BRD7 as key factor in PBAF complex assembly and CD8+ T cell differentiation.

Upon infection, naïve CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodel system in this process remains largely unknown. Here we showed that BRD7, a component of the polybromo-associated BRG1-associated factor complex (PBAF), was required for naïve CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7-deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicated that the expression of BRD7 significantly turned to high from naïve CD8+ T cells to effector cells, bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and up-regulated its expression, leading to the maturation of effector T cells. Our research confirms BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.

Effects of combining rTMs and augmented reality gait adaptive training on walking function of patients with stroke based on three-dimensional gait analysis and sEMG: a randomized controlled trial.

BACKGROUND: Augmented reality gait adaptive training (ARGAT) and repetitive transcranial magnetic stimulation (rTMS) have both demonstrated efficacy in improving lower limb motor function in survivors of stroke. PURPOSE: To investigate the effects of combining rTMS and ARGAT on motor function in survivors of stroke. METHODS: The experimental group received a combination of rTMS and ARGAT, while the control group received ARGAT alone. The interventions comprised a total of 20 sessions, conducted over four weeks with five consecutive daily sessions. Outcome measures included three-dimensional gait analysis (3DGA), surface electromyography (sEMG), Fugl-Meyer assessment for the lower extremity (FMA-LE), and the Berg Balance Scale (BBS). RESULTS: Following the intervention, both groups showed significant improvements in walking speed, symmetry index, affected step length, affected stride length, FMA-LE, and BBS scores (p < .05). Furthermore, the experimental group demonstrated greater improvements in walking speed (F = 4.58, p = .040), cadence (F = 5.67, p = .023), affected step length (F = 5.79, p = .022), affected stride length (F = 4.84, p = .035), FMA-LE (Z = 2.43, p = .019), and BBS (F = 4.76, p = .036) compared to the control group. The experimental group demonstrated a significant improvement in the co-contraction index (CCI) of the knee joint (F = 14.88, p < .001), a change not observed in the control group (F = 2.16, p = .151). However, neither group showed significant alterations in CCI of the ankle joint (F = 1.58, p = .218), step width (F = 0.24, p = .630), unaffected step length (F = 0.22, p = .641), or unaffected stride length (F = 2.99, p = .093). CONCLUSION: The combination of low-frequency rTMS and ARGAT demonstrated superior effects on motor function recovery compared to ARGAT alone in survivors of stroke.

Establishment and evaluation of Voting algorithm-based internal quality control (ViQC), a patient-based real-time quality control.

BACKGROUND: Patient-Based Real-Time Quality Control (PBRTQC) has emerged as a supplementary programme to traditional internal quality control (iQC) mechanisms. Despite its growing popularity, practical applications in clinical settings reveal several challenges. The primary objective of this research is to introduce and develop an Artificial Intelligence (AI)-based method, named Voting algorithm based iQC (ViQC), designed to enhance the precision and reliability of existing PBRTQC systems. METHODS: In this study, we conducted a retrospective analysis of 111,925 inpatient serum glucose test results from Nanjing Drum Tower Hospital, Nanjing, China, to provide an unbiased data set. The Voting iQC (ViQC) algorithm, established by the principles of the Voting algorithm, was then developed. Its analytical performance was evaluated through the calculation of random errors (RE). Subsequently, its clinical efficacy was assessed by comparison with five statistical algorithms: Moving Average (MA), Exponentially Weighted Moving Average (EWMA), Moving Median (movMed, MM), Moving Quartile (MQ), and Moving Standard Deviation (MovSD). RESULTS: The ViQC model incorporates a variety of machine learning models, including logistic regression, Bayesian methods, K-Nearest Neighbor, decision trees, random forests, and gradient boosting decision trees, to establish a robust predictive framework. This model consistently maintains a false positive rate below 0.002 across all six evaluated error factors, showcasing exceptional precision. Notably, its performance further excels with an error factor of 3.0, where the false positive rate drops below 0.001, and achieves an accuracy rate as high as 0.965 at an error factor of 2.0. The classification effectiveness of ViQC model is evaluated by an area under the curve (AUC) exceeding 0.97 for all error factors. In comparison to five conventional PBRTQC statistical methods, ViQC significantly enhances error detection efficiency, maximum reducing the trimmed average number of patient samples required for detecting errors from 724 to 168, thereby affirming its superior error detection capability. CONCLUSION: The new established PBRTQC using artificial intelligence yielded satisfactory performance compared to the traditional PBBTQC in real world setting.

Apigenin inhibits tumor angiogenesis by hindering microvesicle biogenesis via ARHGEF1.

Extracellular vesicles are essential for intercellular communication and are involved in tumor progression. Inhibiting the direct release of extracellular vesicles seems to be an effective strategy in inhibiting tumor progression, but lacks of investigation. Here, we report a natural flavonoid compound, apigenin, could significantly inhibit the growth of hepatocellular carcinoma by preventing microvesicle secretion. Mechanistically, apigenin primarily targets the guanine nucleotide exchange factor ARHGEF1, inhibiting the activity of small G protein Cdc42, which is essential in regulating the release of microvesicles from tumor cells. In turn, this inhibits tumor angiogenesis related to VEGF90K transported on microvesicles, ultimately impeding tumor progression. Collectively, these findings highlight the therapeutic potential of apigenin and shed light on its anticancer mechanisms through inhibiting microvesicle biogenesis, providing a solid foundation for the refinement and practical application of apigenin.

Synthetic Cells and Molecules in Cellular Immunotherapy.

Cellular immunotherapy has emerged as an exciting strategy for cancer treatment, as it aims to enhance the body's immune response to tumor cells by engineering immune cells and designing synthetic molecules from scratch. Because of the cytotoxic nature, abundance in peripheral blood, and maturation of genetic engineering techniques, T cells have become the most commonly engineered immune cells to date. Represented by chimeric antigen receptor (CAR)-T therapy, T cell-based immunotherapy has revolutionized the clinical treatment of hematological malignancies. However, serious side effects and limited efficacy in solid tumors have hindered the clinical application of cellular immunotherapy. To address these limitations, various innovative strategies regarding synthetic cells and molecules have been developed. On one hand, some cytotoxic immune cells other than T cells have been engineered to explore the potential of targeted elimination of tumor cells, while some adjuvant cells have also been engineered to enhance the therapeutic effect. On the other hand, diverse synthetic cellular components and molecules are added to engineered immune cells to regulate their functions, promoting cytotoxic activity and restricting side effects. Moreover, novel bioactive materials such as hydrogels facilitating the delivery of therapeutic immune cells have also been applied to improve the efficacy of cellular immunotherapy. This review summarizes the innovative strategies of synthetic cells and molecules currently available in cellular immunotherapies, discusses the limitations, and provides insights into the next generation of cellular immunotherapies.

Ex vivo pharmacokinetic/pharmacodynamic of hexahydrocolupulone against Clostridium perfringens in broiler chickens.

The economic impact of necrotizing enteritis (NE) resulting from Clostridium perfringens infection has been significant within the broiler industry. This study primarily investigated the antibacterial efficacy of hexahydrocolupulone against C. perfringens, and its pharmacokinetics within the ileal contents of broiler chickens. Additionally, a dosing regimen was developed based on the pharmacokinetic/pharmacodynamic (PK/PD) model specific to broiler chickens. Results of the study indicated that the minimum inhibitory concentration (MIC) of hexahydrocolupulone against C. perfringens ranged from 2 mg/L to 16 mg/L in MH broth. However, in ileal content, the MIC ranged from 8 mg/L to 64 mg/L. The mutation prevention concentration (MPC) in the culture medium was found to be 128 mg/L. After oral administration of hexahydrocolupulone at a single dosage of 10-40 mg/kg bodyweight, the peak concentration (Cmax), maximum concentration time (Tmax), and area under the concentration-time curve (AUC) in ileal content of broiler chickens were 291.42-3519.50 µg/g, 1-1.5 h, and 478.99-3121.41 µg h/g, respectively. By integrating the in vivo PK and ex vivo PD data, the AUC0-24h/MIC values required for achieving bacteriostatic, bactericidal, and bacterial eradication effects were determined to be 36.79, 52.67, and 62.71 h, respectively. A dosage regimen of 32.9 mg/kg at 24 h intervals for a duration of 3 days would yield therapeutic efficacy in broiler chickens against C. perfringens, provided that the MIC below 4 mg/L.

Efficient degradation of tetracycline via peroxymonosulfate activation by phosphorus-doped biochar loaded with cobalt nanoparticles.

The accumulation of tetracycline hydrochloride (TCH) threatens human health because of its potential biological toxicity. Carbon -based materials with easy isolation and excellent performance that can activate peroxymonosulfate (PMS) to generate reactive oxygen species for TCH degradation are essential, but the development of such materials remains a significant challenge. In this study, based on the idea of treating waste, tricobalt tetraoxide loaded P-doped biochar (Co NP-PBC) was synthesised to activate PMS for the degradation of TCH. Possible degradation pathways and intermediate products of TCH were identified using High performance liquid chromatography tandem mass spectrometry (HPLC-MS) detection and density functional theory analysis. Toxicity analysis software was used to predict the toxicity of the intermediate products. Compared to catalysts loaded with Fe and Mn and other Co-based catalysts, Co NP-PBC exhibited an optimal performance (with a kinetic constant of 0.157 min-1 for TCH degradation), and over 99.0% of TCH can be degraded within 20 min. This mechanism demonstrates that the non-free radical oxidation of 1O2 plays a major role in the degradation of TCH. This study provides insights into the purification of wastewater using BC-based catalysts.

Effects of robot-assisted upper limb training combined with intermittent theta burst stimulation (iTBS) on cortical activation in stroke patients: A functional near-infrared spectroscopy study.

BACKGROUND: The therapeutic effect and mechanism of robot-assisted upper limb training (RT) combined with intermittent theta burst stimulation (iTBS) for stroke patients are unclear. OBJECTIVE: The purpose of this study was to evaluate changes in brain activation after combination therapy and RT alone using functional near-infrared spectroscopy (fNIRS). METHODS: Patients were randomly assigned to two groups (iTBS + RT Group, n = 18, and RT Group, n = 18). Training was conducted five times a week for four weeks. fNIRS was used to measure changes in oxyhemoglobin in both the primary motor cortex (M1) and pre-motor and supplementary motor area (pSMA) during affected limb movement. Fugl-Meyer Assessment-Upper Extremity (FMA-UE) was employed for evaluating the function of upper limbs. RESULTS: Thirty-two patients with subacute stroke completed the study. The cortex of both hemispheres was extensively activated prior to treatment in the RT group. After training, overactivation decreased. The brain activation of the combined treatment group transferred to the affected side after the treatment. There was a notable enhancement in the FMA-UE scores for both groups, with the combined group's progress significantly surpassing that of the RT group. CONCLUSION: RT combined with iTBS can improve the motor function of stroke patients and promote the balance between cerebral hemispheres.

Gold-Catalyzed Oxidation Reactions of Thioalkynes with Quinoline N-Oxides: A DFT Study.

Mechanistic investigation of the gold-catalyzed oxidative reactions of thioalkynes with quinoline N-oxides was performed using density functional theory (DFT) calculations. For the oxidative rearrangement of thioalkynes with quinoline N-oxide to yield the same products, the Cß-oxidation of thioalkynes was predicted to be competitive with Cα-oxidation, with the Cß-oxidative process slightly more favorable. However, for the oxidative alkenylation of propargyl aryl thioethers with quinoline N-oxides, the Cß-oxidation of thioether by quinoline N-oxide generated the product 3-hydroxy-1-alkylidene phenylthiopropan-2-one. Moreover, the ring opening of the four-membered sulfonium intermediate was achieved by the nucleophilic attack of quinoline N-oxide rather than a water molecule.

How robot-assisted gait training affects gait ability, balance and kinematic parameters after stroke: a systematic review and meta-analysis.

INTRODUCTION: Gait ability is often cited by stroke survivors. Robot-assisted gait training (RAGT) can help stroke patients with lower limb motor impairment regain motor coordination. EVIDENCE ACQUISITION: PubMed, Cochrane Library, Embase were systematically searched until September 2023, to identify randomized controlled trials presenting: stroke survivors as participants; RAGT as intervention; conventional rehabilitation as a comparator; gait assessment, through scales or quantitative parameters, as outcome measures. EVIDENCE SYNTHESIS: Twenty-seven publications involving 1167 patients met the inclusion criteria. Meta-analysis showed no significant differences in speed, cadence, spatial symmetry, and changes in joint mobility angles between the RAGT group and the control group. In addition, RAGT was associated with changes in affected side step length (SMD=0.02, 95% CI: 0.01, 0.03; P<0.0001), temporal symmetry (SMD=-0.38, 95% CI: -0.6, -0.16; P=0.0006], Six-Minute Walk Test (SMD=25.14, 95% CI: 10.19, 40.09; P=0.0010] and Functional Ambulation Categories (SMD=0.32, 95% CI: 0.01, 0.63; P=0.04). According to the PEDro scale, 19 (70.4%) studies were of high quality and eight were of moderate quality (29.6%). CONCLUSIONS: Taken together, the review synthesis showed that RAGT might have a potential role in the recovery of walking dysfunction after stroke. However, its superiority over conventional rehabilitation requires further research. Additionally, it may provide unexpected benefits that the effects of RAGT with different types or treatment protocols were further compared.

Enhancing Inclusive Teaching in China: Examining the Effects of Principal Transformational Leadership, Teachers' Inclusive Role Identity, and Efficacy.

This research examined the effects of principal transformational leadership on teachers' inclusive teaching behaviour, with a particular inquiry into the mediating effects of teachers' inclusive role identity and efficacy for inclusive practice, as informed by identity theory and social cognitive theory. Structural equation modelling with bootstrapping estimation was conducted using data from 712 teachers delivering inclusive teaching in primary or secondary schools in China. The results revealed the sequentially mediating mechanisms of teachers' inclusive role identity and efficacy underlying the principal transformational leadership effects on teachers' inclusive teaching behaviour. Research implications are also discussed.

Histamine and receptors in neuroinflammation: Their roles on neurodegenerative diseases.

Histamine, an auto-reactive substance and mediator of inflammation, is synthesized from histidine through the action of histidine decarboxylase (HDC). It primarily acts on histamine receptors in the central nervous system (CNS). Increasing evidence suggests that histamine and its receptors play a crucial role in neuroinflammation, thereby modulating the pathology of neurodegenerative diseases. Recent studies have demonstrated that histamine regulates the phenotypic switching of microglia and astrocytes, inhibits the production of pro-inflammatory cytokines, and alleviates inflammatory responses. In the CNS, our research group has also found that histamine and its receptors are involved in regulating inflammatory responses and play a central role in ameliorating chronic neuroinflammation in neurodegenerative diseases. In this review, we will discuss the role of histamine and its receptors in neuroinflammation associated with neurodegenerative diseases, potentially providing a novel therapeutic target for the treatment of chronic neuroinflammation-related neurodegenerative diseases in clinical settings.

Nuclear deformation and cell division of single cell on elongated micropatterned substrates fabricated by DMD lithography.

Cells sense mechanical signals from the surrounding environment and transmit them to the nucleus through mechanotransduction to regulate cellular behavior. Microcontact printing, which utilizes elastomer stamps, is an effective method for simulating the cellular microenvironment and manipulating cell morphology. However, the conventional fabrication process of silicon masters and elastomer stamps requires complex procedures and specialized equipment, which restricts the widespread application of micropatterning in cell biology and hinders the investigation of the role of cell geometry in regulating cell behavior. In this study, we present an innovative method for convenient resin stamp microfabrication based on digital micromirror device planar lithography. Using this method, we generated a series of patterns ranging from millimeter to micrometer scales and validated their effectiveness in controlling adhesion at both collective and individual cell levels. Additionally, we investigated mechanotransduction and cell behavior on elongated micropatterned substrates. We then examined the effects of cell elongation on cytoskeleton organization, nuclear deformation, focal adhesion formation, traction force generation, nuclear mechanics, and the growth of HeLa cells. Our findings reveal a positive correlation between cell length and mechanotransduction. Interestingly, HeLa cells with moderate length exhibit the highest cell division and proliferation rates. These results highlight the regulatory role of cell elongation in mechanotransduction and its significant impact on cancer cell growth. Furthermore, our methodology for controlling cell adhesion holds the potential for addressing fundamental questions in both cell biology and biomedical engineering.

Inflammatory Microenvironment-Responsive Hydrogels Enclosed with Quorum Sensing Inhibitor for Treating Post-Traumatic Osteomyelitis.

Non-antibiotic strategies are desperately needed to treat post-traumatic osteomyelitis (PTO) due to the emergence of superbugs, complex inflammatory microenvironments, and greatly enriched biofilms. Previously, growing evidence indicated that quorum sensing (QS), a chemical communication signal among bacterial cells, can accelerate resistance under evolutionary pressure. This study aims to develop a medical dressing to treat PTO by inhibiting QS and regulating the inflammatory microenvironment, which includes severe oxidative stress and acid abscesses, through a reactive oxygen species (ROS)-responsive bond between N1- (4-borobenzoyl)-N3-(4-borobenzoyl)-the N1, the N1, N3, N3-tetramethylpropane-1,3-diamine (TSPBA) and polyvinyl alcohol (PVA), and the amino side chain of hyperbranched polylysine (HBPL). Physically enclosed QS inhibitors subsequently exerted the antibacterial effects. This hydrogel can scavenge hydrogen peroxide (H2O2), superoxide anion free radical (·O2 -), hydroxyl radicals (·OH) and 2,2-di(4-tert-octylphenyl)-1-picryl-hydrazyl (DPPH) to reduce oxidative stress and inhibit "bacteria-to-bacteria communication", thus clearing planktonic bacteria and biofilms, accelerating bacterial plasmolysis, reducing bacterial virulence and interfering with membrane transport. After in vivo treatment with hydrogel, nearly all bacteria are eliminated, inflammation is effectively inhibited, and osteogenesis and bone repair are promoted to facilitate recovery from PTO. The work demonstrates the clinical translational potential of the hydrogel in the treatment of drug-resistant bacteria induced PTO.

Monocytes in allo-HSCT with aged donors secrete IL-1/IL-6/TNF to increase the risk of GVHD and damage the aged HSCs.

Aging is considered a critical factor of poor prognosis in allogenic hemopoietic stem cell transplantation (allo-HSCT). To elucidate the underlying mechanisms, we comprehensively reintegrated our clinical data from patients after allo-HSCT and public single-cell transcriptomic profile from post-allo-HSCT and healthy individuals, demonstrating that old donors were more prone to acute GVHD (aGVHD) with pronounced inflammation accumulation and worse overall survival (OS). We also found the presence of inflammation-related CXCL2+ HSC subpopulation during aging with significantly enriched pro-inflammatory pathways. Shifting attention to the HSC microenvironment, we deciphered that IL-1/IL-6 and TRAIL (i.e., TNFSF10) ligand‒receptor pair serves as the crucial bridge between CD14/CD16 monocytes and hematopoietic stem/progenitor cells (HSPCs). The profound upregulation of these signaling pathways during aging finally causes HSC dysfunction and lineage-biased differentiation. Our findings provide the theoretical basis for achieving tailored GVHD management and enhancing allo-HSCT regimens efficacy for aged donors.

Proteome analysis develops novel plasma proteins classifier in predicting the mortality of COVID-19.

COVID-19 has been a global concern for 3 years, however, consecutive plasma protein changes in the disease course are currently unclear. Setting the mortality within 28 days of admission as the main clinical outcome, plasma samples were collected from patients in discovery and independent validation groups at different time points during the disease course. The whole patients were divided into death and survival groups according to their clinical outcomes. Proteomics and pathway/network analyses were used to find the differentially expressed proteins and pathways. Then, we used machine learning to develop a protein classifier which can predict the clinical outcomes of the patients with COVID-19 and help identify the high-risk patients. Finally, a classifier including C-reactive protein, extracellular matrix protein 1, insulin-like growth factor-binding protein complex acid labile subunit, E3 ubiquitin-protein ligase HECW1 and phosphatidylcholine-sterol acyltransferase was determined. The prediction value of the model was verified with an independent patient cohort. This novel model can realize early prediction of 28-day mortality of patients with COVID-19, with the area under curve 0.88 in discovery group and 0.80 in validation group, superior to 4C mortality and E-CURB65 scores. In total, this work revealed a potential protein classifier which can assist in predicting the outcomes of COVID-19 patients and providing new diagnostic directions.

Circular RNAs: Potential biomarkers and therapeutic targets for autoimmune diseases.

The outcomes and prognosis of autoimmune diseases depend on early diagnosis and effective treatments. However, symptoms of early autoimmune diseases are often remarkably similar to many inflammatory diseases, leading to difficulty in precise diagnosis. Circular RNAs (circRNAs) belong to a novel class of endogenous RNAs, functioning as microRNA (miRNA) sponges or participating in protein coding. It has been shown in many studies that patients with autoimmune diseases have aberrant circRNA expression in liquid biopsy samples (such as plasma, saliva, and urine). Thus, circRNAs are potential biomarkers for the diagnosis and prognosis of autoimmune diseases. Moreover, overexpression and depletion of target circRNAs can be utilized as possible therapeutic approaches for treating autoimmune diseases. In this review, we summarized recent progress in the roles of circRNAs in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes. We also discussed their potential as biomarkers and therapeutic targets.

A semi-quantitative upconversion nanoparticle-based immunochromatographic assay for SARS-CoV-2 antigen detection.

The unprecedented public health and economic impact of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been met with an equally unprecedented scientific response. Sensitive point-of-care methods to detect SARS-CoV-2 antigens in clinical specimens are urgently required for the rapid screening of individuals with viral infection. Here, we developed an upconversion nanoparticle-based lateral flow immunochromatographic assay (UCNP-LFIA) for the high-sensitivity detection of SARS-CoV-2 nucleocapsid (N) protein. A pair of rabbit SARS-CoV-2 N-specific monoclonal antibodies was conjugated to UCNPs, and the prepared UCNPs were then deposited into the LFIA test strips for detecting and capturing the N protein. Under the test conditions, the limit of detection (LOD) of UCNP-LFIA for the N protein was 3.59 pg/mL, with a linear range of 0.01-100 ng/mL. Compared with that of the current colloidal gold-based LFIA strips, the LOD of the UCNP-LFIA-based method was increased by 100-fold. The antigen recovery rate of the developed method in the simulated pharyngeal swab samples ranged from 91.1 to 117.3%. Furthermore, compared with the reverse transcription-polymerase chain reaction, the developed UCNP-LFIA method showed a sensitivity of 94.73% for 19 patients with COVID-19. Thus, the newly established platform could serve as a promising and convenient fluorescent immunological sensing approach for the efficient screening and diagnosis of COVID-19.

Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors.

BACKGROUND: As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified. METHODS: Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID. FINDINGS: The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder. INTERPRETATION: The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID. FUNDING: National Natural Science Foundation of China; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; Clinical Research Operating Fund of Central High Level Hospitals; the Talent Program of the Chinese Academy of Medical Science; Training Program of the Big Science Strategy Plan; Ministry of Science and Technology of the People's Republic of China; New Cornerstone Science Foundation; Peking Union Medical College Education Foundation; Research Funds from Health@InnoHK Program.

The effect and optimal parameters of repetitive transcranial magnetic stimulation on lower extremity motor function in stroke patient: a systematic review and meta-analysis.

PURPOSE: This study aimed to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in treating lower limb motor dysfunction after stroke and explore the optimal stimulation parameters. METHODS: PubMed, Embase, Cochrane Library, and other relevant databases were systematically queried for randomised controlled trials (RCTs) investigating the efficacy of rTMS in addressing lower limb motor dysfunction post-stroke. The search encompassed records from inception to July 2022. The assessed outcomes encompassed parameters such as the Fugl-Meyer motor function score for lower limbs, balance function, and Barthel index (BI). Three independent researchers were responsible for research selection, data extraction, and quality assessment. Study screening, data extraction, and bias evaluation were performed independently by two reviewers. Data synthesis was undertaken using Review Manager 5.3, while Stata version 14.0 software was employed for generating the funnel plot. RESULTS: A total of 13 studies and 428 patients were included. The meta-analysis indicated that rTMS had a positive effect on the BI (MD = 5.87, 95% CI [0.99, 10.76], p = 0.02, I2 = 86%, N of studies = 8, N of participants = 248). Subgroup analysis was performed on the stimulation frequency, treatment duration, and different stroke stages (stimulation frequency was low-frequency (LF)-rTMS (MD = 4.45, 95% CI [1.05, 7.85], p = 0.01, I2 = 0%, N of studies = 4, N of participants = 120); treatment time ≤ 15 d: (MD = 4.41, 95% CI [2.63, 6.18], p < 0.00001, I2 = 0%, N of studies = 4, N of participants = 124); post-stroke time ≤6 months: (MD = 4.37, 95% CI [2.42, 6.32], p < 0.0001, I2 = 0%, N of studies = 5, N of participants = 172). CONCLUSION: LF-rTMS had a significant improvement effect on BI score, while high-frequency (HF)-rTMS and iTBS had no significant effect. And stroke time ≤6 months in patients with treatment duration ≤15 d had the best treatment effect.

Stroke Lower limb dysfunction is a common complication after stroke, seriously affecting the daily life of patients.Lower limb motor function improved significantly within 6 months after low frequency treatment.To maximise motor gains in patients with lower limb motor dysfunction following stroke in the shortest possible time, it is recommended to initiate early rehabilitation therapy using low-frequency transcranial magnetic stimulation during the subacute phase of stroke.