MicroRNA-124 influenced depressive symptoms via large-scale brain connectivity in major depressive disorder patients.

This study aimed to investigate the neurobiological mechanisms by which microRNA 124 (miR-124) is involved in major depressive disorder (MDD). We enrolled 53 untreated MDD patients and 38 healthy control (HC) subjects who completed behavior assessments and resting-state functional MRI (rs-fMRI) scans. MiR-124 expression levels were detected in the peripheral blood of all participants. We determined that miR-124 levels could influence depressive symptoms via disrupted large-scale intrinsic intra- and internetwork connectivity, including the default mode network (DMN)-DMN, dorsal attention network (DAN)-salience network (SN), and DAN-cingulo-opercular network (CON). This study deepens our understanding of how miR-124 dysregulation contributes to depression.

The FTO-CMPK2 Pathway in Fibroblast-like Synoviocytes Modulates Rheumatoid Arthritis Synovial Inflammation and Cartilage Homeostasis via mtDNA Regulation.

In rheumatoid arthritis (RA), a debilitating autoimmune disorder marked by chronic synovial inflammation and progressive cartilage degradation, fibroblast-like synoviocytes (FLS) are key pathogenic players. Current treatments targeting these cells are limited. Our study focused on the Fat Mass and Obesity-associated protein (FTO), known for its roles in cell proliferation and inflammatory response modulation, and its involvement in RA. We specifically examined the inflammatory regulatory roles of FTO and CMPK2, a mitochondrial DNA synthesis protein, in FLS. Utilizing a combination of in vitro and in vivo methods, including FTO inhibition and gene knockdown, we aimed to understand FTO's influence on RA progression and chondrocyte functionality. Our findings showed that increased FTO expression in RA synovial cells enhanced their proliferation and migration and decreased senescence and apoptosis. Inhibiting FTO significantly slowed the disease progression in our models. Our research also highlighted that the FTO-CMPK2 pathway plays a crucial role in regulating synovial inflammation through the mtDNA-mediated cGAS/STING pathway, affecting chondrocyte homeostasis. This study indicates that targeting the FTO-CMPK2 axis could be a promising new therapeutic strategy for managing RA.

Development and evaluation of a human CD47/HER2 bispecific antibody for Trastuzumab-resistant breast cancer immunotherapy.

The treatment for trastuzumab-resistant breast cancer (BC) remains a challenge in clinical settings. It was known that CD47 is preferentially upregulated in HER2+ BC cells, which is correlated with drug resistance to trastuzumab. Here, we developed a novel anti-CD47/HER2 bispecific antibody (BsAb) against trastuzumab-resistant BC, named IMM2902. IMM2902 demonstrated high binding affinity, blocking activity, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and internalization degradation effects against both trastuzumab-sensitive and trastuzumab-resistant BC cells in vitro. The in vivo experimental data indicated that IMM2902 was more effective than their respective controls in inhibiting tumor growth in a trastuzumab-sensitive BT474 mouse model, a trastuzumab-resistant HCC1954 mouse model, two trastuzumab-resistant patient-derived xenograft (PDX) mouse models and a cord blood (CB)-humanized HCC1954 mouse model. Through spatial transcriptome assays, multiplex immunofluorescence (mIFC) and in vitro assays, our findings provided evidence that IMM2902 effectively stimulates macrophages to generate C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, thereby facilitating the recruitment of T cells and NK cells to the tumor site. Moreover, IMM2902 demonstrated a high safety profile regarding anemia and non-specific cytokines release. Collectively, our results highlighted a novel therapeutic approach for the treatment of HER2+ BCs and this approach exhibits significant anti-tumor efficacy without causing off-target toxicity in trastuzumab-resistant BC cells.

Efficacy and safety of difelikefalin in the treatment of hemodialysis patients with pruritus: A meta-analysis and systematic review.

BACKGROUND: The incidence of pruritus associated with hemodialysis (HD) patients can be as high as 70%, and ~ 40% of patients suffer from moderate to severe systemic pruritus. Difelikefalin (CR845), a peripheral restrictor κ-opioid receptor agonist, activates opioid receptors on peripheral neurons and immune cells to relieve pruritus in patients. However, the clinical effect of difelikefalin on HD-related pruritus is unclear. Therefore, the purpose of this meta-analysis and systematic review was to investigate the safety and efficacy of difelikefalin in the treatment of HD-associated pruritus. OBJECTIVE: This study explored the efficacy and safety of difelikefalin in the treatment of pruritus in HD patients by systematic review and meta-analysis. MATERIALS AND METHODS: Randomized controlled trials on difelikefalin in the treatment of pruritus in HD patients were retrieved from PubMed, Embase, Cochrane Library, and Web of Science electronic databases. The retrieval deadline was January 1, 2023. Stata 15.0 software was used for data analysis of the included studies. RESULTS: A total of 4 randomized controlled trials were included, totaling 1,268 patients (736 patients in the experimental group and 532 patients in the control group). Results of the meta-analysis showed that, compared with the control group, difelikefalin could significantly improve the Worst Itch Numeric Rating Scale score (improvement > 3; risk ratio (RR) = 1.28, 95% confidence interval (CI) (1.07, 1.53)), decrease the 5-D itch score (standardized mean difference = -0.43, 95% CI (-0.55, -0.30)), and significantly improve adverse events (RR = 1.33, 95% CI (1.13, 1.56)). CONCLUSION: Although difelikefalin can improve itching symptoms in HD patients, it can also increase adverse reactions based on the current literature. Therefore, more studies are needed to further explore the safety and efficacy of difelikefalin treatment.

Biogeographic survey of soil bacterial communities across Antarctica.

BACKGROUND: Antarctica and its unique biodiversity are increasingly at risk from the effects of global climate change and other human influences. A significant recent element underpinning strategies for Antarctic conservation has been the development of a system of Antarctic Conservation Biogeographic Regions (ACBRs). The datasets supporting this classification are, however, dominated by eukaryotic taxa, with contributions from the bacterial domain restricted to Actinomycetota and Cyanobacteriota. Nevertheless, the ice-free areas of the Antarctic continent and the sub-Antarctic islands are dominated in terms of diversity by bacteria. Our study aims to generate a comprehensive phylogenetic dataset of Antarctic bacteria with wide geographical coverage on the continent and sub-Antarctic islands, to investigate whether bacterial diversity and distribution is reflected in the current ACBRs. RESULTS: Soil bacterial diversity and community composition did not fully conform with the ACBR classification. Although 19% of the variability was explained by this classification, the largest differences in bacterial community composition were between the broader continental and maritime Antarctic regions, where a degree of structural overlapping within continental and maritime bacterial communities was apparent, not fully reflecting the division into separate ACBRs. Strong divergence in soil bacterial community composition was also apparent between the Antarctic/sub-Antarctic islands and the Antarctic mainland. Bacterial communities were partially shaped by bioclimatic conditions, with 28% of dominant genera showing habitat preferences connected to at least one of the bioclimatic variables included in our analyses. These genera were also reported as indicator taxa for the ACBRs. CONCLUSIONS: Overall, our data indicate that the current ACBR subdivision of the Antarctic continent does not fully reflect bacterial distribution and diversity in Antarctica. We observed considerable overlap in the structure of soil bacterial communities within the maritime Antarctic region and within the continental Antarctic region. Our results also suggest that bacterial communities might be impacted by regional climatic and other environmental changes. The dataset developed in this study provides a comprehensive baseline that will provide a valuable tool for biodiversity conservation efforts on the continent. Further studies are clearly required, and we emphasize the need for more extensive campaigns to systematically sample and characterize Antarctic and sub-Antarctic soil microbial communities. Video Abstract.

Resting-state cerebral blood flow and functional connectivity abnormalities in depressed patients with childhood maltreatment: Potential biomarkers of vulnerability?

AIM: Childhood maltreatment (CM) is an important risk factor for major depressive disorder (MDD). This study aimed to explore the specific effect of CM on cerebral blood flow (CBF) and brain functional connectivity (FC) in MDD patients. METHODS: A total of 150 subjects were collected including 55 MDD patients with CM, 34 MDD patients without CM, 19 healthy controls (HC) with CM, and 42 HC without CM. All subjects completed MRI scans and neuropsychological tests. Two-way analysis of covariance was used to detect the main and interactive effects of disease and CM on CBF and FC across subjects. Then, partial correlation analyses were conducted to explore the behavioral significance of altered CBF and FC in MDD patients. Finally, a support vector classifier model was applied to differentiate MDD patients. RESULTS: MDD patients represented increased CBF in bilateral temporal lobe and decreased CBF in right visual cortex. Importantly, significant depression-by-CM interactive effects on CBF were primarily located in the frontoparietal regions, including orbitofrontal cortex (OFC), lateral prefrontal cortex (PFC), and parietal cortex. Moreover, significant FC abnormalities were seen in OFC-PFC and frontoparietal-visual cortex. Notably, the abnormal CBF and FC were significantly associated with behavioral performance. Finally, a combination of altered CBF and FC behaved with a satisfactory classification ability to differentiate MDD patients. CONCLUSIONS: These results highlight the importance of frontoparietal and visual cortices for MDD with CM experience, proposing a potential neuroimaging biomarker for MDD identification.

The interaction of climate, plant, and soil factors drives putative soil fungal pathogen diversity and community structure in dry grasslands.

Soil pathogens play important roles in shaping soil microbial diversity and controlling ecosystem functions. Though climate and local environmental factors and their influences on fungal pathogen communities have been examined separately, few studies explore the relative contributions of these factors. This is particularly crucial in eco-fragile regions, which are more sensitive to environmental changes. Herein we investigated the diversity and community structure of putative soil fungal pathogens in cold and dry grasslands on the Tibetan Plateau, using high-throughput sequencing. The results showed that steppe soils had the highest diversity of all pathogens and plant pathogens; contrastingly, meadow soils had the highest animal pathogen diversity. Structural equation modelling revealed that climate, plant, and soil had similar levels of influence on putative soil fungal pathogen diversity, with total effects ranging from 52% to 59% (all p < 0.001), with precipitation exhibiting a stronger direct effect than plant and soil factors. Putative soil fungal pathogen community structure gradually changed with desert, steppe, and meadow, and was primarily controlled by the interactions of climate, plant, and soil factors rather than by distinct factors individually. This finding contrasts with most studies of soil bacterial and fungal community structure, which generally report dominant roles of individual environmental factors.

Connectomics-based resting-state functional network alterations predict suicidality in major depressive disorder.

Suicidal behavior is a major concern for patients who suffer from major depressive disorder (MDD). However, dynamic alterations and dysfunction of resting-state networks (RSNs) in MDD patients with suicidality have remained unclear. Thus, we investigated whether subjects with different severity of suicidal ideation and suicidal behavior may have different disturbances in brain RSNs and whether these changes could be used as the diagnostic biomarkers to discriminate MDD with or without suicidal ideation and suicidal behavior. Then a multicenter, cross-sectional study of 528 MDD patients with or without suicidality and 998 healthy controls was performed. We defined the probability of dying by the suicide of the suicidality components as a 'suicidality gradient'. We constructed ten RSNs, including default mode (DMN), subcortical (SUB), ventral attention (VAN), and visual network (VIS). The network connections of RSNs were analyzed among MDD patients with different suicidality gradients and healthy controls using ANCOVA, chi-squared tests, and network-based statistical analysis. And support vector machine (SVM) model was designed to distinguish patients with mild-to-severe suicidal ideation, and suicidal behavior. We found the following abnormalities with increasing suicidality gradient in MDD patients: within-network connectivity values initially increased and then decreased, and one-versus-other network values decreased first and then increased. Besides, within- and between-network connectivity values of the various suicidality gradients are mainly negatively correlated with HAMD anxiety and positively correlated with weight. We found that VIS and DMN-VIS values were affected by age (p < 0.05), cingulo-opercular network, and SUB-VAN values were statistically influenced by sex (p < 0.05). Furthermore, the SVM model could distinguish MDD patients with different suicidality gradients (AUC range, 0.73-0.99). In conclusion, we have identified that disrupted brain connections were present in MDD patients with different suicidality gradient. These findings provided useful information about the pathophysiological mechanisms of MDD patients with suicidality.

Exploring the role of the disulfidptosis-related gene SLC7A11 in adrenocortical carcinoma: implications for prognosis, immune infiltration, and therapeutic strategies.

BACKGROUND: Disulfidptosis and the disulfidptosis-related gene SLC7A11 have recently attracted significant attention for their role in tumorigenesis and tumour management. However, its association with adrenocortical carcinoma (ACC) is rarely discussed. METHODS: Differential analysis, Cox regression analysis, and survival analysis were used to screen for the hub gene SLC7A11 in the TCGA and GTEx databases and disulfidptosis-related gene sets. Then, we performed an association analysis between SLC7A11 and clinically relevant factors in ACC patients. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic value of SLC7A11 and clinically relevant factors. Weighted gene coexpression analysis was used to find genes associated with SLC7A11. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and the LinkedOmics database were used to analyse the functions of SLC7A11-associated genes. The CIBERSORT and Xcell algorithms were used to analyse the relationship between SLC7A11 and immune cell infiltration in ACC. The TISIDB database was applied to search for the correlation between SLC7A11 expression and immune chemokines. In addition, we performed a correlation analysis for SLC7A11 expression and tumour mutational burden and immune checkpoint-related genes and assessed drug sensitivity based on SLC7A11 expression. Immunohistochemistry and RT‒qPCR were used to validate the upregulation of SLC7A11 in the ACC. RESULTS: SLC7A11 is highly expressed in multiple urological tumours, including ACC. SLC7A11 expression is strongly associated with clinically relevant factors (M-stage and MYL6 expression) in ACC. SLC7A11 and the constructed nomogram can accurately predict ACC patient outcomes. The functions of SLC7A11 and its closely related genes are tightly associated with the occurrence of disulfidptosis in ACC. SLC7A11 expression was tightly associated with various immune cell infiltration disorders in the ACC tumour microenvironment (TME). It was positively correlated with the expression of immune chemokines (CXCL8, CXCL3, and CCL20) and negatively correlated with the expression of immune chemokines (CXCL17 and CCL14). SLC7A11 expression was positively associated with the expression of immune checkpoint genes (NRP1, TNFSF4, TNFRSF9, and CD276) and tumour mutation burden. The expression level of SLC7A11 in ACC patients is closely associated withcthe drug sensitivity. CONCLUSION: In ACC, high expression of SLC7A11 is associated with migration, invasion, drug sensitivity, immune infiltration disorders, and poor prognosis, and its induction of disulfidptosis is a promising target for the treatment of ACC.

Sonoactivated Nanomaterials: A potent armament for wastewater treatment.

The world is currently facing a critical issue of water pollution, with wastewater being a major contributor. It comes from different types of pollutants, including industrial, medical, agricultural, and domestic. Effective treatment of wastewater requires efficient degradation of pollutants and carcinogens prior to discharge. Commonly used methods for wastewater treatment include filtration, adsorption, biodegradation, advanced oxidation processes, and Fenton oxidation, among others.The sonochemical effect refers to the decomposition, oxidation, reduction, and other reactions of pollutant molecules in wastewater upon ultrasound activation, achieving pollutants removal. Furthermore, the micro-flow effect generated by ultrasonic waves creates tiny bubbles and eddies. This significantly increases the contact area and exchange speed of pollutants and dissolved oxygen, thereby accelerating pollutant degradation. Currently, ultrasonic-assisted technology has emerged as a promising approach due to its strong oxidation ability, simple and cheap equipments, and minimal secondary pollution. However, the use of ultrasound in wastewater treatment has some limitations, such as high energy consumption, lengthy treatment time, limited water treatment capacity, stringent water quality requirements, and unstable treatment effects. To address these issues, the combination of enhanced ultrasound with nanotechnology is proposed and has shown great potential in wastewater treatment. Such a combination can greatly improve the efficiency of ultrasonic oxidation, resulting in an improved performance of wastewater purification. This article presents recent progress in the development of sonoactivated nanomaterials for enhanced wastewater disposal. Such nanomaterials are systematically classified and discussed. Potential challenges and future prospects of this emerging technology are also highlighted.

Effects of congestion charging and subsidy policy on vehicle flow and revenue with user heterogeneity.

Traffic congestion is a major issue in urban traffic networks. Both congestion charging and subsidy policy can solve traffic congestion to some extent, but which one is better? Based on this, this paper constructs a typical transit network consisting of three travel tools in four common travel modes. Travelers' values of time affect their choice of transportation in the congestion network, thus a stochastic user equilibrium model is established by considering travelers' heterogenous values of time to evaluate the effects of different combinations of congestion charging and subsidy policies on vehicle flow and revenue. Numerical results indicate that the effectiveness of congestion charging and subsidy policy in alleviating traffic congestion depends on the object of charging or subsidizing. Congestion charging for private cars can reduce traffic flow and alleviate traffic congestion, but charging for ridesharing cars does not reduce traffic flow and may even cause traffic congestion. Subsidizing public buses does not reduce traffic flow, but it can ease congestion by coordinating traffic flow on both edges of the dual-modal transport. The combination of no subsidy for public buses and charging for both private cars and ridesharing cars can obtain the greatest revenue, but it does not alleviate traffic congestion. Although the combination of charging for private cars and subsidizing public buses does not bring the most benefits, it can reduce traffic flow, and its revenue is also considerable. This study can provide quantitative decision support for the government to ease traffic congestion and improve government revenue.

The role of vascular endothelial cells in tumor metastasis.

Vascular endothelial cells (VECs) are an integral component of the inner lining of blood vessels, and their functions are essential for the proper functioning of the vascular system. The tight junctions formed by VECs act as a significant barrier to the intravasation and extravasation of tumor cells (TCs). In addition to that, the proliferation, activation, and migration of VECs play a vital role in the growth of new blood vessels, a process known as tumor angiogenesis, which is closely related to the malignant progression of tumors. However, during tumor progression, VECs undergo endothelial-to-mesenchymal transition (EndMT), which further promotes tumor progression. Furthermore, VECs act as the first line of defense against effector immune cells and help prevent immune cells from infiltrating into tumor tissues. VECs also secrete various cytokines that can contribute to regulating the stemness of tumor stem cells. Thus, it has been increasingly recognized that dysfunction of VECs is one of the key driving forces behind tumor metastasis, and therapeutic strategies targeting VECs have the potential to be an effective means of antitumor therapy. This review aims to present a comprehensive overview of the role and mechanisms of VECs in regulating tumor progression and metastasis, providing insights into the possibilities for the development of novel antitumor therapies that target VECs.

Sequencing of 19,219 exomes identifies a low-frequency variant in FKBP5 promoter predisposing to high myopia in a Han Chinese population.

High myopia (HM) is one of the leading causes of visual impairment and blindness worldwide. Here, we report a whole-exome sequencing (WES) study in 9,613 HM cases and 9,606 controls of Han Chinese ancestry to pinpoint HM-associated risk variants. Single-variant association analysis identified three newly identified -genetic loci associated with HM, including an East Asian ancestry-specific low-frequency variant (rs533280354) in FKBP5. Multi-ancestry meta-analysis with WES data of 2,696 HM cases and 7,186 controls of European ancestry from the UK Biobank discerned a newly identified European ancestry-specific rare variant in FOLH1. Functional experiments revealed a mechanism whereby a single G-to-A transition at rs533280354 disrupted the binding of transcription activator KLF15 to the promoter of FKBP5, resulting in decreased transcription of FKBP5. Furthermore, burden tests showed a significant excess of rare protein-truncating variants among HM cases involved in retinal blood vessel morphogenesis and neurotransmitter transport.

Precipitation Drives Soil Protist Diversity and Community Structure in Dry Grasslands.

Protists are essential components of soil microbial communities, mediating nutrient cycling and ecosystem functions in terrestrial ecosystems. However, their distribution patterns and driving factors, particularly, the relative importance of climate, plant and soil factors, remain largely unknown. This limits our understanding of soil protist roles in ecosystem functions and their responses to climate change. This is particularly a concern in dryland ecosystems where soil microbiomes are more important for ecosystem functions because plant diversity and growth are heavily constrained by environmental stresses. Here, we explored protist diversity and their driving factors in grassland soils on the Tibetan Plateau, which is a typical dryland region with yearly low temperatures. Soil protist diversity significantly decreased along the gradient of meadow, steppe, and desert. Soil protist diversity positively correlated with precipitation, plant biomass and soil nutrients, but these correlations were changed by grazing. Structural equation and random forest models demonstrated that precipitation dominated soil protist diversity directly and indirectly by influencing plant and soil factors. Soil protist community structure gradually shifted along meadow, steppe and desert, and was driven more by precipitation than by plant and soil factors. Soil protist community compositions were dominated by Cercozoa, Ciliophora and Chlorophyta. In particular, Ciliophora increased but Chlorophyta decreased in relative abundance along the gradient of meadow, steppe and desert. These results demonstrate that precipitation plays more important roles in driving soil protist diversity and community structure than plant and soil factors, suggesting that future precipitation change profoundly alters soil protist community and functions in dry grasslands.

Controls on diversity of core and indicative microbial subcommunities in Tibetan Plateau grassland soils.

Core subcommunity represents the less diversity but high abundance, while indicative subcommunity is highly diverse but low abundance in soils. The core subcommunity fundamentally maintains ecosystem stability, while the indicative plays important roles in vital ecosystem functions and is more sensitive to environmental change. However, their environmental driving factors and responses to human disturbances remain less defined. Herein, we explored the patterns of core and indicative soil microbes and their responses to animal grazing in dry grasslands across the Tibetan Plateau, using the Illumina sequencing of 16S rRNA gene. The results revealed that the core subcommunity diversity and richness were lower than the indicative in soils. The indicative subcommunity diversity exhibited substantially stronger correlations with nutrient-associated factors than the core diversity, including soil organic carbon, nitrogen, and plant biomass. The core and indicative microbial subcommunities both strongly varied with grassland ecosystems, while the latter was also significantly influenced by grazing. The variation partitioning analysis revealed that indicative microbial subcommunity was explained less by environmental factors than core subcommunity (34.5% vs 73.0%), but more influenced by grazing (2.6% vs 0.1%). Our findings demonstrated that the indicative microbes were particularly sensitive to soil nutrient-associated factors and human disturbances in alpine dry grasslands.

Partial erosion on under-methylated regions and chromatin reprogramming contribute to oncogene activation in IDH mutant gliomas.

BACKGROUND: IDH1/2 hotspot mutations are well known to drive oncogenic mutations in gliomas and are well-defined in the WHO 2021 classification of central nervous system tumors. Specifically, IDH mutations lead to aberrant hypermethylation of under-methylated regions (UMRs) in normal tissues through the disruption of TET enzymes. However, the chromatin reprogramming and transcriptional changes induced by IDH-related hypermethylation in gliomas remain unclear. RESULTS: Here, we have developed a precise computational framework based on Hidden Markov Model to identify altered methylation states of UMRs at single-base resolution. By applying this framework to whole-genome bisulfite sequencing data from 75 normal brain tissues and 15 IDH mutant glioma tissues, we identified two distinct types of hypermethylated UMRs in IDH mutant gliomas. We named them partially hypermethylated UMRs (phUMRs) and fully hypermethylated UMRs (fhUMRs), respectively. We found that the phUMRs and fhUMRs exhibit distinct genomic features and chromatin states. Genes related to fhUMRs were more likely to be repressed in IDH mutant gliomas. In contrast, genes related to phUMRs were prone to be up-regulated in IDH mutant gliomas. Such activation of phUMR genes is associated with the accumulation of active H3K4me3 and the loss of H3K27me3, as well as H3K36me3 accumulation in gene bodies to maintain gene expression stability. In summary, partial erosion on UMRs was accompanied by locus-specific changes in key chromatin marks, which may contribute to oncogene activation. CONCLUSIONS: Our study provides a computational strategy for precise decoding of methylation encroachment patterns in IDH mutant gliomas, revealing potential mechanistic insights into chromatin reprogramming that contribute to oncogenesis.

MiRNA-206 Affects the Recovery of Sciatic Function by Stimulating BDNF Activity through the Down-regulation of Notch3 Expression.

OBJECTIVE: To investigate the effects and mechanisms of microRNA 206 (miRNA-206) on neurological recovery through Notch receptor 3 (Notch3). METHODS: The sciatic functional index (SFI), nerve conduction velocity (NCV), tricipital muscle wet weight (TWW) and cross-sectional area of the muscular fiber, and grip strength of posterior limbs were detected by establishing a model of the sciatic nerve to evaluate the effect of sciatic nerve injury model. miRNA-206 expression in the model was detected by real-time quantitative polymerase chain reaction (qRT-PCR), to regulate the effects of miRNA-206 on the proliferation of gastrocnemius myocytes by Cell Counting Kit-8 (CCK-8). RESULTS: SFI of the model established by immediate epineurium suture after sciatic nerve resection was in the range of -150% to -100% and TWW, the average area of gastrocnemius myocytes, the NCV, and the grasping power of the hind limbs in the model were all lower than those in the normal group. And in the model, TWW, the average area of gastrocnemius myocytes, NCV, and grip strength of posterior limbs were lower in the normal group, which verified the successful establishment of the model. CONCLUSION: Over-expression of miRNA-206 can down-regulate Notch3 expression, and then stimulate brain-derived neurotrophic factor (BDNF) activity to promote the repair and functional recovery of sciatic nerve injury.

Association between vitamin D supplementation and cancer incidence and mortality: A trial sequential meta-analysis of randomized controlled trials.

Observational studies and clinical trials have evaluated the associations between vitamin D supplementation and cancer incidence/mortality and obtained mixed results. Previous meta-analyses have also yielded inconsistent conclusions. In this paper, we conduct an updated meta-analysis by including current randomized clinical trials (RCTs) to assess the association between vitamin D supplementation and cancer incidence and mortality. The PubMed, Scopus and Embase databases were systematically searched from their inception to 6 February 2022. Fixed-effects meta-analyses were conducted. Trial sequential analyses were performed using a risk ratio reduction threshold of 10% for cancer incidence and mortality. Twenty-six RCTs were eligible, and pooled results indicated that vitamin D supplementation, compared to placebo with/without calcium, was not associated with a reduction in total cancer incidence (risk ratio: 0.98, 95% CI: 0.94, 1.02; I2 = 0%). In contrast, vitamin D supplementation significantly reduced total cancer mortality (risk ratio: 0.88, 95% CI: 0.8, 0.96; I2 = 0%). Moreover, trial sequential analysis provided reliable evidence that supplementation with vitamin D lowered the relative risk of total cancer mortality by 10%. Our updated meta-analysis suggested that vitamin D supplementation did not reduce total cancer incidence but significantly lowered total cancer mortality.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022.2056574 .

Bioinformatic identification and validation of autophagy-related genes in rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by progressive synovial inflammation and joint destruction, with a largely unknown etiology. Studies have suggested that autophagy and its expression may be involved in the pathogenesis of RA; however, autophagy-related genes in RA are still largely unidentified. Therefore, in this study, we aimed to identify and validate autophagy-related genes in RA. METHODS: We identified differentially expressed autophagy-related genes between patients with RA and healthy individuals using gene expression profiles in the GSE55235 dataset and R software. Subsequently, correlation analysis, protein-protein interaction, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out using these differentially expressed autophagy-related genes. Finally, our results were validated by examining the expression of differentially expressed autophagy-related hub genes in clinical samples using qRT-PCR. RESULTS: We identified 52 potential autophagy-related genes in RA based on bioinformatic analyses. Ten hub genes, CASP8, CTSB, TNFSF10, FADD, BAX, MYC, FOS, CDKN1A, GABARAPL1, and BNIP3, were validated to be differentially expressed and may serve as valuable prognostic markers and new potential therapeutic targets for RA via the regulation of autophagy. CONCLUSIONS: Our results may help improve the understanding of RA pathogenesis. Autophagy-related genes in RA could be valuable biomarkers for diagnosis and prognosis and they might be exploited clinically as therapeutic targets in the future.

Mutant NPM1 Hijacks Transcriptional Hubs to Maintain Pathogenic Gene Programs in Acute Myeloid Leukemia.

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes-HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention. SIGNIFICANCE: NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517.