Machine learning and deep learning to identifying subarachnoid haemorrhage macrophage-associated biomarkers by bulk and single-cell sequencing.

We investigated subarachnoid haemorrhage (SAH) macrophage subpopulations and identified relevant key genes for improving diagnostic and therapeutic strategies. SAH rat models were established, and brain tissue samples underwent single-cell transcriptome sequencing and bulk RNA-seq. Using single-cell data, distinct macrophage subpopulations, including a unique SAH subset, were identified. The hdWGCNA method revealed 160 key macrophage-related genes. Univariate analysis and lasso regression selected 10 genes for constructing a diagnostic model. Machine learning algorithms facilitated model development. Cellular infiltration was assessed using the MCPcounter algorithm, and a heatmap integrated cell abundance and gene expression. A 3 × 3 convolutional neural network created an additional diagnostic model, while molecular docking identified potential drugs. The diagnostic model based on the 10 selected genes achieved excellent performance, with an AUC of 1 in both training and validation datasets. The heatmap, combining cell abundance and gene expression, provided insights into SAH cellular composition. The convolutional neural network model exhibited a sensitivity and specificity of 1 in both datasets. Additionally, CD14, GPNMB, SPP1 and PRDX5 were specifically expressed in SAH-associated macrophages, highlighting its potential as a therapeutic target. Network pharmacology analysis identified some targeting drugs for SAH treatment. Our study characterised SAH macrophage subpopulations and identified key associated genes. We developed a robust diagnostic model and recognised CD14, GPNMB, SPP1 and PRDX5 as potential therapeutic targets. Further experiments and clinical investigations are needed to validate these findings and explore the clinical implications of targets in SAH treatment.

Ultrahigh Heat/Fire-Resistant, Mechanically Robust, and Closed-Loop Chemical Recyclable Polycarbonate Enabled by Facile Bond Dissociation Energy Modulation.

Plastics serve as an essential foundation in contemporary society. Nevertheless, meeting the rigorous performance demands in advanced applications and addressing their end-of-life disposal are two critical challenges that persist. Here, an innovative and facile method is introduced for the design and scalable production of polycarbonate, a key engineering plastic, simultaneously achieving high performance and closed-loop chemical recyclability. The bisphenol framework of polycarbonate is strategically adjusted from the low-bond-dissociation-energy bisphenol A to high-bond-dissociation-energy 4,4'-dihydroxydiphenyl, in combination with the incorporation of polysiloxane segments. As expected, the enhanced bond dissociation energy endows the polycarbonate with an extremely high glow-wire flammability index surpassing 1025 °C, a 0.8 mm UL-94 V-0 rating, a high LOI value of 39.2%, and more than 50% reduction of heat and smoke release. Furthermore, the π-π stacking interactions within biphenyl structures resulted in a significant enhancement of mechanical strength by as more as 37.7%, and also played a positive role in achieving a lower dielectric constant. Significantly, the copolymer exhibited outstanding closed-loop chemical recyclability, allowing for facile depolymerization into bisphenol monomers and the repolymerized copolymer retains its high heat and fire resistance. This work provides a novel insight in the design of high-performance and closed-loop chemical recyclable polymeric materials.

Proteomics study of primary and recurrent adamantinomatous craniopharyngiomas.

BACKGROUND: Adamantinomatous craniopharyngiomas (ACPs) are rare benign epithelial tumours with high recurrence and poor prognosis. Biological differences between recurrent and primary ACPs that may be associated with disease recurrence and treatment have yet to be evaluated at the proteomic level. In this study, we aimed to determine the proteomic profiles of paired recurrent and primary ACP, gain biological insight into ACP recurrence, and identify potential targets for ACP treatment. METHOD: Patients with ACP (n = 15) or Rathke's cleft cyst (RCC; n = 7) who underwent surgery at Sanbo Brain Hospital, Capital Medical University, Beijing, China and received pathological confirmation of ACP or RCC were enrolled in this study. We conducted a proteomic analysis to investigate the characteristics of primary ACP, paired recurrent ACP, and RCC. Western blotting was used to validate our proteomic results and assess the expression of key tumour-associated proteins in recurrent and primary ACPs. Flow cytometry was performed to evaluate the exhaustion of tumour-infiltrating lymphocytes (TILs) in primary and recurrent ACP tissue samples. Immunohistochemical staining for CD3 and PD-L1 was conducted to determine differences in T-cell infiltration and the expression of immunosuppressive molecules between paired primary and recurrent ACP samples. RESULTS: The bioinformatics analysis showed that proteins differentially expressed between recurrent and primary ACPs were significantly associated with extracellular matrix organisation and interleukin signalling. Cathepsin K, which was upregulated in recurrent ACP compared with that in primary ACP, may play a role in ACP recurrence. High infiltration of T cells and exhaustion of TILs were revealed by the flow cytometry analysis of ACP. CONCLUSIONS: This study provides a preliminary description of the proteomic differences between primary ACP, recurrent ACP, and RCC. Our findings serve as a resource for craniopharyngioma researchers and may ultimately expand existing knowledge of recurrent ACP and benefit clinical practice.

Circuit-based neuromodulation enhances delayed recall in amnestic mild cognitive impairment.

BACKGROUND: This study aimed to investigate the efficacy of circuits-based paired associative stimulation (PAS) in adults with amnestic mild cognitive impairment (aMCI). METHODS: We conducted a parallel-group, randomised, controlled clinical trial. Initially, a cohort of healthy subjects was recruited to establish the cortical-hippocampal circuits by tracking white matter fibre connections using diffusion tensor imaging. Subsequently, patients diagnosed with aMCI, matched for age and education, were randomly allocated in a 1:1 ratio to undergo a 2-week intervention, either circuit-based PAS or sham PAS. Additionally, we explored the relationship between changes in cognitive performance and the functional connectivity (FC) of cortical-hippocampal circuits. RESULTS: FCs between hippocampus and precuneus and between hippocampus and superior frontal gyrus (orbital part) were most closely associated with the Auditory Verbal Learning Test (AVLT)_N5 score in 42 aMCI patients, thus designated as target circuits. The AVLT_N5 score improved from 2.43 (1.43) to 5.29 (1.98) in the circuit-based PAS group, compared with 2.52 (1.44) to 3.86 (2.39) in the sham PAS group (p=0.003; Cohen's d=0.97). A significant decrease was noted in FC between the left hippocampus and left precuneus in the circuit-based PAS group from baseline to postintervention (p=0.013). Using a generalised linear model, significant group×FC interaction effects for the improvements in AVLT_N5 scores were found within the circuit-based PAS group (B=3.4, p=0.017). CONCLUSIONS: Circuit-based PAS effectively enhances long-term delayed recall in adults diagnosed with aMCI, which includes individuals aged 50-80 years. This enhancement is potentially linked to the decreased functional connectivity between the left hippocampus and left precuneus. TRIAL REGISTRATION NUMBER: ChiCTR2100053315; Chinese Clinical Trial Registry.

One-pot Synthesis of PdCuAg and CeO2 Nanowires Hybrid with Abundant Heterojunction Interface for Ethylene Glycol Electrooxidation.

Introducing CeO2 into Pd-based nanocatalysts for electrocatalytic reactions is a good way to solve the intermediate toxicity problem and improve the catalytic performance. Here we reported a simple strategy to synthesize the PdCuAg and CeO2 nanowires hybrid via a one-pot synthesis process under strong nanoconfined effect of specific surfactant as templates. Owing to the structural (ultrathin nanowires, abundant heterojunction/interfaces between metal and metal oxide) and compositional (Pd, Cu, Ag, CeO2) advantages, the hybrid showed significantly enhanced catalytic activity (6.06 A mgPd -1) and stability, accelerated reaction rate, and reduced activation energy toward electrocatalytic ethylene glycol oxidation reaction.

Small Conjugated Organic Ligand-Modified Polyoxometalate-Based Hybrid Materials for Boosting Photocatalytic CO2 Reduction.

Photocatalytic carbon dioxide (CO2) reduction to value-added chemicals is a multielectron transfer process, and the crucial step is the synthesis of photocatalysts. The introduction of small conjugated organic ligands can make the catalytic active site of the compound easier to be exposed in the reaction system and fully contact with the substrate, accelerating the photocatalytic reaction process. In this paper, we synthesized two isomorphic compounds, namely, {[Co(mtrz)3·(H2O)2]2·[SiW12O40]}·6H2O (1) and {[Ni(mtrz)3·(H2O)2]2·[SiW12O40]}·6H2O (2) (mtrz = 1-methyl-1,2,4-triazole). We found that compound 1 has a great photocatalytic performance through a series of experiments, with a CO reduction yield of 7364.92 µmol g-1 h-1 and a CO selectivity of 82.5%. Furthermore, the high catalytic activity can be maintained over four cycle experiments. The catalytic mechanism of its photocatalytic system is also elucidated, which provides an idea for realizing efficient catalytic reduction of CO2 to CO.

Macrophages promote the transition from myocardial ischemia reperfusion injury to cardiac fibrosis in mice through GMCSF/CCL2/CCR2 and phenotype switching.

Following acute myocardial ischemia reperfusion (MIR), macrophages infiltrate damaged cardiac tissue and alter their polarization phenotype to respond to acute inflammation and chronic fibrotic remodeling. In this study we investigated the role of macrophages in post-ischemic myocardial fibrosis and explored therapeutic targets for myocardial fibrosis. Male mice were subjected to ligation of the left coronary artery for 30 min. We first detected the levels of chemokines in heart tissue that recruited immune cells infiltrating into the heart, and found that granulocyte-macrophage colony-stimulating factor (GMCSF) released by mouse cardiac microvascular endothelial cells (MCMECs) peaked at 6 h after reperfusion, and c-c motif chemokine ligand 2 (CCL2) released by GMCSF-induced macrophages peaked at 24 h after reperfusion. In co-culture of BMDMs with MCMECs, we demonstrated that GMCSF derived from MCMECs stimulated the release of CCL2 by BMDMs and effectively promoted the migration of BMDMs. We also confirmed that GMCSF promoted M1 polarization of macrophages in vitro, while GMCSF neutralizing antibodies (NTABs) blocked CCL2/CCR2 signaling. In MIR mouse heart, we showed that GMCSF activated CCL2/CCR2 signaling to promote NLRP3/caspase-1/IL-1ß-mediated and amplified inflammatory damage. Knockdown of CC chemokine receptor 2 gene (CCR2-/-), or administration of specific CCR2 inhibitor RS102895 (5 mg/kg per 12 h, i.p., one day before MIR and continuously until the end of the experiment) effectively reduced the area of myocardial infarction, and down-regulated inflammatory mediators and NLRP3/Caspase-1/IL-1ß signaling. Mass cytometry confirmed that M2 macrophages played an important role during fibrosis, while macrophage-depleted mice exhibited significantly reduced transforming growth factor-ß (Tgf-ß) levels in heart tissue after MIR. In co-culture of macrophages with fibroblasts, treatment with recombinant mouse CCL2 stimulated macrophages to release a large amount of Tgf-ß, and promoted the release of Col1α1 by fibroblasts. This effect was diminished in BMDMs from CCR2-/- mice. After knocking out or inhibiting CCR2-gene, the levels of Tgf-ß were significantly reduced, as was the level of myocardial fibrosis, and cardiac function was protected. This study confirms that the acute injury to chronic fibrosis transition after MIR in mice is mediated by GMCSF/CCL2/CCR2 signaling in macrophages through NLRP3 inflammatory cascade and the phenotype switching.

Metal oxide nanomaterials based electrochemical and optical biosensors for biomedical applications: Recent advances and future prospectives.

The amalgamation of nanostructures with modern electrochemical and optical techniques gave rise to interesting devices, so-called biosensors. A biosensor is an analytical tool that incorporates various biomolecules with an appropriate physicochemical transducer. Over the past few years, metal oxide nanomaterials (MONMs) have significantly stimulated biosensing research due to their desired functionalities, versatile chemical stability, and low cost along with their unique optical, catalytic, electrical, and adsorption properties that provide an attractive platform for linking the biomolecules, for example, antibodies, nucleic acids, enzymes, and receptor proteins as sensing elements with the transducer for the detection of signals or signal amplifications. The signals to be measured are in direct proportionate to the concentration of the bioanalyte. Because of their simplicity, cost-effectiveness, portability, quick analysis, higher sensitivity, and selectivity against a broad range of biosamples, MONMs-based electrochemical and optical biosensing platforms are exhaustively explored as powerful early-diagnosis tools for point of care applications. Herein, we made a bibliometric analysis of past twenty years (2004-2023) on the application of MONMs as electrochemical and optical biosensing units using Web of Science database and the results of which clearly reveal the increasing number of publications since 2004. Geographical area distribution analysis of these publications shows that China tops the list followed by the United States of America and India. In this review, we first describe the electrochemical and optical properties of MONMs that are crucial for the creation of extremely stable, specific, and sensitive sensors with desirable characteristics. Then, the biomedical applications of MONMs-based bare and hybrid electrochemical and optical biosensing frameworks are highlighted in the light of recent literature. Finally, current limitations and future challenges in the field of biosensing technology are addressed.

Evaluating the effect of health insurance reform on health equity and financial protection for elderly in low- and middle-income countries: evidences from China.

BACKGROUND: To achieve Universal Health Coverage (UHC), China have implemented health system reform to expend health coverage and improve health equity. Scholars have explored the implementing effect of this health reform, but gaps remained in health care received by elderly. This study aims to assess the effect of implementing health insurance payment reform on health care received by elderly, as well as to evaluate its effect on cost sharing to identify whether improve financial protection of elderly under this reform. METHODS: We identified hospitalization of 46,714 elderly with cerebral infarction from 2013 to 2023. To examine the determinant role played by DRGs payment reform in healthcare for elderly and their financial protection, this study employs the OLS linear regression model for analysis. In the robustness checks, we validated the baseline results through several methods, including excluding the data from the initial implementation of the reform (2021), reducing the impact of the pandemic, and exploring the group effects of different demographic characteristics. RESULTS: The findings proposed that implementing DRGs payment reduces drug expenses but increases treatment expense of chronic disease for elderly in China. This exacerbates healthcare costs for elderly patients and seems to be contrary to the original purpose of health care reform. Additionally, the implementation of DRGs payment reduced the spending of medical insurance fund, while increased the out-of-pocket of patients, revealing a shift in health care expenses from health insurance fund to out-of-pocket. CONCLUSIONS: This study shares the lessons from China's health reform and provides enlightenment on how to effective implement health reform to improve health equity and achieve UHC in such low- and middle-income countries facing challenges in health financing.

Exploring effective implementation pathways to become an excellent chief financial officer in public hospital: a qualitative comparative analysis (QCA) from China.

BACKGROUND: Hospital chief financial officer (CFO) contributes to improving health system performance. However, how to become an excellent hospital CFO has rarely been considered from a holistic perspective. This paper aims to identify competencies required by hospital CFO to fulfil the position's responsibilities and explore effective implementation pathways to generate high performance and improve healthcare service. METHODS: We conducted 61 semi-structured interviews with individuals in key leadership positions in China's hospitals and researchers focusing on healthcare system management to identify core competencies necessary for hospital CFO. Interviews were analysed through a multi-stage review process and modified via expert vetting using a national panel of 23 professors. Subsequently, interviews were conducted with 32 hospital CFOs from 14 provinces throughout September 2021 to May 2022. We scored the performance of 32 hospital CFOs in various aspects of competency and used the fuzzy-set qualitative comparative analysis to explore the competency configurations of excellent CFOs. RESULTS: We identify seven core competencies necessary for a hospital CFO to fulfil management practices, including personal morality, resource management, strategy management, learning ability, negotiating skill, leadership skill, and financial management. The findings indicate that a single competency factor is not a necessary condition to become an excellent hospital CFO. The results of qualitative comparative analysis then make it possible to propose four configurational paths, namely, supportive, interpersonal, all-around development, and technical, to become an excellent hospital CFO and achieve effective managerial performance. CONCLUSIONS: The responsibilities of hospital CFOs are complex and varied, hence, a better understanding of competencies required by CFO is essential to implement their responsibilities effectively. The identification in this study of the four effective implementation pathways to becoming an excellent hospital CFO enriches the literature on hospital management and provides implications for China's hospitals and their CFOs.

Prolonged efficacy of cefazolin in intraosseous regional prophylaxis for total knee arthroplasty: a rabbit model study.

BACKGROUND: A novel approach known as intraosseous regional administration (IORA) has emerged as a technique for delivering prophylactic antibiotics, and it results in higher tissue concentrations around the knee. It is hypothesized that IORA of cefazolin for antibiotic prophylaxis during total knee arthroplasty will result in sustained effective levels for a longer duration. The aim of the current study was to investigate temporal changes in peri-knee cefazolin blood concentrations after IORA of cefazolin. METHODS: Twelve rabbits were randomly divided into two groups, with six rabbits in each group. In control group a single intravenous bolus injection of cefazolin (10 mL, 100 mg) was administered into the marginal ear vein. In experimental groupexperimental group the same dose of cefazolin was injected into the left tibial marrow cavity after tourniquet inflation at the base of the left thigh. Blood samples were collected periodically at different timepoints, and cefazolin concentrations were determined. RESULTS: The intraosseous treatment resulted in significant differences in plasma cefazolin concentrations at all timepoints. Experimental group exhibited higher plasma cefazolin concentrations than control group. CONCLUSIONS: Cefazolin in intraosseous regional prophylaxis exhibits effectiveness in intraoperative antibiotic prophylaxis by maintaining concentrations above the minimum inhibitory concentration for extended durations, rather than relying solely on high concentrations.

Motor imagery-based brain-computer interface rehabilitation programs enhance upper extremity performance and cortical activation in stroke patients.

BACKGROUND: The most challenging aspect of rehabilitation is the repurposing of residual functional plasticity in stroke patients. To achieve this, numerous plasticity-based clinical rehabilitation programs have been developed. This study aimed to investigate the effects of motor imagery (MI)-based brain-computer interface (BCI) rehabilitation programs on upper extremity hand function in patients with chronic hemiplegia. DESIGN: A 2010 Consolidated Standards for Test Reports (CONSORT)-compliant randomized controlled trial. METHODS: Forty-six eligible stroke patients with upper limb motor dysfunction participated in the study, six of whom dropped out. The patients were randomly divided into a BCI group and a control group. The BCI group received BCI therapy and conventional rehabilitation therapy, while the control group received conventional rehabilitation only. The Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) score was used as the primary outcome to evaluate upper extremity motor function. Additionally, functional magnetic resonance imaging (fMRI) scans were performed on all patients before and after treatment, in both the resting and task states. We measured the amplitude of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), z conversion of ALFF (zALFF), and z conversion of ReHo (ReHo) in the resting state. The task state was divided into four tasks: left-hand grasping, right-hand grasping, imagining left-hand grasping, and imagining right-hand grasping. Finally, meaningful differences were assessed using correlation analysis of the clinical assessments and functional measures. RESULTS: A total of 40 patients completed the study, 20 in the BCI group and 20 in the control group. Task-related blood-oxygen-level-dependent (BOLD) analysis showed that when performing the motor grasping task with the affected hand, the BCI group exhibited significant activation in the ipsilateral middle cingulate gyrus, precuneus, inferior parietal gyrus, postcentral gyrus, middle frontal gyrus, superior temporal gyrus, and contralateral middle cingulate gyrus. When imagining a grasping task with the affected hand, the BCI group exhibited greater activation in the ipsilateral superior frontal gyrus (medial) and middle frontal gyrus after treatment. However, the activation of the contralateral superior frontal gyrus decreased in the BCI group relative to the control group. Resting-state fMRI revealed increased zALFF in multiple cerebral regions, including the contralateral precentral gyrus and calcarine and the ipsilateral middle occipital gyrus and cuneus, and decreased zALFF in the ipsilateral superior temporal gyrus in the BCI group relative to the control group. Increased zReHo in the ipsilateral cuneus and contralateral calcarine and decreased zReHo in the contralateral middle temporal gyrus, temporal pole, and superior temporal gyrus were observed post-intervention. According to the subsequent correlation analysis, the increase in the FMA-UE score showed a positive correlation with the mean zALFF of the contralateral precentral gyrus (r = 0.425, P < 0.05), the mean zReHo of the right cuneus (r = 0.399, P < 0.05). CONCLUSION: In conclusion, BCI therapy is effective and safe for arm rehabilitation after severe poststroke hemiparesis. The correlation of the zALFF of the contralateral precentral gyrus and the zReHo of the ipsilateral cuneus with motor improvements suggested that these values can be used as prognostic measures for BCI-based stroke rehabilitation. We found that motor function was related to visual and spatial processing, suggesting potential avenues for refining treatment strategies for stroke patients. TRIAL REGISTRATION: The trial is registered in the Chinese Clinical Trial Registry (number ChiCTR2000034848, registered July 21, 2020).

How does diagnosis-related group payment impact the health care received by rural residents? Lessons learned from China.

OBJECTIVES: There is growing evidence that differences exist between rural and urban residents in terms of health, access to care and the quality of health care received, especially in low- and middle-income countries (LMICs). To improve health equity and the performance of health systems, a diagnosis-related group (DRG) payment system has been introduced in many LMICs to reduce financial risk and improve the quality of health care. The aim of this study was to examine the impact of DRG payments on the health care received by rural residents in China, and to help policymakers identify and design implementation strategies for DRG payment systems for rural residents in LMICs. STUDY DESIGN: Health impact assessment. METHODS: This study compared the impact of DRG payments on the healthcare received by rural residents in China between the pre- and post-reform periods by applying a difference-in-difference (DID) methodology. The study population included individuals with three common conditions; namely, cerebral infarction, transient ischaemic attack (TIA), and vertebrobasilar insufficiency (VBI). Data on patient medical insurance type were assessed, and those who did not have rural insurance were excluded. RESULTS: This study included 13,088 patients. In total, 33.63% were from Guangdong (n = 4401), 38.21% were from Shandong (n = 5002), and 28.16% were from Guangxi (n = 3685). The DID results showed that the implementation of DRGs was positively associated with hospitalization expense (ß4 = 0.265, P = 0.000), treatment expense (ß4 = 0.343, P = 0.002), drug expense (ß4 = 0.607, P = 0.000), the spending of medical insurance funds (ß4 = 0.711, P = 0.000) and out-of-pocket costs (ß4 = 0.164, P = 0.000). CONCLUSIONS: The findings of this study suggest that the implementation of DRG payments increases health care costs and the financial burden on health systems and rural patients in LMICs. This is contrary to the original intention of implementing the DRG payment system.

Morphological alterations of contralesional hemisphere relate to functional outcomes after stroke.

The present study aimed to investigate poststroke morphological alterations contralesionally and correlations with functional outcomes. Structural magnetic resonance images were obtained from 27 poststroke patients (24 males, 50.21 ± 10.97 years) and 20 healthy controls (13 males, 46.63 ± 12.18 years). Voxel-based and surface-based morphometry analysis were conducted to detect alterations of contralesional grey matter volume (GMV), cortical thickness (CT), gyrification index (GI), sulcus depth (SD), and fractal dimension (FD) in poststroke patients. Partial correlation analysis was used to explore the relationship between regions with significant structural differences and scores of clinical assessments, including Modified Barthel Index (MBI), Berg Balance Scale (BBS), Fugl-Meyer Assessment of Upper Extremity (FMA-UE), Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). Correction for multiplicity was conducted within each parameter and for all tests. GMV significantly decreased in the contralesional motor-related, occipital and temporal cortex, limbic system, and cerebellum lobe (P < 0.01, family-wise error [FWE] correction). Lower CT was found in the contralesional precentral and lingual gyrus (P < 0.01, FWE correction), while lower GI found in the contralesional superior temporal gyrus and insula (P < 0.01, FWE correction). There were significant correlations between GMV of contralesional lingual gyrus and MBI (P = 0.031, r = 0.441), and BBS (P = 0.047, r = 0.409) scores, and GMV of contralesional hippocampus and FMA-UE scores (P = 0.048, r = 0.408). In conclusion, stroke patients exhibited wide grey matter loss and cortical morphological changes in the contralesional hemisphere, which correlated with sensorimotor functions and the ability of daily living.

P38-DAPK1 axis regulated LC3-associated phagocytosis (LAP) of microglia in an in vitro subarachnoid hemorrhage model.

BACKGROUND: The phagocytosis and homeostasis of microglia play an important role in promoting blood clearance and improving prognosis after subarachnoid hemorrhage (SAH). LC3-assocaited phagocytosis (LAP) contributes to the microglial phagocytosis and homeostasis via autophagy-related components. With RNA-seq sequencing, we found potential signal pathways and genes which were important for the LAP of microglia. METHODS: We used an in vitro model of oxyhemoglobin exposure as SAH model in the study. RNA-seq sequencing was performed to seek critical signal pathways and genes in regulating LAP. Bioparticles were used to access the phagocytic ability of microglia. Western blot (WB), immunoprecipitation, quantitative polymerase chain reaction (qPCR) and immunofluorescence were performed to detect the expression change of LAP-related components and investigate the potential mechanisms. RESULTS: In vitro SAH model, there were increased inflammation and decreased phagocytosis in microglia. At the same time, we found that the LAP of microglia was inhibited in all stages. RNA-seq sequencing revealed the importance of P38 MAPK signal pathway and DAPK1 in regulating microglial LAP. P38 was found to regulate the expression of DAPK1, and P38-DAPK1 axis was identified to regulate the LAP and homeostasis of microglia after SAH. Finally, we found that P38-DAPK1 axis regulated expression of BECN1, which indicated the potential mechanism of P38-DAPK1 axis regulating microglial LAP. CONCLUSION: P38-DAPK1 axis regulated the LAP of microglia via BECN1, affecting the phagocytosis and homeostasis of microglia in vitro SAH model. Video Abstract.

Radioactive and Fluorescent Dual Modality Cysteine Cathepsin B Activity-Based Probe for Cancer Theranostics.

Cysteine cathepsin B (CTS-B) is a crucial enzyme that is overexpressed in numerous malignancies and contributes to the invasion and metastasis of cancer. Therefore, this study sets out to develop and evaluate an activity-based multimodality theranostic agent targeting CTS-B for cancer imaging and therapy. A CTS-B activity-based probe, BMX2, was synthesized and labeled efficiently with 68Ga and 90Y to produce 68Ga-BMX2 for multimodality imaging and 90Y-BMX2 for radiation therapy. The affinity and specificity of BMX2 binding with the CTS-B enzyme were determined by fluorescent western blots using recombined active human CTS-B enzyme (rh-CTS-B) and four cancer cell lines including HeLa, HepG2, MCF7, and U87MG, with CA074 as the CTS-B inhibitor for control. Confocal laser scanning microscope imaging and cell uptake measurement were also performed. Then, in vivo PET imaging and fluorescence imaging were acquired on HeLa xenografts. Finally, the therapeutic effect of 90Y-BMX2 was tested. BMX2 could be specifically activated by rh-CTS-B and stably bound to the enzyme. The binding of BMX2 with CTS-B is time-dependent and enzyme concentration-dependent. Although CTS-B expression varied between cell lines, all showed significant uptake of BMX2 and 68Ga-BMX2. In vivo optical and PET imaging showed a high tumor uptake of BMX2 and 68Ga-BMX2 and accumulation for more than 24 h. 90Y-BMX2 could significantly inhibit HeLa tumor growth. The development of 68Ga/90Y-BMX2, a radioactive and fluorescent dual modality theranostic agent, demonstrated an effective theranostic approach for PET diagnostic imaging, fluorescence imaging, and radionuclide therapy of cancers, which may have a potential for clinical translation for cancer theranostics in the future.

Layered Co-O Cluster Applied to Photocatalytic CO2 Reduction.

In the field of recycling CO2, the photocatalytic CO2 reduction reaction (CO2RR) is a typical example, and researchers have designed a variety of photocatalysts to improve the conversion rate of CO2 over the years. In this paper, two metal-oxygen clusters are designed and formulated as [Co3Zn(OH)6(SO4)]·4H2O (1) and [Ni3Zn(OH)6(SO4)]·4H2O (2). As for compound 1, the main structure is composed of {CoO6} octahedra connected by edge-sharing to form a two-dimensional layer, on which {ZnO4} and {SO4} tetrahedra are supported. More interestingly, compound 1 has outstanding photocatalytic activity, which is mainly attributed to the open-framework structure and the cobalt ions as active sites. Upon catalysis for eight hours, its maximum CO generation rate is 9982.13 µmol g-1 h-1, with a selectivity of 81.8%. Additionally, compound 1 takes on weak antiferromagnetic coupling due to Co(II) ions.

Effects of cortico-cortical paired associative stimulation based on multisensory integration to brain network connectivity in stroke patients: study protocol for a randomized doubled blind clinical trial.

INTRODUCTION: Brain has a spontaneous recovery after stroke, reflecting the plasticity of the brain. Currently, TMS is used for studies of single-target brain region modulation, which lacks consideration of brain networks and functional connectivity. Cortico-cortical paired associative stimulation (ccPAS) promotes recovery of motor function. Multisensory effects in primary visual cortex(V1) directly influence behavior and perception, which facilitate motor functional recovery in stroke patients. Therefore, in this study, dual-targeted precise stimulation of V1 and primary motor cortex(M1) on the affected hemisphere of stroke patients will be used for cortical visuomotor multisensory integration to improve motor function. METHOD: This study is a randomized, double-blind controlled clinical trial over a 14-week period. 69 stroke subjects will be enrolled and divided into sham stimulation group, ccPAS low frequency group, and ccPAS high frequency group. All groups will receive conventional rehabilitation. The intervention lasted for two weeks, five times a week. Assessments will be performed before the intervention, at the end of the intervention, and followed up at 6 and 14 weeks. The primary assessment indicator is the 'Fugl-Meyer Assessment of the Upper Extremity ', secondary outcomes were 'The line bisection test', 'Modified Taylor Complex Figure', 'NIHSS' and neuroimaging assessments. All adverse events will be recorded. DISCUSSION: Currently, ccPAS is used for the modulation of neural circuits. Based on spike-timing dependent plasticity theory, we can precisely intervene in the connections between different cortices to promote the recovery of functional connectivity on damaged brain networks after stroke. We hope to achieve the modulation of cortical visuomotor interaction by combining ccPAS with the concept of multisensory integration. We will further analyze the correlation between analyzing visual and motor circuits and explore the alteration of neuroplasticity by the interactions between different brain networks. This study will provide us with a new clinical treatment strategy to achieve precise rehabilitation for patient with motor dysfunction after stroke. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry with code ChiCTR2300067422 and was approved on January 16, 2023.

Different Clinical Features of Pediatric Generalized Pustular Psoriasis in Patients with or without IL36RN Variants.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare and life-threatening autoinflammatory dermatological disease. IL36RN was reported to be the main pathogenetic basis for GPP. Only a few studies have reported on the correlation analysis of IL36RN variants and the phenotype of pediatric-onset GPP. METHODS: IL36RN was screened in 60 children diagnosed with GPP from January 2013 to January 2020, and their detailed clinical profiles were obtained. RESULTS: Forty-six out of 60 (76.67%) patients harbored IL36RN variants, and six IL36RN variants were found, of which two were novel variants that were reported for the first time. The frequency of IL36RN variants was significantly different among the subtypes of GPP (GPP with acrodermatitis continua of Hallopeau group (ACH), 100%; GPP without plaque psoriasis (PV) and ACH, 78.05%; GPP with PV group, 44.44%) (p = 0.018), while the percentage of IL36RN variants in the GPP with ACH group was higher than that in the GPP with PV group (p < 0.05). IL36RN variants were associated with a lower percentage of PV, longer length of hospitalization, and longer time to reach normal body temperature after treatment (p < 0.05). After treatment, marked responses, moderate responses, and no responses were recorded in 75.00%, 8.33%, and 16.67% of patients, respectively. No significant difference was observed during efficacy assessment in patients with or without IL36RN variants (χ2 = 1.122, p > 0.05). CONCLUSIONS: IL36RN variants are associated with GPP with ACH subtypes, an absence of concurrent PV, and a greater extent of severe inflammation. Acitretin was an effective treatment for patients in our study and mostly resulted in a marked response in our cohort.

Association between nineteen dietary fatty acids and hearing thresholds: findings from a nationwide survey.

INTRODUCTION: Hearing loss is a prevalent health concern, and dietary factors, such as fatty acid intake, may play a role in its development. The current study aimed to investigate the association between the intake of dietary fatty acids and hearing thresholds among U.S. adults. METHODS: The researchers examined data from the National Health and Nutrition Examination Survey (NHANES), including 7,623 participants with available dietary fatty acid intake and audiometry data. Dietary fatty acid intake was assessed using dietary recalls, and hearing thresholds were measured using pure-tone audiometry. Multivariate linear regression models and smoothing curve fitting were utilized to explore the associations between dietary fatty acid intake and hearing thresholds, adjusting for relevant covariates. RESULTS: This study reveals a direct association between both low and high frequency pure tone average (PTA) hearing thresholds and the dietary intake of total saturated fatty acids (SFAs) and total polyunsaturated fatty acids (PUFAs). Conversely, the intake of total monounsaturated fatty acids (MUFAs) demonstrates an inverted U-shaped correlation with low-frequency and high-frequency PTA hearing thresholds, having inflection points at 11.91 (energy (%)) and 10.88 (energy (%)), respectively. CONCLUSION: Dietary intake of certain fatty acids may influence hearing thresholds in adults.