Feasibility and preliminary effects of a mindfulness-based physical exercise (MBPE) program for community-dwelling older people with sarcopenia: A protocol for a parallel, two-armed pilot randomised controlled trial.

INTRODUCTION: Physical exercise (PE) is essential for alleviating the symptoms of sarcopenia. Low motivation is a major barrier to PE. Mindfulness-based intervention (MBI) has the potential to improve motivation. However, few studies have used a mindfulness-based PE (MBPE) intervention among older people with sarcopenia. OBJECTIVES: To assess the feasibility, acceptability and preliminary effects of the MBPE program among community-dwelling older people with sarcopenia. METHODS AND ANALYSIS: A two-arm pilot randomised controlled trial will be conducted to assess the feasibility, acceptability and preliminary effects of an MBPE program among community-dwelling older people with sarcopenia. A total of 60 participants will be randomised into the intervention group, receiving the MBPE intervention twice a week over 12 weeks, or the control group, receiving health education with the same duration, number of sessions and frequency as the intervention group. Each session of the MBPE program will last about 60 min, including 5-10- min introduction, 20-min MBI, 30-min PE and 5-10-min sharing and discussion. The primary outcomes will be the feasibility (i.e., the time spent recruiting participants, the eligibility rate and the recruitment rate) and acceptability (i.e., the attendance rate, completion rate and attrition rate) of the MBPE program. The secondary outcomes will be the preliminary effects of the MBPE program on symptoms of sarcopenia, motivation for PE, psychological well-being, mindfulness level, physical activity level and quality of life. Individual interviews will be conducted to identify the strengths, limitations and therapeutic components of the intervention. The quantitative data will be analysed by generalised estimating equations. The qualitative data will be analysed by Braun and Clarke's thematic approach. CONCLUSION: The findings of this study will be able to provide evidence for the health professionals in adopting MBPE as a supportive intervention for the older adults with sarcopenia and the groundworks for the researchers in developing non-pharmacological intervention for older adults. The positive effects could facilitate healthy ageing and relief the burden of the medical system, especially in the countries facing the ageing population. TRIAL REGISTRATION NUMBER: NCT05982067; ClinicalTrials.gov.

Data-Driven Discovery of Gas-Selective Organic Linkers in Metal-Organic Frameworks for the Separation of Ethylene and Ethane.

Metal-organic frameworks (MOFs) are potential candidates for gas-selective adsorbents for the separation of an ethylene/ethane mixture. To accelerate material discovery, high-throughput computational screening is a viable solution. However, classical force fields, which were widely employed in recent studies of MOF adsorbents, have been criticized for their failure to cover complicated interactions such as those involving π electrons. Herein, we demonstrate that machine learning force fields (MLFFs) trained on quantum-chemical reference data can overcome this difficulty. We have constructed a MLFF to accurately predict the adsorption energies of ethylene and ethane on the organic linkers of MOFs and discovered that the π electrons from both the ethylene molecule and the aromatic rings in the linkers could substantially influence the selectivity for gas adsorption. Four kinds of MOF linkers are identified as having promise for the separation of ethylene and ethane, and our results could also offer a new perspective on the design of MOF building blocks for diverse applications.

Salicin alleviates periodontitis via Tas2r143/gustducin signaling in fibroblasts.

Introduction: Cells expressing taste signaling elements in non-gustatory tissues have been described as solitary chemosensory cells (SCCs) or tuft cells. These "taste-like" cells play a critical role in the maintenance of tissue homeostasis. Although the expression of SCC markers and taste signaling constituents has been identified in mouse gingivae, their role in periodontal homeostasis is still unclear. Methods: Public RNA sequencing datasets were re-analyzed and further validated with RT-PCR/qRT-PCR and immunofluorescent staining to explore the expression of TAS2Rs and downstream signaling constituents in mouse gingival fibroblasts (MGFs). The specific action of salicin on MGFs via Tas2r143 was validated with RNA silence, heterologous expression of taste receptor/Gα-gustducin and calcium imaging. The anti-inflammatory effects of salicin against LPS-induced MGFs were investigated in cell cultures, and were further validated with a ligature-induced periodontitis mouse model using Ga-gustducin-null (Gnat3-/-) mice. Results: The expression of Tas2r143, Gnat3, Plcb2, and TrpM5 was detected in MGFs. Moreover, salicin could activate Tas2r143, elicited taste signaling and thus inhibited LPS-induced chemokines expression (CXCL1, CXCL2, and CXCL5) in MGFs. Consistently, salicin-treatment inhibited periodontal bone loss, inflammatory/chemotactic factors expression, and neutrophil infiltration in periodontitis mice, while these effects were abolished in Gnat3-/- mice. Discussion: Gingival fibroblasts play a critical role in the maintenance of periodontal homeostasis via "SCC-like" activity. Salicin can activate Tas2r143-mediated bitter taste signaling and thus alleviate periodontitis in mouse, indicating a promising approach to the resolution of periodontal inflammation via stimulating the "SCC-like" function of gingival fibroblasts.

Correlation Between miR-497-5p Expression With Clinicopathological Characteristics and Prognosis in Patients With Breast Cancer.

Breast cancer (BC) comprises multiple biological and histologic properties. MicroRNAs show key functions in cancer prognosis. This paper explored the relationship between miR-497-5p with clinicopathological characteristics and prognosis in BC. Cancer tissues and normal adjacent tissues (NATs) were collected from 140 included patients with BC. The clinical baseline data, including age, tumor size, pathologic grade, clinical stage, modified Scraff-Bloom-Richardson grade, and lymph node metastasis, were recorded. miR-497-5p expression in cancer tissues and NAT was determined by reverse transcription-quantitative polymerase chain reaction. Patients with BC were followed up for 5 years to record their survival. Patients were divided into the miR-497-5p low expression and high expression groups to assess the correlation between miR-497-5p expression with clinicopathological characteristics and overall survival of patients. The role of miR-497-5p as an independent risk factor for death was further analyzed by a multivariate Cox regression model. miR-497-5p was downregulated in BC tissues than NAT. Tumor size, clinical stage, and lymph node metastasis showed significant differences among patients with high and low miR-497-5p expression levels. Patients with BC with low miR-497-5p expression presented decreased survival. Lowly-expressed miR-497-5p was an independent risk factor for death in patients. Collectively, cancer tissue miR-497-5p low expression increases the risk of death and serves as an independent risk factor for death in patients with BC.

Copper-Catalyzed Domino-Double Annulation of o-Aminobenzamides with 2-Iodoisothiocyanates for the Synthesis of 12H-Benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones.

A facile and efficient copper-catalyzed domino-double annulation strategy was developed from easily accessible o-aminobenzamides and 2-iodoisothiocyanates, which affords a direct pathway for the synthesis of tetracyclic fused 12H-benzo[4,5]thiazolo[2,3-b]quinazolin-12-ones in moderate to good yields without the addition of ligands, bases, and external oxidants. The reaction involves a C-N bond cleavage and the formation of a C-N/C-S bond in one step with the advantages of using an inexpensive copper catalyst and easy operation. Mechanistic studies suggest that this transformation proceeds via intermolecular condensation of o-aminobenzamides with 2-iodoisothiocyanates, followed by an intramolecular Ullmann-type cross-coupling cyclization reaction.

Palladium-Copper-Catalyzed Oxidative Intermolecular [2 + 2 + 2] Coupling-Annulation: Regioselective Synthesis of Multiaryl-Substituted Benzenes.

A palladium-catalyzed intermolecular [2 + 2 + 2] oxidative coupling-annulation of terminal alkenes and alkynes using copper(II) as the oxidant has been developed through direct C-C bond formation. These reactions provide effective access to multiaryl-substituted benzenes with high regioselectivity in the absence of any ligands. The features of this protocol are broad substrate scope, and high atom and step economy. The aggregation-induced emission properties of selected products were further investigated. These synthesized multiaryl-substituted benzenes may be worth exploring for further applications in the fields of advanced functional materials or drugs.

Newcastle disease virus activates diverse signaling pathways via Src to facilitate virus entry into host macrophages.

As an intrinsic cellular mechanism responsible for the internalization of extracellular ligands and membrane components, caveolae-mediated endocytosis (CavME) is also exploited by certain pathogens for endocytic entry [e.g., Newcastle disease virus (NDV) of paramyxovirus]. However, the molecular mechanisms of NDV-induced CavME remain poorly understood. Herein, we demonstrate that sialic acid-containing gangliosides, rather than glycoproteins, were utilized by NDV as receptors to initiate the endocytic entry of NDV into HD11 cells. The binding of NDV to gangliosides induced the activation of a non-receptor tyrosine kinase, Src, leading to the phosphorylation of caveolin-1 (Cav1) and dynamin-2 (Dyn2), which contributed to the endocytic entry of NDV. Moreover, an inoculation of cells with NDV-induced actin cytoskeletal rearrangement through Src to facilitate NDV entry via endocytosis and direct fusion with the plasma membrane. Subsequently, unique members of the Rho GTPases family, RhoA and Cdc42, were activated by NDV in a Src-dependent manner. Further analyses revealed that RhoA and Cdc42 regulated the activities of specific effectors, cofilin and myosin regulatory light chain 2, responsible for actin cytoskeleton rearrangement, through diverse intracellular signaling cascades. Taken together, our results suggest that an inoculation of NDV-induced Src-mediated cellular activation by binding to ganglioside receptors. This process orchestrated NDV endocytic entry by modulating the activities of caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPases and downstream effectors. IMPORTANCE: In general, it is known that the paramyxovirus gains access to host cells through direct penetration at the plasma membrane; however, emerging evidence suggests more complex entry mechanisms for paramyxoviruses. The endocytic entry of Newcastle disease virus (NDV), a representative member of the paramyxovirus family, into multiple types of cells has been recently reported. Herein, we demonstrate the binding of NDV to induce ganglioside-activated Src signaling, which is responsible for the endocytic entry of NDV through caveolae-mediated endocytosis. This process involved Src-dependent activation of the caveolae-associated Cav1 and Dyn2, as well as specific Rho GTPase and downstream effectors, thereby orchestrating the endocytic entry process of NDV. Our findings uncover a novel molecular mechanism of endocytic entry of NDV into host cells and provide novel insight into paramyxovirus mechanisms of entry.

Genetically engineering of Saccharomyces cerevisiae for enhanced oral delivery vaccine vehicle.

As a series of our previous studies reported, recombinant yeast can be the oral vaccines to deliver designed protein and DNA, as well as functional shRNA, into dendritic cells (DCs) in mice for specific immune regulation. Here, we report the further optimization of oral yeast-based vaccine from two aspects (yeast characteristics and recombinant DNA constitution) to improve the effect of immune regulation. After screening four genes in negative regulation of glucan synthesis in yeast (MNN9, GUP1, PBS2 and EXG1), this research combined HDR-based genome editing technology with Cre-loxP technology to acquire 15 gene-knockout strains without drug resistance-gene to exclude biosafety risks; afterward, oral feeding experiments were performed on the mice using 15 oral recombinant yeast-based vaccines constructed by the gene-knockout strains harboring pCMV-MSTN plasmid to screen the target strain with more effective inducing mstn-specific antibody which in turn increasing weight gain effect. And subsequently based on the selected gene-knockout strain, the recombinant DNA in the oral recombinant yeast-based vaccine is optimized via a combination of protein fusion expression (OVA-MSTN) and interfering RNA technology (shRNA-IL21), comparison in terms of both weight gain effect and antibody titer revealed that the selected gene-knockout strain (GUP1ΔEXG1Δ) combined with specific recombinant DNA (pCMV-OVA-MSTN-shIL2) had a better effect of the vaccine. This study provides a useful reference to the subsequent construction of a more efficient oral recombinant yeast-based vaccine in the food and pharmaceutical industry.

GPNMB promotes peripheral nerve regeneration by activating the Erk1/2 and Akt pathways via binding Na+/K+-ATPase α1 in Schwann cells.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is ubiquitously expressed and has protective effects on the central nervous system. In particular, it is also expressed in the peripheral nervous system (PNS) and upregulated after peripheral nerve injury. However, the role and underlying mechanism of GPNMB in the PNS, especially in peripheral nerve regeneration (PNR), are still unknown and need to be further investigated. In this study, recombinant human GPNMB (rhGPNMB) was injected into a sciatic nerve injury model. It was found that rhGPNMB facilitated the regeneration and functional recovery of the injured sciatic nerve in vivo. Moreover, it was also confirmed that GPNMB activated the Erk1/2 and Akt pathways via binding with Na+/K + -ATPase α1 (NKA α1) and promoted the proliferation and migration of Schwann cells (SCs) and their expression and secretion of neurotrophic factors and neural adhesion molecules in vitro. Our findings demonstrate that GPNMB facilitates PNR through activation of the Erk1/2 and Akt pathways in SCs by binding with NKA α1 and may be a novel strategy for PNR.

Evaluating the efficacy of recombinant human growth factors in scar remodelling for patients with facial soft tissue injuries.

Facial soft tissue injuries, often resulting in scarring, pose a challenge in reconstructive and aesthetic surgery due to the need for functional and aesthetic restoration. This study evaluates the efficacy of recombinant human growth factors (rhGFs) in scar remodelling for such injuries. A retrospective evaluation was conducted from January 2020 to January 2023, involving 100 patients with facial soft tissue injuries. Participants were divided equally into a control group, receiving standard cosmetic surgical repair, and an observation group, treated with rhGFs supplemented cosmetic surgery. The study assessed scar characteristics (pigmentation, pliability, vascularity, height), hospital stay duration, tissue healing time, complication rates and patient satisfaction. The observation group demonstrated significant improvements in all scar characteristics, with notably better pigmentation, pliability, vascularity and height compared with the control group. The rhGF treatment also resulted in reduced hospital stay duration and faster tissue healing. Notably, the total complication rate was significantly lower in the observation group (10%) compared with the control group (34%). Additionally, patient satisfaction levels were higher in the observation group, with 98% combined satisfaction compared with 76% in the control group. The application of rhGFs in treating facial soft tissue injuries significantly enhances scar remodelling, expedites healing, reduces complications and improves patient satisfaction. These findings establish rhGFs as a valuable tool in the management of facial soft tissue injuries, highlighting their potential in improving both functional and aesthetic outcomes.

A potent and broad-spectrum neutralizing nanobody for SARS-CoV-2 viruses, including all major Omicron strains.

SARS-CoV-2 viruses are highly transmissible and immune evasive. It is critical to develop broad-spectrum prophylactic and therapeutic antibodies for potential future pandemics. Here, we used the phage display method to discover nanobodies (Nbs) for neutralizing SARS-CoV-2 viruses especially Omicron strains. The leading nanobody (Nb), namely, Nb4, with excellent physicochemical properties, can neutralize Delta and Omicron subtypes, including BA.1, BA.1.1 (BA.1 + R346K), BA.2, BA.5, BQ.1, and XBB.1. The crystal structure of Nb4 in complex with the receptor-binding domain (RBD) of BA.1 Spike protein reveals that Nb4 interacts with an epitope on the RBD overlapping with the receptor-binding motif, and thus competes with angiotensin-converting enzyme 2 (ACE2) binding. Nb4 is expected to be effective for neutralizing most recent Omicron variants, since the epitopes are evolutionarily conserved among them. Indeed, trivalent Nb4 interacts with the XBB1.5 Spike protein with low nM affinity and competes for ACE2 binding. Prophylactic and therapeutic experiments in mice indicated that Nb4 could reduce the Omicron virus loads in the lung. In particular, in prophylactic experiments, intranasal administration of multivalent Nb4 completely protected mice from Omicron infection. Taken together, these results demonstrated that Nb4 could serve as a potent and broad-spectrum prophylactic and therapeutic Nb for COVID-19.

[A novel CRISPR/Cas9-hLacI donor adapting system for dsDNA-templated gene editing].

During the gene editing process mediated by CRISPR/Cas9, precise genome editing and gene knock-in can be achieved by the homologous recombination of double-stranded DNA (dsDNA) donor template. However, the low-efficiency of homologous recombination in eukaryotic cells hampers the development and application of this gene editing strategy. Here, we developed a novel CRISPR/Cas9-hLacI donor adapting system (DAS) to enhance the dsDNA-templated gene editing, taking the advantage of the specific binding of the LacI repressor protein and the LacO operator sequence derived for the Escherichia coli lactose operon. The codon-humanized LacI gene was fused as an adaptor to the Streptococcus pyogenes Cas9 (SpCas9) and Staphylococcus lugdunensis Cas9 (SlugCas9-HF) genes, and the LacO operator sequence was used as the aptamer and linked to the dsDNA donor template by PCR. The Cas9 nuclease activity after the fusion and the homology-directed repair (HDR) efficiency of the LacO-linked dsDNA template were firstly examined using surrogate reporter assays with the corresponding reporter vectors. The CRISPR/Cas9-hLacI DASs mediated genome precise editing were further checked, and we achieved a high efficiency up to 30.5% of precise editing at the VEGFA locus in HEK293T cells by using the CRISPR/SlugCas9-hLacI DAS. In summary, we developed a novel CRISPR/Cas9-hLacI DAS for dsDNA-templated gene editing, which enriches the CRISPR/Cas9-derived gene editing techniques and provides a novel tool for animal molecular design breeding researches.

Molecular Biology Mechanisms and Emerging Therapeutics of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is conventionally characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), accounting for approximately 15-20% of all breast cancers. Compared to other molecular phenotypes, TNBC is typically associated with high malignancy and poor prognosis. Cytotoxic agents have been the mainstay of treatment for the past few decades due to the lack of definitive targets and limited therapeutic interventions. However, recent developments have demonstrated that TNBC has peculiar molecular classifications and biomarkers, which provide the possibility of evolving treatment from basic cytotoxic chemotherapy to an expanding domain of targeted therapies. This review presents a framework for understanding the current clinical experience surrounding molecular biology mechanisms in TNBC (Figure 1). Including immunotherapy, polymerase (PARP) and PI3K/AKT pathway inhibitors, antibody-drug conjugates, and androgen receptor (AR) blockade. Additionally, the role of miRNA therapeutics targeting TNBC and potential strategies targeting cancer stem cells (CSCs) are discussed and highlighted. As more and more treatments arise on the horizon, we believe that patients with TNBC will have a new sense of hope.

Oral proprietary Chinese medicine for lupus nephritis: A bayesian network meta-analysis.

Objective: To analyze the efficacy and safety of proprietary Chinese medicines for the treatment of Lupus Nephritis (LN) based on the reticulated meta analysis. The study aim to provide evidence-based evidence for the clinical treatment of LN. Methods: The studies related to the randomized controlled studies (RCTs) on the treatment of LN with oral proprietary Chinese medicines were obtained from China National Knowledge Infrastructure (CNKI), Database for Chinese Technical Periodicals (VIP), SinoMed, Wanfang, PubMed, Web of Science, Embase and Cochrane Library databases since its inception-August 2022. Cochrane tools were used for risk bias assessment, Stata 13.0 and ADDIS 1.16.5 software were used for net evidence analysis.Results.1) 41 RCTs with 3124 L N patients were included, involving 9 types of proprietary Chinese medicines.2) The meta-analysis showed that in terms of efficacy, the top 3 Chinese patent medicine interventions were Xin Gan Bao Capsule (XGB) +western medicines (WM), Huang Kui Capsule (HK) + WM, Kun Xian Capsule (KX) + WM; in terms of reducing adverse event rate, the top 3 Chinese patent medicine interventions were Yi Shen Hua Shi Granules (YSHS) + WM, Jin Shui Bao Capsule (JSB) + WM, HK + WM; in terms of reducing 24 h urine protein, the top 3 Chinese patent medicine interventions were XGB + WM, YSHS + WM, Bai Ling Capsule (BL) + WM; in terms of reducing blood creatinine (Cr), the top 3 Chinese patent medicine interventions were Yi Shen Granules (YS) + WM, JSB + WM, KX + WM; in terms of reducing urea nitrogen (BUN), the top 3 Chinese patent medicine interventions were Shen Kang Capsule (SK) + WM, HK + WM, JSB + WM; in terms of reducing systemic lupus erythematosus disease activity index (SLEDAI) scores, the top 3 Chinese patent medicine interventions were JSB + WM, BL + WM, YSHS + WM; in terms of improving complement C3, the top 3 Chinese patent medicine interventions were HK + WM, XGB + WM, BL + WM; in terms of improving complement C4, the top 3 Chinese patent medicine interventions were KX + WM, YSHS + WM, BL + WM. Conclusion: Xin Gan Bao Capsule has a good efficacy in improving efficiency and the level of complement C3, lowering 24 h urine protein. Jin Shui Bao Capsule and Huang Kui Capsule have a good efficacy in treating LN. However, more multicentre, large sample and high quality RCTs are needed for validation the results.

Novel PVAMA/GelMA aerogels prepared by liquid-phase collection of photoinitiated polymerisation: injectable and flowable low-density 3D scaffolds for bone regeneration.

Nanofibrous scaffolds, which are morphologically/structurally similar to native extracellular matrix, are ideal biomaterials for tissue engineering and regenerative medicine. However, the use of traditional electrospinning techniques to produce three-dimensional (3D) nanofibrous scaffolds with desired structural properties presents difficulty. To address this challenge, we prepared a novel liquid-phase-collected photoinitiated polymerised aerogel 3D scaffold (LPPI-AG) using the thermally induced (nanofiber) self-aggregation method after liquid-phase electrospinning of the hydroxyapatite-doped methacrylated polyvinyl alcohol/methacrylated gelatine solution obtained by photoinitiated polymerisation. The fabricated aerogel scaffolds had a high porosity of approximately 99.01% ± 0.40% and an interconnected network structure with pore sizes ranging from submicron to ∼300 µm. The new aerogel rapidly became flowable when exposed to a solution, and it can fill gaps and repair gap edges effectively and be loaded with nutrients and growth factors that promote bone growth for bone tissue engineering. LPPI-AG scaffolds can considerably promote osteogenic differentiation of bone marrow mesenchymal stem cells in vitro. Furthermore, in vivo studies showed that the LPPI-AG scaffold significantly promoted bone formation in a mouse model of critical-size calvarial defects.

Exploration of the molecular mechanism of insulin resistance in adipose tissue of patients with type 2 diabetes mellitus through a bioinformatic analysis.

BACKGROUND: We aimed to determine the cis-expression Quantitative Trait Loci (cis-eQTL) and trans-eQTL of differentially expressed genes (DEGs) in insulin resistance (IR) related pathways. METHODS: The expression profile data for insulin sensitivity (IS) and IR in the adipose tissue of patients with type 2 diabetes mellitus (T2DM) were acquired from the Gene Expression Omnibus databases. Then, the Gene set enrichment analysis (GSEA) and Gene set variation analysis (GSVA) methods were performed to identify the significant enrichment of potential Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between IS and IR groups, and the Wilcoxon rank sum test was carried out to identify the DEGs related to KEGG pathways. Finally, the cis-eQTLs and trans-eQTLs that can affect the expression of DEGs were screened from the eQTLGen database. RESULTS: The GSEA and GSVA analysis indicated that the mTOR signaling pathway, insulin signaling pathway and T2DM had a strong correlation with the pathological process of T2DM. Furthermore, six genes (ACACA, GYS2, PCK1, PRKAR1A, SLC2A4, and VEGFA) were found to be significantly differentially expressed in IR-related pathways. Finally, we have identified a total of 1073 cis-eQTLs and 24 trans-eQTLs. CONCLUSIONS: We screened out six genes that were significantly differentially expressed in IR-related pathways, including ACACA, GYS2, PCK1, PRKAR1A, SLC2A4, and VEGFA. Moreover, we discovered that these six genes were affected by 1073 cis-eQTLs and 24 trans-eQTLs.

Changes in expression levels of erythrocyte and immune-related genes are associated with high altitude polycythemia.

BACKGROUND: As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood. METHODS: 37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis. RESULTS: The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent. CONCLUSION: This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.

Gut microbiome alterations in pulmonary hypertension in highlanders and lowlanders.

Background: Alterations in the gut microbiota have been observed in patients with pulmonary hypertension (PH), though whether the roles of the gut microbiota in PH at different altitudes are the same is unknown. This study aims to evaluate the associations of the gut microbiome with PH in highlanders and lowlanders. Methods: PH patients and controls were recruited from those who permanently live on the Tibetan plateau (highlanders) or the plains (lowlanders), and underwent transthoracic echocardiography close to their altitude of residence (at 5070 m for highlanders versus6 m for lowlanders). The gut microbiome was profiled using metagenomic shotgun sequencing. Results: In total, 13 PH patients (46% highlanders) and 88 controls (70% highlanders) were included. The overall microbial composition was different in PH patients compared to controls (p=0.003). Notably, among lowlanders, a composite microbial score of pro-atherosclerotic trimethylamine-producing species was increased in PH patients compared with that in controls (p=0.028), while among highlanders no such difference was observed (p=0.087). Another composite gut microbial score including eight species of Lactobacillus, which has shown beneficial effects on cardiovascular functions, was higher in highlanders than lowlanders (p<0.01). Furthermore, this score tended to be lower in PH patients than controls among highlanders (p=0.056) but not among lowlanders (p=0.840). In addition, the gut microbiome showed a good performance in distinguishing PH patients from controls in both lowlanders and highlanders. Conclusions: Our study reported differently altered gut microbiome profiles between highland and lowland PH patients, highlighting the distinct microbial mechanism in PH in highlanders compared with lowlanders.

Reducedhumoral response against variants of concern in childhood solid cancer patients compared to adult patients and healthy children after SARS-CoV-2 vaccination.

Introduction: Although there is extended research on the response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in adult cancer patients (ACP), the immunogenicity to the variants of concern (VOCs) in childhood cancer patients (CCP) and safety profiles are now little known. Methods: A prospective, multi-center cohort study was performed by recruiting children with a solid cancer diagnosis and childhood healthy control (CHC) to receive standard two-dose SARS-CoV-2 vaccines. An independent ACP group was included to match CCP in treatment history. Humoral response to six variants was performed and adverse events were followed up 3 months after vaccination. Responses to variants were compared with ACP and CHC by means of propensity score-matched (PSM) analysis. Results: The analysis included 111 CCP (27.2%, median age of 8, quartile 5.5-15 years), 134 CHC (32.8%), and 163 ACP (40.0%), for a total 408 patients. Pathology included carcinoma, neural tumors, sarcoma, and germ cell tumors. Median chemotherapy time was 7 (quartile, 5-11) months. In PSM sample pairs, the humoral response of CCP against variants was significantly decreased, and serology titers (281.8 ± 315.5 U/ml) were reduced, as compared to ACP (p< 0.01 for the rate of neutralization rate against each variant) and CHC (p< 0.01 for the rate of neutralization against each variant) groups. Chemotherapy time and age (Pearson r ≥ 0.8 for all variants) were associated with the humoral response against VOCs of the CHC group. In the CCP group, less than grade II adverse events were observed, including 32 patients with local reactions, and 29 patients had systemic adverse events, including fever (n = 9), rash (n = 20), headache (n = 3), fatigue (n = 11), and myalgia (n = 15). All reactions were well-managed medically. Conclusions: The humoral response against VOCs after the CoronaVac vaccination in CCP was moderately impaired although the vaccine was safe. Age and chemotherapy time seem to be the primary reason for poor response and low serology levels.

Barriers and facilitators of family doctor contract services in caring for disabled older adults in Beijing, China: a mixed methods study.

OBJECTIVE: To evaluate the current state of family doctor contract services (FDCS) in Beijing, identify the roles of family doctors who have worked with disabled older adults and investigate the barriers and facilitators faced by family doctors in providing care for them. DESIGN: A convergent mixed methods study was carried out from October 2020 to January 2021 to collect and analyse both quantitative and qualitative data. The integration strategies in this study were connecting the results of the quantitative phase to data collection of the qualitative phase. SETTING: A multi-stage sampling strategy was used to select 15 community health centres (CHCs) in four districts of Beijing. Of the four districts, two were from urban areas and two were from rural areas. PARTICIPANTS: The inclusion criteria for participants were (1) family doctors, (2) contracted with disabled older adults, (3) engaged in related work for disabled older adults more than 6 months. METHODS: A cluster sampling of 283 family doctors was used in the questionnaire. A purposive sample of 30 family doctors from the same CHCs was selected during the same period. Frequency and rank, rank-sum test, Kruskal-Wallis test were conducted in qualitative data analysis, the views of the interviewees were analysed through the thematic framework method. RESULTS: Currently, family doctors provided various services to satisfy the health needs of disabled older adults, while the usage of FDCS for disabled older adults is affected by many factors. The differences of the importance of family doctors' role (p<0.001) and service satisfaction (p=0.004) were significant among four districts. Compared with contracted health senior citizens, this study has identified five unique roles of family doctors, including 'psychological consultant', 'rehabilitation physiotherapist', 'health educator', 'health manager' and 'family health guardian'. Moreover, family doctors are confronted with a myriad of barriers (including high risks in the process of home visits, a lack of supervisory and incentive mechanisms, insufficiency of time and energy, etc) and facilitators (including establishing a doctor-patient trust relationship, developing humanistic care services, etc) in the FDCS for disabled older adults. CONCLUSIONS: Family doctors play a pivotal role in the FDCS for disabled older adults, while the effect and quality of FDCS in China needs to be improved. It is suggested that further research needs to focus on solving existing barriers of FDCS to optimise the health of disabled older adults and improve the quality of their lives.