phagocytosis was detected by flow cytometry. The antitumor activity of blocking CD74 was validated in vivo using a CD74 humanized subcutaneous tumor model. RESULTS: Pathway enrichment analysis indicated that NACT activated cytokine and complement-related immune responses. Cell-cell communication analysis revealed that after NACT therapy, interaction strength between T cells and cancer cells decreased, but intensified between macrophages and cancer cells. We verified that macrophages were necessary for the PD-1 blockade to exert antitumor effects in vitro. Additionally, CD74-positive macrophages frequently interacted with the most immunoreactive epithelial subgroup 3 (Epi3) cancer subgroup during combination NACT. We found that CD74 upregulation limited phagocytosis and stimulated M2 polarization, whereas CD74 blockade enhanced macrophage phagocytosis, decreasing cervical cancer cell viability in vitro and in vivo. CONCLUSIONS: Our study reveals the dynamic cell-cell interaction network in the cervical cancer microenvironment influenced by combining NACT and PD-1 blockade. Furthermore, blocking tumor-associated macrophage-derived CD74 could augment neoadjuvant therapeutic efficacy.

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.

D-Limonene Inhibits Pichia kluyveri Y-11519 in Sichuan Pickles by Disrupting Metabolism.

The Pichia kluyveri, a proliferation commonly found in Sichuan pickles (SCPs), can accelerate the growth and reproduction of spoilage bacteria, causing off-odor development and decay. Although D-limonene, a common natural preservative, effectively restricts P. kluyveri, its inhibitory mechanism remains unclear. This study aimed to elucidate this molecular mechanism by investigating the impact on basic P. kluyveri metabolism. The findings revealed that D-limonene inhibited P. kluyveri growth and disrupted the transcription of the genes responsible for encoding the enzymes involved in cell wall and membrane synthesis, oxidative phosphorylation, glycolysis, and the tricarboxylic acid (TCA) cycle pathway. The results indicated that these events disrupted crucial metabolism such as cell wall and membrane integrity, adenosine triphosphate (ATP) synthesis, and reactive oxygen species (ROS) balance. These insights provided a comprehensive understanding of the inhibitory effect of D-limonene on the growth and reproduction of P. kluyveri while highlighting its potential application in the SCP industry.

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.

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.

An unusual winter bloom of dinoflagellates with notable damage to kelp cultivation around Shandong peninsula, China.

In the coastal waters around Shandong peninsula, an unprecedented winter bloom of dinoflagellates Gonyaulax polygramma and Akashiwo sanguinea occurred in 2021 from late November to early December. The bloom affected a wide area of coastal waters extending from west to east along the northern Shandong peninsula and had a devastating blow to the kelp cultivation industry. Based on the remote-sensing data, the initiation of the bloom was traced back to the region adjacent to the mouth of the Yellow River in Laizhou Bay, where enhanced freshwater discharge from the Yellow River was recorded from September to November. It's proposed that the increased precipitation in the Yellow River basin associated with northward extension of the precipitation band in China could be an important reason for this winter bloom. This unusual winter bloom around Shandong peninsula highlights the potential risks of harmful algal blooms and their impacts on coastal ecosystems under the background of climate change.

Prime Editing of Vascular Endothelial Growth Factor Receptor 2 Attenuates Angiogenesis In Vitro.

Vascular endothelial growth factor receptor (VEGFR)-2 is a key switch for angiogenesis, which is observed in various human diseases. In this study, a novel system for advanced prime editing (PE), termed PE6h, is developed, consisting of dual lentiviral vectors: (1) a clustered regularly interspaced palindromic repeat-associated protein 9 (H840A) nickase fused with reverse transcriptase and an enhanced PE guide RNA and (2) a dominant negative (DN) MutL homolog 1 gene with nicking guide RNA. PE6h was used to edit VEGFR2 (c.18315T>A, 50.8%) to generate a premature stop codon (TAG from AAG), resulting in the production of DN-VEGFR2 (787 aa) in human retinal microvascular endothelial cells (HRECs). DN-VEGFR2 impeded VEGF-induced phosphorylation of VEGFR2, Akt, and extracellular signal-regulated kinase-1/2 and tube formation in PE6h-edited HRECs in vitro. Overall, our results highlight the potential of PE6h to inhibit angiogenesis in vivo.

Giant Second Harmonic Generation in Supertwisted WS2 Spirals Grown in Step-Edge Particle-Induced Non-Euclidean Surfaces.

In moiré crystals resulting from the stacking of twisted two-dimensional (2D) layered materials, a subtle adjustment in the twist angle surprisingly gives rise to a wide range of correlated optical and electrical properties. Herein, we report the synthesis of supertwisted WS2 spirals and the observation of giant second harmonic generation (SHG) in these spirals. Supertwisted WS2 spirals featuring different twist angles are synthesized on a Euclidean or step-edge particle-induced non-Euclidean surface using carefully designed water-assisted chemical vapor deposition. We observed an oscillatory dependence of SHG intensity on layer number, attributed to atomically phase-matched nonlinear dipoles within layers of supertwisted spiral crystals where inversion symmetry is restored. Through an investigation into the twist angle evolution of SHG intensity, we discovered that the stacking model between layers plays a crucial role in determining the nonlinearity, and the SHG signals in supertwisted spirals exhibit enhancements by a factor of 2 to 136 when compared with the SHG of the single-layer structure. These findings provide helpful perspectives on the rational growth of 2D twisted structures and the implementation of twist angle adjustable endowing them great potential for exploring strong coupling correlation physics and applications in the field of twistronics.

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.

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.

Biomechanical behavior of temporomandibular joint movements driven by mastication muscles.

Surgery of jawbones has a high potential risk of causing complications associated with temporomandibular joint disorder (TMD). The objective of this study was to investigate the effects of two drive modeling methods on the biomechanical behavior of the temporomandibular joint (TMJ) including articular disc during mandibular movements. A finite element (FE) model from a healthy human computed tomography was used to evaluate TMJ dynamic using two methods, namely, a conventional spatial-oriented method (displacement-driven) and a compliant muscle-initiated method (masticatory muscle-driven). The same virtual FE model was 3D printed and a custom designed experimental platform was established to validate the accuracy of experimental and theoretical results of the TMJ biomechanics during mandibular movements. The results show that stress distributed to TMJ and articular disc from mandibular movements provided better representation from the muscle-driving approach than those of the displacement-driven modeling. The simulation and experimental data exhibited significant strong correlations during opening, protrusion, and laterotrusion (with canonical correlation coefficients of 0.994, 0.993, and 0.932, respectively). The use of muscle-driven modeling holds promise for more accurate forecasting of stress analysis of TMJ and articular disc during mandibular movements. The compliant approach to analyze TMJ dynamics would potentially contribute to clinic diagnosis and prediction of TMD resulting from occlusal disease and jawbone surgery such as orthognathic surgery or tumor resection.