Quantitative analysis of the morphing wing mechanism of raptors: Bionic design of Falco Peregrinus wing skeleton.

The wing is one of the most important parts of a bird's locomotor system and is the inspiration origination for bionic wing design. During wing motions, the wing shape is closely related to the rotation angles of wing bones. Therefore, the research on the law of bone movement in the process of wing movement can be good guidance for the design of the bionic morphing wing. In this paper, the skeletal posture of the peregrine falcon wing during the extension/flexion is studied to obtain critical data on skeletal posture. Since an elbow joint and a wrist joint rotate correlatively to drive a wing to flex/extend, the wing skeleton is simplified as a four-bar mechanism in this paper. The degree of reproduction of wing skeleton postures was quantitatively analyzed using the four-bar mechanism model, and the bionic wing skeleton was designed. It is found that the wing motions have been reproduced with high precision.

Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.

PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce. METHODS: A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo. RESULTS: As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment. CONCLUSION: Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.

LLDT-8 ameliorates experimental autoimmune encephalomyelitis by mediating macrophage functions in the priming stage.

Multiple sclerosis (MS) is an inflammatory demyelinating disease in the central nervous system caused by T cell activation mediated by peripheral macrophages, resulting in severe neurological deficits and disability. Due to the currently limited and expensive treatments for MS, we here introduce an economic Chinese medicine extract, (5R)-5-Hydroxytriptolide (LLDT-8), which shows low toxicity and high immunosuppressive activity. We used the widely accepted mouse model of MS, experimental autoimmune encephalomyelitis (EAE), to examine the immunosuppressive effect of LLDT-8 in vivo. Through the RNA-sequence analysis of peripheral macrophages in EAE mice, we discovered that LLDT-8 alleviates the symptoms of EAE by inhibiting the proinflammatory effect of macrophages, thereby blocking the activation and proliferation of T cells. In all, we found that LLDT-8 could be a potential treatment for MS.

Development of a radiomics-based model to predict occult liver metastases of pancreatic ductal adenocarcinoma: a multicenter study.

BACKGROUND: Undetectable occult liver metastases block the long-term survival of pancreatic ductal adenocarcinoma (PDAC). This study aimed to develop a radiomics-based model to predict occult liver metastases and assess its prognostic capacity for survival. MATERIALS AND METHODS: Patients who underwent surgical resection and were pathologically proven with PDAC were recruited retrospectively from five tertiary hospitals between January 2015 and December 2020. Radiomics features were extracted from tumors, and the radiomics-based model was developed in the training cohort using LASSO-logistic regression. The model's performance was assessed in the internal and external validation cohorts using the area under the receiver operating curve (AUC). Subsequently, the association of the model's risk stratification with progression-free survival (PFS) and overall survival (OS) was then statistically examined using Cox regression analysis and the log-rank test. RESULTS: A total of 438 patients [mean (SD) age, 62.0 (10.0) years; 255 (58.2%) male] were divided into the training cohort ( n =235), internal validation cohort ( n =100), and external validation cohort ( n =103). The radiomics-based model yielded an AUC of 0.73 (95% CI: 0.66-0.80), 0.72 (95% CI: 0.62-0.80), and 0.71 (95% CI: 0.61-0.80) in the training, internal validation, and external validation cohorts, respectively, which were higher than the preoperative clinical model. The model's risk stratification was an independent predictor of PFS (all P <0.05) and OS (all P <0.05). Furthermore, patients in the high-risk group stratified by the model consistently had a significantly shorter PFS and OS at each TNM stage (all P <0.05). CONCLUSION: The proposed radiomics-based model provided a promising tool to predict occult liver metastases and had a great significance in prognosis.

Acute ischemia induces spatially and transcriptionally distinct microglial subclusters.

BACKGROUND: Damage in the ischemic core and penumbra after stroke affects patient prognosis. Microglia immediately respond to ischemic insult and initiate immune inflammation, playing an important role in the cellular injury after stroke. However, the microglial heterogeneity and the mechanisms involved remain unclear. METHODS: We first performed single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) on middle cerebral artery occlusion (MCAO) mice from three time points to determine stroke-associated microglial subclusters and their spatial distributions. Furthermore, the expression of microglial subcluster-specific marker genes and the localization of different microglial subclusters were verified on MCAO mice through RNAscope and immunofluorescence. Gene set variation analysis (GSVA) was performed to reveal functional characteristics of microglia sub-clusters. Additionally, ingenuity pathway analysis (IPA) was used to explore upstream regulators of microglial subclusters, which was confirmed by immunofluorescence, RT-qPCR, shRNA-mediated knockdown, and targeted metabolomics. Finally, the infarct size, neurological deficits, and neuronal apoptosis were evaluated in MCAO mice after manipulation of specific microglial subcluster. RESULTS: We discovered stroke-associated microglial subclusters in the brains of MCAO mice. We also identified novel marker genes of these microglial subclusters and defined these cells as ischemic core-associated (ICAM) and ischemic penumbra-associated (IPAM) microglia, according to their spatial distribution. ICAM, induced by damage-associated molecular patterns, are probably fueled by glycolysis, and exhibit increased pro-inflammatory cytokines and chemokines production. BACH1 is a key transcription factor driving ICAM generation. In contrast, glucocorticoids, which are enriched in the penumbra, likely trigger IPAM formation, which are presumably powered by the citrate cycle and oxidative phosphorylation and are characterized by moderate pro-inflammatory responses, inflammation-alleviating metabolic features, and myelinotrophic properties. CONCLUSIONS: ICAM could induce excessive neuroinflammation, aggravating brain injury, whereas IPAM probably exhibit neuroprotective features, which could be essential for the homeostasis and survival of cells in the penumbra. Our findings provide a biological basis for targeting specific microglial subclusters as a potential therapeutic strategy for ischemic stroke.

KIF11 serves as a cell cycle mediator in childhood acute lymphoblastic leukemia.

OBJECTIVE: To identify key gene in childhood acute lymphoblastic leukemia (ALL) through weighted gene co-expression network analysis (WGCNA), and their enriched biological functions and signaling pathways. METHODS: Array data of the GSE73578 dataset, involving 46 childhood ALL samples, were acquired from the Gene Expression Omnibus (GEO) database. Hub modules associated with childhood ALL were screened out by WGCNA. Enriched biological functions and signaling pathways were then identified by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Hub genes were selected by overlapping those between down-regulated genes in GSE73578, GSE4698 and the hub module. Guilt by association (GBA) was adopted to verify the function of the identified KIF11 gene and to predict its target genes. Regulatory effects of KIF11 on the proliferation and cell cycle progression of ALL in vitro were determined by cytological experiments. RESULTS: WGCNA showed that the yellow module was the most relevant to childhood ALL treatment, containing 698 genes that were enriched in cell division, mitotic nuclear division, DNA replication and DNA repair, cell cycle, DNA replication and the P53 signaling pathway. The KIF11 gene was screened out and predicted as a cell cycle mediator in childhood ALL. Knockdown of KIF11 in ALL cells inhibited cell proliferation and arrested cell cycle progression in G2/M phase. CONCLUSIONS: The KIF11 gene is critical in the treatment process of childhood ALL, which is a promising therapeutic target for childhood ALL.

Pharmacological Upregulation of Microglial Lipid Droplet Alleviates Neuroinflammation and Acute Ischemic Brain Injury.

Lipid droplets (LDs) were reported to play an important role in the modulation of inflammation and various cellular processes among multiple cell types. However, LDs accumulation, its function and mechanisms of its formation during ischemic stroke remained poorly-identified. In this study, we observed increased LDs accumulation in microglia at the acute stage of ischemic stroke by immunofluorescence and flow cytometry. Transcriptomic analysis indicated that microglia accumulated with LDs were associated with inflammation and phagocytosis. Both inflammatory activation and phagocytosis of tissue debris in microglia could contribute to LDs formation. Moreover, through specific LDs depletion and overload experiments by pharmacological approaches, we proposed that LDs was critical for the maintenance of anti-inflammatory properties of microglia. Furthermore, Atglistatin, a specific adipose triglyceride lipase (ATGL) inhibitor, was shown to prevent proinflammatory cytokines production in primary microglia through decreased LDs lipolysis. After Atglistatin treatment, middle cerebral artery occlusion (MCAO) mice showed decreased infarct volume and improved neurobehavioral performance at the acute stage of stroke. Our findings provided a biological basis for microglial LDs regulation as a potential therapeutic strategy for acute ischemic stroke and uncovered the neuroprotective role of Atglistatin in the treatment of MCAO mice.

Domain Matching Strategy for Orientation Control of van der Waals Epitaxial Perovskite Thin Films.

The advantages of van der Waals epitaxy have attracted great interest because they can meet the requirements that conventional epitaxy struggles to satisfy. The weak adatom-substrate interaction without directional covalent bonding drastically relaxes the lattice matching limitation. However, the weak adatom-substrate interaction also leads to ineffectiveness in directing the crystal growth structure, limiting it to one orientation in epitaxial growth. In this work, we propose a domain matching strategy to guide the perovskite-type crystal epitaxial growth on 2D substrates, and we have demonstrated selective deposition of highly (001)-, (110)-, and (111)-oriented epitaxial Fe4N thin films on mica substrates using applicable transition structure design. Our work makes it possible to achieve and control different orientations of van der Waals epitaxy on the same substrate.

Cold-adapted enzymes: mechanisms, engineering and biotechnological application.

Most cold-adapted enzymes display high catalytic activity at low temperatures (20-25 °C) and can still maintain more than 40-50% of their maximum activity at lower temperatures (0-10 °C) but are inactivated after a moderate increase in temperature. The activity of some cold-adapted enzymes increases significantly in the presence of high salt concentrations and metal ions. Interestingly, we also observed that some cold-adapted enzymes have a wide range of optimum temperatures, exhibiting not only maximum activity under low-temperature conditions but also the ability to maintain high enzyme activity under high-temperature conditions, which is a novel feature of cold-adapted enzymes. This unique property of cold-adapted enzymes is generally attractive for biotechnological and industrial applications because these enzymes can reduce energy consumption and the chance of microbial contamination, thereby lowering the production costs and maintaining the flavor, taste and quality of foods. How high catalytic activity is maintained at low temperatures remains unknown. The relationship between the structure of cold-adapted enzymes and their activity, flexibility and stability is complex, and thus far, a unified explanation has not been provided. Herein, we systematically review the sources, catalytic characteristics and cold adaptation of enzymes from four enzymes categories systematically and discuss how these properties may be exploited in biotechnology. A thorough understanding of the properties, catalytic mechanisms, and engineering of cold-adapted enzymes is critical for future biotechnological applications in the detergent industry and food and beverage industries.

Can the new adipokine asprosin be a metabolic troublemaker for cardiovascular diseases? A state-of-the-art review.

Adipokines play a significant role in cardiometabolic diseases. Asprosin, a newly discovered adipokine, was first identified as a glucose-raising protein hormone. Asprosin also stimulates appetite and regulates glucose and lipid metabolism. Its identified receptors so far include Olfr734 and Ptprd. Clinical studies have found that asprosin may be associated with cardiometabolic diseases. Asprosin may have diagnostic and therapeutic potential in obesity, diabetes, metabolic syndrome and atherosclerotic cardiovascular diseases. Herein, the structure, receptors, and functions of asprosin and its relationship with cardiometabolic diseases are summarized based on recent findings.

ZNF384-Related Fusion Genes in Acute Lymphoblastic Leukemia.

Zinc finger protein 384 (ZNF384) encodes a C2H2-type zinc finger protein that can function as a transcription factor. ZNF384 rearrangement in acute lymphoblastic leukemia (ALL) was first reported in 2002. More than 19 different ZNF384 fusion partners have been detected in ALL. These include E1A-binding protein P300 (EP300), CREB-binding protein (CREBBP), transcription factor 3 (TCF3), TATA-box binding protein associated factor 15 (TAF15), Ewing sarcoma breakpoint region 1 gene (EWSR1), AT-rich interactive domain-containing protein 1B (ARID1B), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4 (SMARCA4), SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2), synergin gamma (SYNRG), clathrin heavy chain (CLTC), bone morphogenic protein 2-inducible kinase (BMP2K), Nipped-B-like protein (NIPBL), A Kinase Anchoring Protein 8 (AKAP8), Chromosome 11 Open Reading Frame 74 (C11orf74), DEAD-Box Helicase 42 (DDX42), ATP Synthase F1 Subunit Gamma (ATP2C1), Euchromatic Histone Lysine Methyltransferase 1 (EHMT1), Testic Expressed 41 (TEX41), etc. Patients diagnosed with ALL harboring ZNF384 rearrangements commonly had a good prognosis. The mechanisms, performance, and features of different ZNF384 rearrangements in acute lymphoblastic leukemia have been well evaluated.

Prevalence of preoperative deep vein thrombosis in long bone fractures of lower limbs: a systematic review and meta-analysis.

BACKGROUND: There is a paucity of data regarding the prevalence of preoperative deep vein thrombosis (DVT) in patients with long bone (including femur, tibia and fibula) fractures of the lower limbs. We performed a meta-analysis to address the issue. METHODS: Electronic databases, including PubMed, EMBASE, the Web of Science, the Cochrane Library, the VIP database, CNKI, and the Wanfang database, were systematic searched for original articles that reported the prevalence of preoperative DVT in long bone fractures of the lower limbs from January 2016 to September 2021. The prevalence of preoperative DVT was pooled using random-effects models, and subgroups were established according to study type, detection method, sample size and fracture site. RESULTS: Twenty-three articles reporting on 18,119 patients were eligible. The overall pooled preoperative DVT prevalence was 24.1% (95% CI 19.3-28.8%). In different subgroups, the preoperative DVT prevalences were 18.2-27.3%, 15.2-28.6%, 23.1-24.9%, 18.2-26.0% and 23.2-23.4% for different study designs, sample sizes, age groups, detection methods and fracture sites, respectively. CONCLUSIONS: Despite the heterogeneity among studies, this systematic review suggests that the prevalence of preoperative DVT, which may seriously affect the prognosis of patients, is high. Therefore, greater efforts should be devoted to the improvement of screening and prevention strategies for preoperative DVT in lower-extremity long bone fractures. LEVEL OF EVIDENCE: Level III. Trial Registration The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database with the registration number CRD42022324706.

Postoperative Complications Following Prepectoral Versus Partial Subpectoral Implant-Based Breast Reconstruction Using ADM: A Systematic Review and Meta-analysis.

BACKGROUND: There is a paucity of evidence comparing the safety of prepectoral and partial subpectoral implant-based breast reconstruction using acellular dermal matrices (ADM). We performed a meta-analysis to evaluate the postoperative complications of the two approaches. METHODS: PubMed, EMBASE, Web of Science and Cochrane Library were searched to retrieve relevant articles. The rates of the complications were, respectively, pooled, and relative risk (RR) was estimated with 95% confidence intervals (CIs) to compare the incidence between the two cohorts. RESULTS: Ten articles reporting on 2667 breast reconstructions were eligible. The hematoma rate was lower in the prepectoral group (RR = 0.590, 95% CI 0.351-0.992). No significant difference was observed in terms of seroma (RR = 1.079, 95% CI 0.489-2.381), skin flap necrosis (RR = 0.936, 95% CI 0.587-1.493), infection (RR = 0.985, 95% CI 0.706-1.375), tissue expander/implant explantation (RR = 0.741, 95% CI 0.506-1.085), wound dehiscence (RR = 1.272, 95% CI 0.605-2.673), capsular contracture (RR = 0.939, 95% CI 0.678-1.300) and rippling (RR = 2.485, 95% CI 0.986-6.261). The RR of animation deformity for the prepectoral group compared with the subpectoral group was 0.040 (95% CI, 0.002-0.853). CONCLUSIONS: This systematic review suggested that with appropriate patient selection, prepectoral breast reconstruction could avoid animation deformity without incurring higher risk of early wound complications, capsular contracture or rippling than partial subpectoral breast reconstruction. Plastic surgeons should complete a comprehensive assessment of the patients before choosing appropriate surgical approaches in clinical practice. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

RBBP4 regulates the expression of the Mre11-Rad50-NBS1 (MRN) complex and promotes DNA double-strand break repair to mediate glioblastoma chemoradiotherapy resistance.

For treatment of glioblastoma (GBM), temozolomide (TMZ) and radiotherapy (RT) exert antitumor effects by inducing DNA double-strand breaks (DSBs), mainly via futile DNA mismatch repair (MMR) and inducing apoptosis. Here, we provide evidence that RBBP4 modulates glioblastoma resistance to chemotherapy and radiotherapy by recruiting transcription factors and epigenetic regulators that bind to their promoters to regulate the expression of the Mre11-Rad50-NBS1(MRN) complex and the level of DNA-DSB repair, which are closely associated with recovery from TMZ- and radiotherapy-induced DNA damage in U87MG and LN229 glioblastoma cells, which have negative MGMT expression. Disruption of RBBP4 induced GBM cell DNA damage and apoptosis in response to TMZ and radiotherapy and enhanced radiotherapy and chemotherapy sensitivity by the independent pathway of MGMT. These results displayed a possible chemo-radioresistant mechanism in MGMT negative GBM. In addition, the RBBP4-MRN complex regulation axis may provide an interesting target for developing therapy-sensitizing strategies for GBM.

MYPT1SMKO Mice Function as a Novel Spontaneous Age- and Hypertension-Dependent Animal Model of CSVD.

Cerebral small vessel disease (CSVD) is the most common progressive vascular disease that causes vascular dementia. Aging and hypertension are major contributors to CSVD, but the pathophysiological mechanism remains unclear, mainly due to the lack of an ideal animal model. Our previous study revealed that vascular smooth muscle cell (VSMC)-specific myosin phosphatase target subunit 1 (MYPT1) knockout (MYPT1SMKO) leads to constant hypertension, prompting us to explore whether hypertensive MYPT1SMKO mice can be considered a novel CSVD animal model. Here, we found that MYPT1SMKO mice displayed age-dependent CSVD-like neurobehaviors, including decreased motion speed, anxiety, and cognitive decline. MYPT1SMKO mice exhibited remarkable white matter injury compared with control mice, as shown by the more prominent loss of myelin at 12 months of age. Additionally, MYPT1SMKO mice were found to exhibit CSVD-like small vessel impairment, including intravascular hyalinization, perivascular space enlargement, and microbleed and blood-brain barrier (BBB) disruption. Last, our results revealed that the brain of MYPT1SMKO mice was characterized by an exacerbated inflammatory microenvironment, which is similar to patients with CSVD. In light of the above structural and functional phenotypes that closely mimic the conditions of human CSVD, we suggest that MYPT1SMKO mice are a novel age- and hypertension-dependent animal model of CSVD.

Clinical manifestations of 17 Chinese children with hereditary spherocytosis caused by novel mutations of the ANK1 gene and phenotypic analysis.

Background: Hereditary spherocytosis (HS) is an autosomal dominant (AD) and autosomal recessive (AR) disorder that is mostly caused by mutations of the erythrocyte membrane-related gene ANK1. Methods: Clinical and genetic testing data of 17 HS children with ANK1 gene mutations were retrospectively collected. Clinical manifestations and phenotypic analysis of HS were summarized based on our experience and literature review. Results: A total of 17 mutations of the ANK1 gene were identified from 17 probands (12 sporadic cases and five familial cases), including 15 novel mutations and two previously reported ones. Among the 15 novel variants of ANK1, there were four non-sense mutations, four frameshift mutations, three splicing mutations, three missense mutations and one in-frame deletion of three amino acids. In the present study, HS patients with mutations in membrane binding domains had significantly lower hemoglobin (Hb) levels and higher total bilirubin (T-Bil) levels than those with mutations in regulatory domains. After reviewing and analyzing all available published reports of Chinese HS patients carrying ANK1 mutations in PubMed and Chinese journals, there were no significant differences in Hb, Ret and T-Bil between different mutation types or mutation regions. Conclusion: Mutations of the ANK1 can be inherited or de novo. Clinical manifestations of HS in children caused by ANK1 mutations are similar to those of other types of hemolytic anemia. Our report expands the mutation spectrum of HS, thus providing references for clinical management and genetic counseling of HS.

The positive feedback loop of MAD2L1/TYK2/STAT3 induces progression in B-cell acute lymphoblastic leukaemia.

PURPOSE: Mitotic arrest deficient 2 like 1 (MAD2L1) has been extensively studied in several malignancies; however, its role in B-cell acute lymphoblastic leukaemia (B-ALL) remains unclear. METHODS: The expression of MAD2L1 was evaluated by real-time quantitative polymerase chain reaction. The biological functions of MAD2L1 in B-ALL were explored through Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine assay (EDU), transwell assay, flow cytometry and xenograft models. The Western blotting and co-immunoprecipitation were utilized to evaluate the interplay between MAD2L1 and the TYK2/STAT3 pathway. The luciferase reporter and chromatin immunoprecipitation (ChIP) assay were employed to identify interactions between STAT3 and MAD2L1. RESULTS: We demonstrated that MAD2L1 was markedly upregulated in B-ALL, and its expression level not only correlated with the relapse and remission of the condition but also with a poor prognosis. MAD2L1 promoted the proliferation, migration and invasion of B-ALL cells in vitro and in vivo, whereas MAD2L1 knockdown had the opposite effects. Mechanistically, MAD2L1 induces the progression of B-ALL by activating the TYK2/STAT3 signaling pathway to phosphorylate. Interestingly, STAT3 induces the expression of MAD2L1 by binding directly to its promoter region, resulting in a positive-feedback loop of MAD2L1/TYK2/STAT3. CONCLUSION: This study uncovered a reciprocal loop of MAD2L1/TYK2/STAT3, which contributed to the development of B-ALL. Therefore, MAD2L1 can be considered a potential diagnostic biomarker as well as a novel therapeutic target for B-ALL.