The relationship between childhood adversity and sleep quality among rural older adults in China: the mediating role of anxiety and negative coping.

BACKGROUND: Studies have revealed the effects of childhood adversity, anxiety, and negative coping on sleep quality in older adults, but few studies have focused on the association between childhood adversity and sleep quality in rural older adults and the potential mechanisms of this influence. In this study, we aim to evaluate sleep quality in rural older adults, analyze the impact of adverse early experiences on their sleep quality, and explore whether anxiety and negative coping mediate this relationship. METHODS: Data were derived from a large cross-sectional study conducted in Deyang City, China, which recruited 6,318 people aged 65 years and older. After excluding non-agricultural household registration and lack of key information, a total of 3,873 rural older adults were included in the analysis. Structural equation modelling (SEM) was used to analyze the relationship between childhood adversity and sleep quality, and the mediating role of anxiety and negative coping. RESULTS: Approximately 48.15% of rural older adults had poor sleep quality, and older adults who were women, less educated, widowed, or living alone or had chronic illnesses had poorer sleep quality. Through structural equation model fitting, the total effect value of childhood adversity on sleep quality was 0.208 (95% CI: 0.146, 0.270), with a direct effect value of 0.066 (95% CI: 0.006, 0.130), accounting for 31.73% of the total effect; the total indirect effect value was 0.142 (95% CI: 0.119, 0.170), accounting for 68.27% of the total effect. The mediating effects of childhood adversity on sleep quality through anxiety and negative coping were significant, with effect values of 0.096 (95% CI: 0.078, 0.119) and 0.024 (95% CI: 0.014, 0.037), respectively. The chain mediating effect of anxiety and negative coping between childhood adversity and sleep quality was also significant, with an effect value of 0.022 (95% CI: 0.017, 0.028). CONCLUSIONS: Anxiety and negative coping were important mediating factors for rural older adult's childhood adversity and sleep quality. This suggests that managing anxiety and negative coping in older adults may mitigate the negative effects of childhood adversity on sleep quality.

Ganoderic acid A ameliorates depressive-like behaviors in CSDS mice: Insights from proteomic profiling and molecular mechanisms.

OBJECTIVE: Ganoderic Acid A (GAA), a primary bioactive component in Ganoderma, has demonstrated ameliorative effects on depressive-like behaviors in a Chronic Social Defeat Stress (CSDS) mouse model. This study aims to elucidate the underlying molecular mechanisms through proteomic analysis. METHODS: C57BL/6 J mice were allocated into control (CON), chronic social defeat stress (CSDS), GAA, and imipramine (IMI) groups. Post-depression induction via CSDS, the GAA and IMI groups received respective treatments of GAA (2.5 mg/kg) and imipramine (10 mg/kg) for five days. Behavioral assessments utilized standardized tests. Proteins from the prefrontal cortex were analyzed using LC-MS, with further examination via bioinformatics and PRM for differential expression. Western blot analysis confirmed protein expression levels. RESULTS: Chronic social defeat stress (CSDS) induced depressive-like behaviors in mice, which were significantly alleviated by GAA treatment, comparably to imipramine (IMI). Proteomic analysis identified distinct proteins in control (305), GAA-treated (949), and IMI-treated (289) groups. Enrichment in mitochondrial and synaptic proteins was evident from GO and PPI analyses. PRM analysis revealed significant expression changes in proteins crucial for mitochondrial and synaptic functions (namely, Naa30, Bnip1, Tubgcp4, Atxn3, Carmil1, Nup37, Apoh, Mrpl42, Tprkb, Acbd5, Dcx, Erbb4, Ppp1r2, Fam3c, Rnf112, and Cep41). Western blot validation in the prefrontal cortex showed increased levels of Mrpl42, Dcx, Fam3c, Ppp1r2, Rnf112, and Naa30 following GAA treatment. CONCLUSION: GAA exhibits potential antidepressant properties, with its action potentially tied to the modulation of synaptic functions and mitochondrial activities.

Differentiation and Regulation of Bovine Th2 Cells In Vitro.

Bovine Th2 cells have usually been characterized by IL4 mRNA expression, but it is unclear whether their IL4 protein expression corresponds to transcription. We found that grass-fed healthy beef cattle, which had been regularly exposed to parasites on the grass, had a low frequency of IL4+ Th2 cells during flow cytometry, similar to animals grown in feedlots. To assess the distribution of IL4+ CD4+ T cells across tissues, samples from the blood, spleen, abomasal (draining), and inguinal lymph nodes were examined, which revealed limited IL4 protein detection in the CD4+ T cells across the examined tissues. To determine if bovine CD4+ T cells may develop into Th2 cells, naïve cells were stimulated with anti-bovine CD3 under a Th2 differentiation kit in vitro. The cells produced primarily IFNγ proteins, with only a small fraction (<10%) co-expressing IL4 proteins. Quantitative PCR confirmed elevated IFNγ transcription but no significant change in IL4 transcription. Surprisingly, GATA3, the master regulator of IL4, was highest in naïve CD4+ T cells but was considerably reduced following differentiation. To determine if the differentiated cells were true Th2 cells, an unbiased proteomic assay was carried out. The assay identified 4212 proteins, 422 of which were differently expressed compared to those in naïve cells. Based on these differential proteins, Th2-related upstream components were predicted, including CD3, CD28, IL4, and IL33, demonstrating typical Th2 differentiation. To boost IL4 expression, T cell receptor (TCR) stimulation strength was reduced by lowering anti-CD3 concentrations. Consequently, weak TCR stimulation essentially abolished Th2 expansion and survival. In addition, extra recombinant bovine IL4 (rbIL4) was added during Th2 differentiation, but, despite enhanced expansion, the IL4 level remained unaltered. These findings suggest that, while bovine CD4+ T cells can respond to Th2 differentiation stimuli, the bovine IL4 pathway is not regulated in the same way as in mice and humans. Furthermore, Ostertagia ostertagi (OO) extract, a gastrointestinal nematode in cattle, inhibited signaling via CD3, CD28, IL4, and TLRs/MYD88, indicating that external pathogens can influence bovine Th2 differentiation. In conclusion, though bovine CD4+ T cells can respond to IL4-driven differentiation, IL4 expression is not a defining feature of differentiated bovine Th2 cells.

The MuSK agonist antibody protects the neuromuscular junction and extends the lifespan in C9orf72-ALS mice.

The disassembly of the neuromuscular junction (NMJ) is an early event in amyotrophic lateral sclerosis (ALS), ultimately leading to motor dysfunction and lethal respiratory paralysis. The hexanucleotide GGGGCC repeat expansion in the C9orf72 gene is the most common genetic mutation, and the dipeptide repeat (DPR) proteins have been shown to cause neurodegeneration. While no drugs can treat ALS patients efficiently, new treatment strategies are urgently needed. Here, we report that a MuSK agonist antibody alleviates poly-PR-induced NMJ deficits in C9orf72-ALS mice. The HB9-PRF/F mice, which express poly-PR proteins in motor neurons, exhibited impaired motor behavior and NMJ deficits. Mechanistically, poly-PR proteins interacted with Agrin to disrupt the interaction between Agrin and Lrp4, leading to attenuated activation of MuSK. Treatment with a MuSK agonist antibody rescued NMJ deficits, and extended the lifespan of C9orf72-ALS mice. Moreover, impaired NMJ transmission was observed in C9orf72-ALS patients. These findings identify the mechanism by which poly-PR proteins attenuate MuSK activation and NMJ transmission, highlighting the potential of promoting MuSK activation with an agonist antibody as a therapeutic strategy to protect NMJ function and prolong the lifespan of ALS patients.

FBXO22 is a potential therapeutic target for recurrent chondrosarcoma.

Chondrosarcoma (CHS) is a malignant bone tumor with insensitivity to both radiotherapy and chemotherapy, and a high recurrence rate. However, the latent mechanism of recurrent CHS (Re-CHS) remains elusive. Here, we discovered that FBXO22 was highly expressed in clinical samples of Re-CHS. FBXO22 played a significant role in various cancers. However, the role of FBXO22 in Re-CHS remained unclear. Our research demonstrated that suppressing FBXO22 abated the proliferation and migration of CHS cells and facilitated their apoptosis. In addition, suppressing FBXO22 raised the expression of PD-L1 in Re-CHS. All these findings provide new evidence for using FBXO22 and PD-L1 as combined targets to prevent and treat Re-CHS, which may prove to be a novel strategy for immunotherapy of CHS, especially Re-CHS.

Photoacoustic trace gas detection of OCS using a 2.45 mL Helmholtz resonator and a 4823.3 nm ICL light source.

A miniaturized photoacoustic spectroscopy-based gas sensor is proposed for the purpose of detecting sub-ppm-level carbonyl sulfide (OCS) using a tunable mid-infrared interband cascade laser (ICL) and a Helmholtz photoacoustic cell. The tuning characteristics of the tunable ICL with a center wavelength of 4823.3 nm were investigated to achieve the optimal driving parameters. A Helmholtz photoacoustic cell with a volume of ∼2.45 mL was designed and optimized to miniaturize the measurement system. By optimizing the modulation parameters and signal processing, the system was verified to have a good linear response to OCS concentration. With a lock-in amplifier integration time of 10 s, the 1σ noise standard deviation in differential mode was 0.84 mV and a minimum detection limit (MDL) of 409.2 ppbV was achieved at atmospheric pressure and room temperature.

Importance of computed tomography perfusion on assessing collateral circulation and prognosis of patients with acute anterior circulation large vessel occlusion after endovascular therapy.

This study probed the importance of computed tomography perfusion (CTP) on assessing collateral circulation and prognosis in patients with acute anterior circulation large vessel occlusion (AAC-LVO) after endovascular therapy (EVT). Retrospective analysis was performed on the case data of 124 AAC-LVO patients who achieved EVT in the First People's Hospital of Lianyungang. All patients received computed tomography (CT) examination. Based on the multi-phase computed tomography angiography (mCTA) score, patients were separated into poor collateral circulation group and good collateral circulation group. Based on modified Rankin scale (mRS) score, patients were separated into good prognosis group and poor prognosis group. The receiver operating characteristic (ROC) curve was used to measure the efficacy of CTP parameters in predicting good collateral circulation or good prognosis. Correlation between CTP parameters with mCTA collateral and 90-day mRS circulation score was analyzed using the Spearman correlation analysis. The age and admission national Institutes of Health stroke scale (NIHSS) scores of the good collateral circulation group were lower than the poor collateral circulation group, and low perfusion area volume with Tmax > 6 s (VTmax>6s), infarct core area volume (VCBF<30%)and hypoperfusion intensity ratio (HIR) were also lower. The mCTA collateral cycle score was negatively related to VTmax>6 s, VCBF<30% and HIR. The area under the curve (AUC) values of VTmax>6 s and VCBF<30% and HIR for predicting good collateral circulation were 0.763, 0.884 and 0.842, respectively, which suggested that perfusion parameters VTmax>6 s, VCBF<30% and HIR could effectively indicate the status of patients' collateral circulation. Relative to the poor prognosis group, patients in the good prognosis group possessed lower admission NIHSS score, younger age, smaller final infarct volume, lower HIR, VCBF<30%, VTmax>6s, Alberta Stroke Program Early CT(ASPECT) score, and higher mCTA score. Spearman correlation analysis unveiled that ASPECT score, mCTA score and 90-day mRS were negatively correlated. The final infarct volume, perfusion parameters HIR and VCBF<30% were positively correlated with 90-day mRS. ROC analysis showed that all variates had good prognostic value for acute anterior circulation great vessel occlusion patients, while VCBF<30% and HIR had high diagnostic value for prognosis. To sum up, CTP can provide a comprehensive imaging assessment of the collateral circulation of patients with AAC-LVO and has a higher predictive value for the prognosis assessment of patients with EVT in terms of VCBF<30%, HIR score and mCTA collateral circulation score.

Bradykinin protects nucleus pulposus cells from tert-butyl hydroperoxide-induced damage and delays intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of degenerative spinal disorders, involving complex biological processes. This study investigates the role of the kallikrein-kinin system (KKS) in IVDD, focusing on the protective effects of bradykinin (BK) on nucleus pulposus cells (NPCs) under oxidative stress. Clinical specimens were collected, and experiments were conducted using human and rat primary NPCs to elucidate BK's impact on tert-butyl hydroperoxide (TBHP)-induced oxidative stress and damage. The results demonstrate that BK significantly inhibits TBHP-induced NPC apoptosis and restores mitochondrial function. Further analysis reveals that this protective effect is mediated through the BK receptor 2 (B2R) and its downstream PI3K/AKT pathway. Additionally, BK/PLGA sustained-release microspheres were developed and validated in a rat model, highlighting their potential therapeutic efficacy for IVDD. Overall, this study sheds light on the crucial role of the KKS in IVDD pathogenesis and suggests targeting the B2R as a promising therapeutic strategy to delay IVDD progression and promote disc regeneration.

Bactericidal and sterilizing activity of sudapyridine-clofazimine-TB47 combined with linezolid or pyrazinamide in a murine model of tuberculosis.

As an obligate aerobe, Mycobacterium tuberculosis relies on its branched electron transport chain (ETC) for energy production through oxidative phosphorylation. Regimens targeting ETC exhibit promising potential to enhance bactericidal activity against M. tuberculosis and hold the prospect of shortening treatment duration. Our previous research demonstrated that the bacteriostatic drug candidate TB47 (T) inhibited the growth of M. tuberculosis by targeting the cytochrome bc1 complex and exhibited synergistic activity with clofazimine (C). Here, we found synergistic activities between C and sudapyridine (S), a structural analog of bedaquiline (B). S has shown similar anti-tuberculosis efficacy and may share a mechanism of action with B, which inhibits ATP synthesis and the energy metabolism of bacteria. We evaluated the efficacy of SCT in combination with linezolid (L) or pyrazinamide (Z) using a well-established murine model of tuberculosis. Compared to the BPa(pretomanid)L regimen, SCT and SCTL demonstrated similar bactericidal and sterilizing activities. There was no significant difference in activity between SCT and SCTL. In contrast, SCZ and SCTZ showed much higher activities, with none of the 15 mice experiencing relapse after 2 months of treatment with either SCZ or SCTZ. However, T did not contribute to the activity of the SCZ. Our findings emphasize the efficacy and the potential clinical significance of combination therapy with ETC inhibitors. Additionally, cross-resistance exists not only between S and B but also between S/B and C. This is supported by our findings, as spontaneous S-resistant mutants exhibited mutations in Rv0678, which are associated with cross-resistance to B and C.

Self-Assembled MXene@Fluorographene Hybrid for High Dielectric Constant and Low Loss Ferroelectric Polymer Composite Films.

Modern electrical applications urgently need flexible polymer films with a high dielectric constant (εr) and low loss. Recently, the MXene-filled percolative composite has emerged as a potential material choice because of the promised high εr. Nevertheless, the typically accompanied high dielectric loss hinders its applications. Herein, a facile and effective surface modification strategy of cladding Ti3C2Tx MXene (T = F or O; FMX) with fluorographene (FG) via self-assembly is proposed. The obtained FMX@FG hybrid yields high εr (up to 108 @1 kHz) and low loss (loss tangent tan δ = 1.16 @ 1 kHz) in a ferroelectric polymer composite at a low loading level (the equivalent of 1.5 wt % FMX), which is superior to its counterparts in our work (e.g., FMX: εr = 104, tan δ = 10.71) and other studies. It is found that the FG layer outside FMX plays a critical role in both the high dielectric constant and low loss from experimental characterizations and finite element simulations. For one thing, FG with a high F/C ratio would induce a favorable structure of high ß-phase crystallinity, extensive microcapacitor networks, and abundant interfacial dipoles in polymer composites that account for the high εr. For another, FG, as a highly insulating layer, can inhibit the formation of conductive networks and inter-FMX electron tunneling, which is responsible for conduction loss. The results demonstrate the potential of a self-assembled FMX@FG hybrid for high εr and low loss polymer composite films and offer a new strategy for designing advanced polymer composite dielectrics.

Appropriate Drought Training Induces Optimal Drought Tolerance by Inducing Stepwise H2O2 Homeostasis in Soybean.

Soybean is considered one of the most drought-sensitive crops, and ROS homeostasis can regulate drought tolerance in these plants. Understanding the mechanism of H2O2 homeostasis and its regulatory effect on drought stress is important for improving drought tolerance in soybean. We used different concentrations of polyethylene glycol (PEG) solutions to simulate the progression from weak drought stress (0.2%, 0.5%, and 1% PEG) to strong drought stress (5% PEG). We investigated the responses of the soybean plant phenotype, ROS level, injury severity, antioxidant system, etc., to different weak drought stresses and subsequent strong drought stresses. The results show that drought-treated plants accumulated H2O2 for signaling and exhibited drought tolerance under the following stronger drought stress, among which the 0.5% PEG treatment had the greatest effect. Under the optimal treatment, there was qualitatively describable H2O2 homeostasis, characterized by a consistent increasing amplitude in H2O2 content compared with CK. The H2O2 signal formed under the optimum treatment induced the capacity of the antioxidant system to remove excess H2O2 to form a primary H2O2 homeostasis. The primary H2O2 homeostasis further induced senior H2O2 homeostasis under the following strong drought and maximized the improvement of drought tolerance. These findings might suggest that gradual drought training could result in stepwise H2O2 homeostasis to continuously improve drought tolerance.

NeighborNet: Learning Intra- and Inter-Image Pixel Neighbor Representation for Breast Lesion Segmentation.

Breast lesion segmentation from ultrasound images is essential in computer-aided breast cancer diagnosis. To alleviate the problems of blurry lesion boundaries and irregular morphologies, common practices combine CNN and attention to integrate global and local information. However, previous methods use two independent modules to extract global and local features separately, such feature-wise inflexible integration ignores the semantic gap between them, resulting in representation redundancy/insufficiency and undesirable restrictions in clinic practices. Moreover, medical images are highly similar to each other due to the imaging methods and human tissues, but the captured global information by transformer-based methods in the medical domain is limited within images, the semantic relations and common knowledge across images are largely ignored. To alleviate the above problems, in the neighbor view, this paper develops a pixel neighbor representation learning method (NeighborNet) to flexibly integrate global and local context within and across images for lesion morphology and boundary modeling. Concretely, we design two neighbor layers to investigate two properties (i.e., number and distribution) of neighbors. The neighbor number for each pixel is not fixed but determined by itself. The neighbor distribution is extended from one image to all images in the datasets. With the two properties, for each pixel at each feature level, the proposed NeighborNet can evolve into the transformer or degenerate into the CNN for adaptive context representation learning to cope with the irregular lesion morphologies and blurry boundaries. The state-of-the-art performances on three ultrasound datasets prove the effectiveness of the proposed NeighborNet. The code is available at: https://github.com/fjcaoww/NeighborNet.

An individualised 3D computational flow and particle model to predict the deposition of inhaled medicines - A case study using a nebuliser.

BACKGROUND AND OBJECTIVE: Drug inhalation is generally accepted as the preferred administration method for treating respiratory diseases. To achieve effective inhaled drug delivery for an individual, it is necessary to use an interdisciplinary approach that can cope with inter-individual differences. The paper aims to present an individualised pulmonary drug deposition model based on Computational Fluid and Particle Dynamics simulations within a time frame acceptable for clinical use. METHODS: We propose a model that can analyse the inhaled drug delivery efficiency based on the patient's airway geometry as well as breathing pattern, which has the potential to also serve as a tool for a sub-regional diagnosis of respiratory diseases. The particle properties and size distribution are taken for the case of drug inhalation by using nebulisers, as they are independent of the patient's breathing pattern. Finally, the inhaled drug doses that reach the deep airways of different lobe regions of the patient are studied. RESULTS: The numerical accuracy of the proposed model is verified by comparison with experimental results. The difference in total drug deposition fractions between the simulation and experimental results is smaller than 4.44% and 1.43% for flow rates of 60 l/min and 15 l/min, respectively. A case study involving a COVID-19 patient is conducted to illustrate the potential clinical use of the model. The study analyses the drug deposition fractions in relation to the breathing pattern, aerosol size distribution, and different lobe regions. CONCLUSIONS: The entire process of the proposed model can be completed within 48 h, allowing an evaluation of the deposition of the inhaled drug in an individual patient's lung within a time frame acceptable for clinical use. Achieving a 48-hour time window for a single evaluation of patient-specific drug delivery enables the physician to monitor the patient's changing conditions and potentially adjust the drug administration accordingly. Furthermore, we show that the proposed methodology also offers a possibility to be extended to a detection approach for some respiratory diseases.

Strong and Tough MXene Bridging-induced Conductive Nacre.

Nacre is a classic model, providing an inspiration for fabricating high-performance bulk nanocomposites with the two-dimensional platelets. However, the "brick" of nacre, aragonite platelet, is an ideal building block for making high-performance bulk nanocomposites. Herein, we demonstrated a strong and tough conductive nacre through reassembling aragonite platelets with bridged by MXene nanosheets and hydrogen bonding, not only providing high mechanical properties but also excellent electrical conductivity. The flexural strength and fracture toughness of the obtained conductive nacre reach ~ 282 MPa and ~ 6.3 MPa m1/2, which is 1.6 and 1.6 times higher than that of natural nacre, respectively. These properties are attributed to densification and high orientation degree of the conductive nacre, which is effectively induced by the combined interactions of hydrogen bonding and MXene nanosheets bridging. The crack propagations in conductive nacre are effectively inhibited through crack deflection with hydrogen bonding, and MXene nanosheets bridging between aragonite platelets. In addition, our conductive nacre also provides a self-monitoring function for structural damage and offers exceptional electromagnetic interference shielding performance. Our strategy of reassembling the aragonite platelets exfoliated from waste nacre into high-performance artificial nacre, provides an avenue for fabricating high-performance bulk nanocomposites through the sustainable reutilization of shell resources.

MKLN1-AS promotes pancreatic cancer progression as a crucial downstream mediator of HIF-1α through miR-185-5p/TEAD1 pathway.

In pancreatic ductal adenocarcinomas (PDAC), profound hypoxia plays key roles in regulating cancer cell behavior, including proliferation, migration, and resistance to therapies. The initial part of this research highlights the important role played by long noncoding RNA (lncRNA) MKLN1-AS, which is controlled by hypoxia-inducible factor-1 alpha (HIF-1α), in the progression of PDAC. Human samples of PDAC showed a notable increase in MKLN1-AS expression, which was linked to a worse outcome. Forced expression of MKLN1-AS greatly reduced the inhibitory impact on the growth and spread of PDAC cells caused by HIF-1α depletion. Experiments on mechanisms showed that HIF-1α influences the expression of MKLN1-AS by directly attaching to a hypoxia response element in the promoter region of MKLN1-AS.MKLN1-AS acts as a competitive endogenous RNA (ceRNA) by binding to miR-185-5p, resulting in the regulation of TEAD1 expression and promoting cell proliferation, migration, and tumor growth. TEAD1 subsequently enhances the development of PDAC. Our study results suggest that MKLN1-AS could serve as a promising target for treatment and a valuable indicator for predicting outcomes in PDAC. PDAC is associated with low oxygen levels, and the long non-coding RNA MKLN1-AS interacts with TEAD1 in this context.

Brain development of a school-aged boy with autism spectrum condition talented in arithmetic: a case report.

Whereas autism spectrum condition is known for its social and communicative challenges, some autistic children demonstrate unusual islets of abilities including those related to mathematics, the neurobiological underpinnings of which are increasingly becoming the focus of research. Here we describe an 8-year-old autistic boy with intellectual and language challenges, yet exceptional arithmetic ability. He can perform verbal-based multiplication of three- and even four-digit numbers within 20 seconds. To gain insights into the neural basis of his talent, we investigated the gray matter in the child's brain in comparison to typical development, applying voxel-based morphometry to magnetic resonance imaging data. The case exhibited reduced gray matter volume in regions associated with arithmetic, which may suggest an accelerated development of brain regions with arithmetic compared to typically developing individuals: potentially a key factor contributing to his exceptional talent. Taken together, this case report describes an example of the neurodiversity of autism. Our research provides valuable insights into the potential neural basis of exceptional arithmetic abilities in individuals with the autism spectrum and its potential contribution to depicting the diversity and complexity of autism.

Early warning model for stroke recurrence in acute ischemic stroke patients based on traditional Chinese medicine syndrome theory.

OBJECTIVE: This study aimed to establish an early warning model for stroke recurrence in acute ischemic stroke patients based on Traditional Chinese Medicine (TCM) syndrome theory. METHODS: This retrospective study collected the data of 1741 patients with ischemic stroke from 7 clinical centers between July 2016 and November 2019. Distance correlation coefficient, mutual information entropy, and statistical correlation test were used for univariate analysis. Cox proportional hazards regression model was applied to construct and validate the stroke recurrence warning model at different time. The area under the ROC curve (AUC) was used to evaluate the early warning ability of the model. RESULTS: We successfully constructed the early warning model. The median follow-up time was 1.42 years (95% CI [1.37, 1.47]). Recurrence events occurred in 175 patients, with a cumulative recurrence rate of 10.05% (95% CI [8.64, 11.47]). The AUC of the model was 0.64±0.02 in the training set and 0.70±0.03 in the validation set. CONCLUSION: The TCM syndrome model can give an early warning for the recurrence of stroke and provide reference for the secondary prevention of ischemic stroke.

The intrinsic substrate specificity of the human tyrosine kinome.

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1-3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4-7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.

Orally Administrated Hydrogel Harnessing Intratumoral Microbiome and Microbiota-Related Immune Responses for Potentiated Colorectal Cancer Treatment.

The intestinal and intratumoral microbiota are closely associated with tumor progression and response to antitumor treatments. The antibacterial or tumor microenvironment (TME)-modulating approaches have been shown to markedly improve antitumor efficacy, strategies focused on normalizing the microbial environment are rarely reported. Here, we reported the development of an orally administered inulin-based hydrogel with colon-targeting and retention effects, containing hollow MnO2 nanocarrier loaded with the chemotherapeutic drug Oxa (Oxa@HMI). On the one hand, beneficial bacteria in the colon specifically metabolized Oxa@HMI, resulting in the degradation of inulin and the generation of short-chain fatty acids (SCFAs). These SCFAs play a crucial role in modulating microbiota and stimulating immune responses. On the other hand, the hydrogel matrix underwent colon microbiota-specific degradation, enabling the targeted release of Oxa and production of reactive oxygen species in the acidic TME. In this study, we have established, for the first time, a microbiota-targeted drug delivery system Oxa@HMI that exhibited high efficiency in colorectal cancer targeting and colon retention. Oxa@HMI promoted chemotherapy efficiency and activated antitumor immune responses by intervening in the microbial environment within the tumor tissue, providing a crucial clinical approach for the treatment of colorectal cancer that susceptible to microbial invasion.

Recycling of Polydicyclopentadiene Enabled with N-Coordinated Boronic Bonds.

In this contribution, we reported the transformation of polydicyclopentadiene (PDCPD) from thermoset into vitrimer. First, two N-coordinated diboronic diols were successfully synthesized via the reaction of N,N,N-tri(2-hydroxyethyl)amine and/or N,N,N",N"-tetrakis(2-hydroxyethyl)ethylene diamine with 4-(hydroxymethyl) phenylboronic acid and then they were transformed into two N-coordinated cyclic boronic diacrylates. The latter two dienes carrying electron-withdrawing substituents were used for the ring opening insertion metathesis copolymerization (ROIMP) of dicyclopentadiene to afford the crosslinked PDCPD. In the crosslinked PDCPD networks, N-coordinated cyclic boronic bonds were integrated. It was found that the as-obtained PDCPD networks displayed the excellent reprocessing properties. In the meantime, the fracture toughness was significantly improved. Owing to the inclusion of N-coordinated cyclic boronic ester bonds, the modified PDCPDs had the thermal stability much superior to plain PDCPD. The results reported in this work demonstrated that PDCPD can successfully be transformed into the vitrimers via the introduction of N-coordinated cyclic boronic ester bonds. This article is protected by copyright. All rights reserved.