Highly intense NIR emissive Cu4Pt2 bimetallic clusters featuring Pt(i)-Cu4-Pt(i) sandwich kernel.

Metal nanoclusters (NCs) capable of near-infrared (NIR) photoluminescence (PL) are gaining increasing interest for their potential applications in bioimaging, cell labelling, and phototherapy. However, the limited quantum yield (QY) of NIR emission in metal NCs, especially those emitting beyond 800 nm, hinders their widespread applications. Herein, we present a bright NIR luminescence (PLQY up to 36.7%, ∼830 nm) bimetallic Cu4Pt2 NC, [Cu4Pt2(MeO-C6H5-C[triple bond, length as m-dash]C)4(dppy)4]2+ (dppy = diphenyl-2-pyridylphosphine), with a high yield (up to 67%). Furthermore, by modifying the electronic effects of R in RC[triple bond, length as m-dash]C- (R = MeO-C6H5, F-C6H5, CF3-C6H5, Nap, and Biph), we can effectively modulate phosphorescence properties, including the PLQY, emission wavelength, and excited state decay lifetime. Experimental and computational studies both demonstrate that in addition to the electron effects of substituents, ligand modification enhances luminescence intensity by suppressing non-radiation transitions through intramolecular interactions. Simultaneously, it allows the adjustment of emitting wavelengths by tuning the energy gaps and first excited triplet states through intermolecular interactions of ligand substituents. This study provides a foundation for rational design of the atomic-structures of alloy metal NCs to enhance their PLQY and tailor the PL wavelength of NIR emission.

Mechanism of targeting the mTOR pathway to regulate ferroptosis in NSCLC with different EGFR mutations.

Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-activating mutations can be treated with EGFR-tyrosine kinase inhibitors (TKIs). Although EGFR-TKI-targeted drugs bring survival promotion in patients with EGFR mutations, drug resistance is inevitable, so it is urgent to explore new treatments to overcome drug resistance. In addition, wild-type EGFR lacks targeted drugs, and new targeted therapies need to be explored. Ferroptosis is a key research direction for overcoming drug resistance. However, the role and mechanism of regulating ferroptosis in different EGFR-mutant NSCLC types remains unclear. In the present study, H1975 (EGFR T790M/L858R mutant), A549 (EGFR wild-type) and H3255 (EGFR L858R mutant) NSCLC cell lines were used. The expression of ferroptosis markers in these cell lines was detected using western blotting and reverse transcription-quantitative PCR. Cell viability was determined using the MTT assay and reactive oxygen species (ROS) levels were measured using flow cytometry. The results showed that, compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to the ferroptosis inducer, erastin. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor, everolimus (RAD001), induced cell death in all three cell lines in a dose-dependent manner. The ferroptosis inhibitor, ferrostatin-1, could reverse cell death in EGFR-resistant mutant and EGFR wild-type cells induced by RAD001, but could not reverse cell death in EGFR-sensitive mutant cells. Compared with EGFR wild-type/sensitive mutant cells, EGFR-resistant mutant cells were more sensitive to RAD001 combined with erastin. In addition, a high-dose of RAD001 reduced the expression levels of ferritin heavy-chain polypeptide 1 (FTH1), glutathione peroxidase 4 (GPX4) and ferroportin and significantly increased ROS and malondialdehyde (MDA) levels in EGFR-resistant mutant and EGFR wild-type cells. In the present study, GPX4 inhibitor only or combined with RAD001 inhibited the AKT/mTOR pathway in EGFR-resistant mutant cells. Therefore, the results of the present study suggested that inhibition of the mTOR pathway may downregulate the expression of ferroptosis-related proteins in EGFR-resistant and EGFR wild-type NSCLC cells, increase the ROS and MDA levels and ultimately induce ferroptosis.

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.

Sleep disturbances, cognitive decline, and AD biomarkers alterations in early Parkinson's disease.

OBJECTIVE: We aimed to investigate whether each type of sleep disturbances (i.e., pRBD, EDS, and insomnia) is specifically associated with faster decline in global cognition and different cognitive domains among de novo PD patients. We also assessed the influence of sleep disturbances on core AD CSF biomarkers alterations and conversion to dementia. METHODS: Prospectively longitudinal data were obtained from the PPMI cohort. Sleep disturbances and cognition ability were assessed by questionnaires at baseline and follow-up visits. Generalized linear mixed models were utilized to assess the effect of sleep disturbances on cognitive decline and core AD CSF biomarkers change. The associations between sleep disturbances and conversion to dementia were analyzed using Cox regression analysis. RESULTS: Baseline pRBD was associated with faster decline in global cognition and all cognitive domains, including verbal episodic memory, visuospatial ability, executive function, language, and processing speed. EDS was associated with faster decline in three cognitive domains, including verbal episodic memory, executive function/working memory, and processing speed. Insomnia was associated with faster decline in global cognition and verbal episodic memory. Meanwhile, pRBD and EDS were associated with longitudinal decrease of CSF Aß42. Baseline pRBD increased the risk of conversion to dementia. The risk of dementia in PD patients with multiple sleep disturbances also increased compared with those without sleep disturbance. INTERPRETATION: Sleep disturbances (i.e., pRBD, EDS, and insomnia) were associated with cognitive decline in early PD. EDS and pRBD were associated with decrease of CSF Aß42. Moreover, pRBD was associated with conversion to dementia.

Association of coffee intake with bone mineral density: a Mendelian randomization study.

Background: In observational studies, the relationship between coffee intake and bone mineral density (BMD) is contradictory. However, residual confounding tends to bias the results of these studies. Therefore, we used a two-sample Mendelian randomization (MR) approach to further investigate the potential causal relationship between the two. Methods: Genetic instrumental variables (IVs) associated with coffee intake were derived from genome-wide association studies (GWAS) of the Food Frequency Questionnaire (FFQ) in 428,860 British individuals and matched using phenotypes in PhenoScanner. Summarized data on BMD were obtained from 537,750 participants, including total body BMD (TB-BMD), TB-BMD in five age brackets ≥60, 45-60, 30-45, 15-30, and 0-15 years, and BMD in four body sites: the lumbar spine, the femoral neck, the heel, and the ultradistal forearm. We used inverse variance weighting (IVW) methods as the primary analytical method for causal inference. In addition, several sensitivity analyses (MR-Egger, Weighted median, MR-PRESSO, Cochran's Q test, and Leave-one-out test) were used to test the robustness of the results. Results: After Bonferroni correction, Coffee intake has a potential positive correlation with total body BMD (effect estimate [Beta]: 0.198, 95% confidence interval [Cl]: 0.05-0.35, P=0.008). In subgroup analyses, coffee intake was potentially positively associated with TB-BMD (45-60, 30-45 years) (Beta: 0.408, 95% Cl: 0.12-0.69, P=0.005; Beta: 0.486, 95% Cl: 0.12-0.85, P=0.010). In addition, a significant positive correlation with heel BMD was also observed (Beta: 0.173, 95% Cl: 0.08-0.27, P=0.002). The results of the sensitivity analysis were generally consistent. Conclusion: The results of the present study provide genetic evidence for the idea that coffee intake is beneficial for bone density. Further studies are needed to reveal the biological mechanisms and offer solid support for clinical guidelines on osteoporosis prevention.

TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis.

Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.

Synthesis of Tetrasubstituted Alkenes by Rhodium-Catalyzed Regioselective Cyano Transfer.

We describe herein a novel, general, and robust approach to structurally diversified alkenyl nitriles through a Rh-catalyzed cyano transfer reaction between alkynyl-malononitrile derivatives and aryl/alkenyl boronic acids. This reaction exhibits high chemo- and regioselectivity and a broad substrate scope. The tetrasubstituted alkenyl dinitriles (34 examples, average 58% yield) are obtained through substrate tuning and ligand control.

SPI1 exacerbates iron accumulation and promotes osteoclast formation through inhibiting the expression of Hepcidin.

BACKGROUND: Osteoporosis (OP) can be caused by an overactive osteoclastic function. Anti-osteoporosis considerable therapeutic effects in tissue repair and regeneration because bone resorption is a unique osteoclast function. In this study, we mainly explored the underlying mechanisms of osteoclasts' effects on osteoporosis. METHODS: RAW264.7 cells were used and induced toward osteoclast and iron accumulation by M-CSF and RANKL administration. We investigated Hepcidin and divalent metal transporter 1 (DMT1) on iron accumulation and osteoclast formation in an ovariectomy (OVX)-induced osteoporosis. Osteoporosis was induced in mice by OVX, and treated with Hepcidin (10, 20, 40, 80 mg/kg, respectively) and overexpression of DMT1 by tail vein injection. Hepcidin, SPI1, and DMT1 were detected by immunohistochemical staining, western blot and RT-PCR. The bioinformatics assays, luciferase assays, and Chromatin Immunoprecipitation (ChIP) verified that Hepcidin was a direct SPI1 transcriptional target. Iron accumulation was detected by laser scanning confocal microscopy, Perl's iron staining and iron content assay. The formation of osteoclasts was assessed using tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: We found that RAW264.7 cells differentiated into osteoclasts when exposed to M-CSF and RANKL, which increased the protein levels of osteoclastogenesis-related genes, including c-Fos, MMP9, and Acp5. We also observed higher concentration of iron accumulation when M-CSF and RANKL were administered. However, Hepcidin inhibited the osteoclast differentiation cells and decreased intracellular iron concentration primary osteoclasts derived from RAW264.7. Spi-1 proto-oncogene (SPI1) transcriptionally repressed the expression of Hepcidin, increased DMT1, facilitated the differentiation and iron accumulation of mouse osteoclasts. Overexpression of SPI1 significantly declined luciferase activity of HAMP promoter and increased the enrichment of HAMP promoter. Furthermore, our results showed that Hepcidin inhibited osteoclast differentiation and iron accumulation in mouse osteoclasts and OVX mice. CONCLUSION: Therefore, the study revealed that SPI1 could inhibit Hepcidin expression contribute to iron accumulation and osteoclast formation via DMT1 signaling activation in mouse with OVX.

CDKN1A regulation on chondrogenic differentiation of human chondrocytes in osteoarthritis through single-cell and bulk sequencing analysis.

Objective: Chondrocyte death is the hallmark of cartilage degeneration during osteoarthritis (OA). However, the specific pathogenesis of cell death in OA chondrocytes has not been elucidated. This study aims to validate the role of CDKN1A, a key programmed cell death (PCD)-related gene, in chondrogenic differentiation using a combination of single-cell and bulk sequencing approaches. Design: OA-related RNA-seq data (GSE114007, GSE55235, GSE152805) were downloaded from Gene Expression Omnibus database. PCD-related genes were obtained from GeneCards database. RNA-seq was performed to annotate the cell types in OA and control samples. Differentially expressed genes (DEGs) among those cell types (scRNA-DEGs) were screened. A nomogram of OA was constructed based on the featured genes, and potential drugs targeting the featured genes were predicted. The presence of key genes was confirmed using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC). Micromass culture and Alcian blue staining were used to determine the effect of CDKN1A on chondrogenesis. Results: Six cell types, namely HomC, HTC, RepC, preFC, FC, and RegC, were annotated in scRNA-seq data. Five featured genes (JUN, CDKN1A, HMGB2, DDIT3, and DDIT4) were screened by multiple biological information analysis methods. TAXOTERE had the highest ability to dock with DDIT3. Functional analysis indicated that CDKN1A was enriched in processes related to collagen catabolism and acts as a positive regulator of autophagy. Additionally, CDKN1A was found to be associated with several KEGG pathways, including those involved in acute myeloid leukemia and autoimmune thyroid disease. CDKN1A was confirmed down-regulated in the joint tissues of OA mouse model and OA model cell. Inhibiting the expression of CDKN1A can significantly suppress the differentiation of OA chondrocytes. Conclusion: Our findings highlight the critical role of CDKN1A in promoting cartilage formation in both in vivo and in vitro and suggest its potential as a therapeutic target for OA treatment.

ROS-induced oxidative stress and mitochondrial dysfunction: a possible mechanism responsible for noise-induced ribbon synaptic damage.

Evidence suggests that damage to the ribbon synapses (RS) may be the main cause of auditory dysfunction in noise-induced hearing loss (NIHL). Oxidative stress is implicated in the pathophysiology of synaptic damage. However, the relationship between oxidative stress and RS damage in NIHL remains unclear. To investigate the hypothesis that noise-induced oxidative stress is a key factor in synaptic damage within the inner ear, we conducted a study using mice subjected to single or repeated noise exposure (NE). We assessed auditory function using auditory brainstem response (ABR) test and examined cochlear morphology by immunofluorescence staining. The results showed that mice that experienced a single NE exhibited a threshold shift and recovered within two weeks. The ABR wave I latencies were prolonged, and the amplitudes decreased, suggesting RS dysfunction. These changes were also demonstrated by the loss of RS as evidenced by immunofluorescence staining. However, we observed threshold shifts that did not return to baseline levels following secondary NE. Additionally, ABR wave I latencies and amplitudes exhibited notable changes. Immunofluorescence staining indicated not only severe damage to RS but also loss of outer hair cells. We also noted decreased T-AOC, ATP, and mitochondrial membrane potential levels, alongside increased hydrogen peroxide concentrations post-NE. Furthermore, the expression levels of 4-HNE and 8-OHdG in the cochlea were notably elevated. Collectively, our findings suggest that the production of reactive oxygen species leads to oxidative damage in the cochlea. This mitochondrial dysfunction consequently contributes to the loss of RS, precipitating an early onset of NIHL.

Engineered probiotic overcomes pathogen defences using signal interference and antibiotic production to treat infection in mice.

Probiotic supplements are suggested to promote human health by preventing pathogen colonization. However, the mechanistic bases for their efficacy in vivo are largely uncharacterized. Here using metabolomics and bacterial genetics, we show that the human oral probiotic Streptococcus salivarius K12 (SAL) produces salivabactin, an antibiotic that effectively inhibits pathogenic Streptococcus pyogenes (GAS) in vitro and in mice. However, prophylactic dosing with SAL enhanced GAS colonization in mice and ex vivo in human saliva. We showed that, on co-colonization, GAS responds to a SAL intercellular peptide signal that controls SAL salivabactin production. GAS produces a secreted protease, SpeB, that targets SAL-derived salivaricins and enhances GAS survival. Using this knowledge, we re-engineered probiotic SAL to prevent signal eavesdropping by GAS and potentiate SAL antimicrobials. This engineered probiotic demonstrated superior efficacy in preventing GAS colonization in vivo. Our findings show that knowledge of interspecies interactions can identify antibiotic- and probiotic-based strategies to combat infection.

Effects of elevated remnant cholesterol on outcomes of acute ischemic stroke patients receiving mechanical thrombectomy.

OBJECTIVE: Large cohort studies provided evidence that elevated remnant cholesterol (RC) was an important risk factor for ischemic stroke. However, the association between high RC and clinical outcomes in acute ischemic stroke (AIS) individuals was still undetermined. METHODS: This retrospective study enrolled 165 AIS patients undergoing mechanical thrombectomy in one tertiary stroke center. We divided patients into two groups based on the median of their RC levels (0.49 mmol/L). The modified Rankin Scale (mRS) was used to evaluate the primary outcome 90 days after the onset of symptoms. The mRS scores ≤ 2 and ≤ 1 at 90 days were deemed as favorable and excellent outcomes, respectively. RESULTS: In the overall AIS patients undergoing mechanical thrombectomy, there was no obvious distinction between the high and low RC group at 90-day favorable outcome (41.0% vs. 47.1%, P = 0.431) or excellent outcome (23.1% vs. 31.0%, P = 0.252). In the subgroup analysis stratified by stroke etiology, non-large artery atherosclerosis (non-LAA) stroke patients yielded with less favorable or excellent prognosis in the high RC group (26.8% vs. 46.8%, adjusted OR = 0.31, 95%CI: 0.11-0.85, P = 0.023; or 12.2% vs. 29.0%, adjusted OR = 0.18, 95%CI: 0.04-0.80, P = 0.024, respectively.). Post hoc power analyses indicated that the power was sufficient for favorable outcome (80.38%) and excellent outcome (88.72%) in non-LAA stroke patients. Additionally, RC can enhance the risk prediction value of a poor outcome (mRS scores 3-6) based on traditional risk indicators (including age, initial NIHSS score, operative duration, and neutrophil-to-lymphocyte ratio) for non-LAA stroke patients (AUC = 0.86, 95%CI: 0.79-0.94, P < 0.001). CONCLUSION: In AIS patients undergoing mechanical thrombectomy, elevated RC was independently related to poor outcome for non-LAA stroke patients, but not to short-term prognosis of LAA stroke patients.

Recyclable N-Heterocyclic Carbene Porous Coordination Polymers with Two Distinct Metal Sites for Transformation of CO2 to Cyclic Carbonates.

Single-component catalysts with integrated multiple reactive centers could work in concert to achieve enhanced activity tailored for specific catalytic reactions, but they remain underdeveloped. Herein, we report the construction of heterogeneous bimetallic porous coordination polymers (PCPs) containing both porphyrin and N-heterocyclic carbene (NHC) metal sites via the coordinative assembly of the NHC functionalities. Three heterobimetallic PCPs (TIPP-Zn-Pd, TIPP-Cu-Pd and TIPP-Ni-Pd) have been prepared to verify this facile synthetic strategy for the first time. In order to establish a cooperative action toward the catalytic CO2 cycloaddition with epoxides, an additional tetraalkylammonium bromide functionality has also been incorporated into these polymeric structures through the N-substituent of the NHC moieties. The resulting heterogeneous bimetallic catalyst TIPP-Zn-Pd exhibits the best catalytic performance in CO2 cycloaddition with styrene oxide (SO) under solvent-free conditions at atmospheric pressure and is applicable to a wide range of epoxides. More importantly, TIPP-Zn-Pd works smoothly and is recyclable in the absence of a cocatalyst under 1.0 MPa of CO2 at 60 °C. This indicates that TIPP-Zn-Pd is quite competitive with the reported heterogeneous catalysts, which typically require a high reaction temperature above 100 °C under cocatalyst-free conditions. Thus, this work provides a new approach to design heterogeneous bimetallic PCP catalysts for high-performance CO2 fixation under mild reaction conditions.

Iron accumulation induced by hepcidin1 knockout accelerates the progression of aging osteoporosis.

OBJECTIVE: Iron accumulation is associated with osteoporosis. This study aims to explore the effect of chronic iron accumulation induced by hepcidin1 deficiency on aging osteoporosis. METHODS: Iron accumulation in hepcidin1 knockout aging mice was assessed by atomic absorption spectroscopy and Perl's staining. Bone microarchitecture was observed using Micro-CT. Hepcidin, ferritin, oxidative stress, and markers of bone turnover in serum were detected by enzyme-linked immunosorbent assay. Bone formation and resorption markers were measured by real-time quantitative PCR. Cell aging was induced by D-galactose treatment. CCK-8, flow cytometry, EdU assays, and Alizarin red staining were performed to reveal the role of hepcidin1 knockout in cell model. Iron Colorimetric Assay Kit and western blot were applied to detect iron and ferritin levels in cells, respectively. RESULTS: In hepcidin1-knockout mice, the ferritin and iron contents in liver and tibia were significantly increased. Iron accumulation induced by hepcidin1 knockout caused a phenotype of low bone mass and deteriorated bone microarchitecture. Osteogenic marker was decreased and osteoclast marker was increased in mice, accompanied by increased oxidative stress level. The mRNA expression levels of osteoclast differentiation markers (RANKL, Mmp9, OPG, Trap, and CTSK) were up-regulated, while bone formation markers (OCN, ALP, Runx2, SP7, and Col-1) were down-regulated in model group, compared to wild type mice. In vitro, hepcidin1 knockdown inhibited proliferation and osteogenic differentiation, while promoted apoptosis, with increased levels of iron and ferritin. CONCLUSION: Iron accumulation induced by hepcidin1 deficiency aggravates the progression of aging osteoporosis via inhibiting osteogenesis and promoting osteoclast genesis.

Effect of zwitterionic sulfobetaine incorporation on blood behaviours, phagocytosis, and in vivo biodistribution of pH-responsive micelles with positive charges.

pH-responsive micelles with positive charges are challenged by their significant effect on the cells/proteins and compromise their final fate due to electrostatic interactions. As one of the promising strategies, zwitterion incorporation in micelles has attracted considerable attention and displayed improved protein adsorption and blood circulation performances. However, previous reports in this field have been mostly limited in hemolysis for studying blood behaviour and lack a comprehensive understanding of their interactions with blood components. Herein, we present a prelimilary study on the effect of zwitterionic sulfobetaine incorporation on blood behaviour, phagocytosis, and in vivo biodistribution of pH-responsive micelles with positive charges. Amphiphilic triblock copolymers, namely poly(ε-caprolactone)-b-poly(N,N-diethylaminoethyl methacrylate)-(N-(3-sulfopropyl-N-methacryloxyethy-N,N-diethylammonium betaine)) (PCL-PDEAPSx, x = 2, 6, 10), containing different numbers of sulfobetaine groups were synthesized through four steps to prepare the pH-responsive micelles with positive charges. The effect of the sulfobetaine incorporation displayed different profiles, e.g., the micelles had no effect on RBC aggregation, thrombin time (TT), and platelet aggregation, while the cytotoxicity, hemolysis, RBC deformability, activated partial thromboplastin time (APTT), prothrombin time (PT), platelet activation, protein (albumin, fibrinogen, plasma) adsorption, phagocytosis, and in vivo biodistribution decreased with the increase in the sulfobetaine number, in which the transition mainly occurred at a sulfobetaine/tertiary amine group ratio of 3/7-1/1 compared to that of the mPEG control. In addition, the micelles displayed a strong inhibitory effect on the intrinsic coagulation pathway, which was associated with a significant decrease in the coagulation factor activity. Based on these findings, the related mechanism is discussed and proposed, which can aid the rational design of pH-responsive micelles for improved therapeutics.

Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.

Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance. Herein, our findings revealed a novel mechanism of LSD1 neddylation and its contribution to decreasing GC cell stemness and chemoresistance. Taken together, our findings may whistle about the future application of neddylation inhibitors.

Carrier rate of thalassemia among 25,910 high school students in Shaoguan area, China.

OBJECTIVES: As one of the most common hereditary diseases, thalassemia affects a large number of people in China. The aim of this study was to investigate the feasibility of a method based on next-generation sequencing (NGS) for screening of thalassemia carriers among high school students in the Shaoguan area. MATERIALS AND METHODS: The NGS-based method was performed using 25,910 high school students recruited from 38 schools. The screening yield was systematically analyzed. Before screening, a lecture on how the disease is inherited, the symptoms of thalassemia, and how to prevent it was given to 28,780 students. RESULTS: Implying successful delivery of information on the disease, 90.03% (25,910 of 28,780) of the students agreed to join this program for thalassemia screening. A thalassemia carrier rate of 15.99% (4144 of 25,910) was found. Also, 69 rare genotypes (28 of α-thalassemia and 41 of ß-thalassemia) and 9 novel variants were identified. CONCLUSIONS: This NGS-based method provided a feasible platform for high school population thalassemia screening. Combined with a clinical follow-up strategy, it could help eventually to prevent the births of affected children.

Mitigating cadmium accumulation in dicotyledonous vegetables by iron fertilizer through inhibiting Fe transporter IRT1-mediated Cd uptake.

The solubility of cadmium (Cd) in soil and its transfer to plants are influenced by soil pH. While increasing soil pH reduces Cd solubility and accumulation in rice plants grown in acidic soils, its effect on Cd accumulation in vegetables remains inconclusive. Here, we investigated the impact of soil pH on Cd accumulation in dicotyledonous vegetables and elucidated the underlying molecular mechanisms. Soils collected from various locations were supplemented with varying quantities of lime to achieve soil pH values of around 5.0, 6.0, 7.0, and 8.0. Raising soil pH from around 5.0 to 8.0 markedly decreased extractable Cd. However, increasing soil pH tended to promote shoot Cd accumulation in dicotyledonous vegetable species including lettuce, pakchoi, and Chinese cabbage, and the model dicotyledonous plant Arabidopsis thaliana. Conversely, soil pH increase resulted in a monotonic decrease in rice Cd accumulation. In our hydroponic experiments, we discovered that iron (Fe) deficiency substantially increased Cd uptake and accumulation in dicotyledonous plants but not in rice. Increasing soil pH reduced soil Fe availability and induced the Fe transporter gene IRT1 expression in dicotyledonous vegetables roots, which led to an increase in IRT1-mediated Cd uptake and subsequently increased Cd accumulation as soil pH increases. A comprehensive model incorporating extractable Cd and root IRT1 expression better explained Cd accumulation in vegetable shoots. The application of 50 mg/kg of Fe fertilizer in neutral or alkaline soils resulted in a significant reduction in Cd accumulation by 34-58% in dicotyledonous vegetables. These findings reveal that increasing soil pH has two opposite effects, decreasing soil Cd availability while promoting Cd uptake through IRT1 upregulation, reconciling the inconsistency in its effect on Cd accumulation in dicotyledonous plants. Our findings provide important insights for understanding the factors affecting Cd uptake in plants and offer a practical solution to mitigate Cd contamination in vegetables.

A novel surgical strategy of three column osteotomy at non-lesioned area for correcting severe angular kyphosis due to Pott's disease: a retrospectively study.

Severe sharp angular kyphosis resulting from Pott's disease typically necessitates surgical intervention. The deployment of three-column osteotomy within the lesion and apical regions has been validated as an effective modality for the amelioration of angular kyphosis. Nonetheless, a propensity for residual kyphosis persists, accompanied by a significant perioperative risk profile. In pursuit of optimizing correctional outcomes and diminishing complication rates, we proposed an innovative surgical approach, utilizing osteotomy in the non-lesioned zones for the rectification of severe angular kyphosis associated with Pott's disease. This retrospective investigation encompasses 16 subjects who underwent this novel surgical tactic, involving osteotomies in non-lesioned vertebral segments, at our institution from 2016 to 2018. Radiographic measures, encompassing kyphotic angle and sagittal vertical axis (SVA), were documented at baseline and during terminal follow-up. Neurological status was evaluated via the American Spinal Injury Association (ASIA) grading system. Operative duration, volume of hemorrhage, and perioperative complications were systematically recorded. The cohort included 6 males and 10 females with an average age of 30.7 ± 11.41 years. Follow-up intervals spanned 24 to 42 months. Mean operative time and blood loss were 492 ± 127.3 min and 1791 ± 788.8 ml, respectively. The kyphotic angle improved from 97.6 ± 14.6° to 28.8 ± 18.70°. In cases with lumbar afflictions, vertebral restoration was achieved (L1-L5 and L2-S1). Initial mean SVA of 6.7 ± 3.58 cm was reduced to 3.3 ± 1.57 cm at follow-up. Neurological function enhancement was observed in six patients, while ten maintained baseline status. Complication rates, including wound infection and rod fracture at 12 months, were observed in approximately 11.8% of cases. Our findings suggest that the surgical strategy is both effective and safe for addressing severe angular kyphosis due to Pott's disease, contingent upon the expertise of the surgical unit.