blf and the drl cluster synergistically regulate cell fate commitment during zebrafish primitive hematopoiesis.

Hematopoiesis is a highly coordinated process that generates all the body's blood cells, and perturbations in embryonic hematopoiesis may result in illnesses ranging from fetal anemia to various leukemias. Correct establishment of hematopoietic progenitor cell fate is essential for the development of adequate blood cell subpopulations, although regulators of cell fate commitment have not been fully defined. Here, we show that primary erythropoiesis and myelopoiesis in zebrafish embryos are synergistically regulated by blf and the drl cluster, as simultaneous depletion led to severe erythrocyte aplasia and excessive macrophage formation at the expense of neutrophil development. Integrative analysis of transcriptome- and genome-wide binding data revealed that blf and drl cluster genes are responsible for constraining the expression of vasculogenesis-promoting genes in the intermediate cell mass and monocytopoiesis-promoting genes in the rostral blood island. This indicates that blf and drl cluster genes act as determinants of the fate commitment of erythroid and myeloid progenitor cells. Furthermore, a rescue screen demonstrated that Zfp932 is a potential mammalian functional equivalent to zebrafish blf and drl cluster genes. Our data provide insight into conserved cell fate commitment mechanisms of primitive hematopoiesis.

Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.

BACKGROUND: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown. METHODS: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. RESULTS: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis. CONCLUSIONS: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

[Research Progress on Influence of Centrifugal Blood Pump on Blood Injury].

Centrifugal blood pumps drive blood flow by regulating blood flow rate, and have been widely used in clinical applications, including extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass (CPB), and extracorporeal circulation carbon dioxide removal (ECCO2R). However, because different structures and different forms of centrifugal pumps have different requirements for blood extracorporeal circulation in clinical application scenarios, blood pumps face different application conditions in clinical use. In this study, the effects of different structures of centrifugal pumps and different working conditions on blood damage are summarized for reference by relevant institutions and R&D personnel.

Synthesis of C4-Aminated Carbazoles and Their Derivatives via Pd/NBE Chemistry.

Carbazole, as one of the most important organic frameworks, has been used in optoelectronic materials and biochemistry. However, the synthesis of C4-substituted carbazole has always been an unsolved problem. This report describes the one-step synthesis of C4-aminated carbazoles and their derivatives through the series reaction of C-H amination and arylation. The substrate scope is wide. C4-Amino carbazoles substituted by C2, C6, C7, and C8 methyl groups, especially carbazole derivatives of fused rings, pyridine, and dibenzofuran, can be synthesized.

Significance of levothyroxine treatment on serum lipid in pregnant women with subclinical hypothyroidism.

BACKGROUND: There is no consensus reference range for serum lipid levels during pregnancy. The benefit of levothyroxine (L-T4) on serum lipid levels are unclear among pregnant women with subclinical hypothyroidism (SCH). OBJECTIVE: To determine the recommended reference ranges for serum lipid concentrations during pregnancy and effects of L-T4 treatment on serum lipids in pregnant women with SCH. DESIGN: Cohort study. METHODS: A analysis of 20,365 women in the first trimester was conducted at Beijing Obstetrics and Gynecology Hospital, Capital Medical University during 2018-2020. After excluding women with adverse pregnancy outcomes, we determined the reference range of serum lipid in the first and third trimesters of pregnancy by using median and quartile to determine appropriate percentiles. Next, we divided into three groups as follows: SCH L-T4 treatment group (n = 319), SCH non-intervention group (n = 103) and the control group(n = 9598). RESULTS: The recommended reference range for serum lipids in the first trimester of pregnancy should be: TC < 5.33 mmol/L, TG < 1.73 mmol/L, LDL-C < 3.12 mmol/L and HDL-C > 1.1 mmol/L, and in third trimester of pregnancy should be: TC < 8.47 mmol/L, TG < 4.86 mmol/L, LDL-C < 5.3 mmol/L and HDL-C > 1.34 mmol/L. There are significant differences in TC and LDL-C levels between SCH treatment group and SCH non-intervention Group (P = 0.043, P = 0.046; respectively). CONCLUSIONS: We determine the recommended reference ranges for serum lipid concentrations during pregnancy. TC and LDL-C levels in pregnant women with SCH could improve after L-T4 treatment.

Dynamics of gut microbiota during pregnancy in women with TPOAb-positive subclinical hypothyroidism: a prospective cohort study.

BACKGROUND: Anti-thyroid peroxidase antibody (TPOAb) positivity can contribute to inhibit thyroxine synthesis. Gut microbiota can interact with metabolic or immune diseases. However, dynamics of gut microbiota from the second (T2) to the third trimester (T3) in women with TPOAb-positive/negative subclinical hypothyroidism (TPOAb+/TPOAb- SCH) have not been reported. Therefore, we aimed to evaluate whether gut microbiota can be potential therapeutic targets for managing TPOAb+ SCH. METHODS: In this single-center prospective cohort study, we observed gut microbiota dynamics by sequencing 16S rRNA from fecal samples collected in T2 (20-23+ 6 weeks) and T3 (28-33+ 6 weeks). TPOAb+/TPOAb- SCH were stratified depending on whether or not they used levothyroxine (LT4) during the pregnancy (LT4+/LT4-). Microbiome bioinformatics analyses were performed using QIIME2. The linear discriminant analysis effect size (LEfSe) was used for the quantitative analysis of biomarkers. Functional profiling was performed with PICRUSt2. RESULTS: Distinct gut microbiota dynamics from T2 to T3 were noted in the TPOAb- (n = 68) and TPOAb+ (n = 64) SCH groups. The TPOAb+ LT4- group was characterized by enriched bacterial amplicon sequence variants (ASVs) of Prevotella in T2 and Bacteria, Lachnospirales, Lachnospiraceae, Blautia, and Agathobacter in T3 and by depleted ASVs of Gammaproteobacteria, Enterobacterales, and Enterobacteriaceae in T2 and Actinobacteriota, Coriobacteriia, Actinobacteria, Coriobacteriales, Bifidobacteriales, Bifidobacteriaceae, Bifidobacterium, Dorea formicigenerans, and Bifidobacterium longum in T3. The TPOAb+ LT4+ group was characterized by enriched bacterial ASVs of Blautia, Streptococcus salivarius, and Bifidobacterium longum in T3 and by depleted ASVs of Bacteroidota, Bacteroidia, Bacteroidales, and Prevotella in T2 and Agathobacter in T3. Moreover, we identified 53 kinds of metabolic functions that were mainly involved in sugar, lipid, and amino acid metabolism. CONCLUSIONS: Our results indicated that low dynamics of gut microbiota composition and high dynamics of its metabolic function from T2 to T3 were associated with TPOAb+ SCH. We concluded that gut microbiota could be new targets for treatment of TPOAb+ SCH during pregnancy. TRIAL REGISTRATION: This study was retrospectively registered at the Chinese Clinical Trial Registry (registration number ChiCTR2100047175 ) on June 10, 2021.

Nickel-Catalyzed Cross-Redistribution between Hydrosilanes and Silacyclobutanes.

Silanes are important in chemistry and material science. The self-redistribution of HSiCl3 is an industrial process to prepare SiH4 , which is widely used in electronics and automobile industries. However, selective silane cross-redistribution to prepare advanced silanes is challenging. We now report an enthalpy-driven silane cross-redistribution to access bis-silanes that contain two different types of Si-H bonds in the same molecule. Compared with entropy-driven reactions, the enthalpy-driven reaction shows high regioselectivity, broad substrate scope (62 examples) and high atom economy. Our combined experimental and computational study indicates that the reaction proceeds through a Ni0 -NiII -NiIV catalytic cycle.

The DEAD-box RNA helicase Ddx39ab is essential for myocyte and lens development in zebrafish.

RNA helicases from the DEAD-box family are found in almost all organisms and have important roles in RNA metabolism, including RNA synthesis, processing and degradation. The function and mechanism of action of most of these helicases in animal development and human disease remain largely unexplored. In a zebrafish mutagenesis screen to identify genes essential for heart development we identified a mutant that disrupts the gene encoding the RNA helicase DEAD-box 39ab (ddx39ab). Homozygous ddx39ab mutant embryos exhibit profound cardiac and trunk muscle dystrophy, along with lens abnormalities, caused by abrupt terminal differentiation of cardiomyocyte, myoblast and lens fiber cells. Loss of ddx39ab hindered splicing of mRNAs encoding epigenetic regulatory factors, including members of the KMT2 gene family, leading to misregulation of structural gene expression in cardiomyocyte, myoblast and lens fiber cells. Taken together, these results show that Ddx39ab plays an essential role in establishment of the proper epigenetic status during differentiation of multiple cell lineages.

TIMELESS inhibits breast cancer cell invasion and metastasis by down-regulating the expression of MMP9.

Breast cancer is the first killer leading to female death, and tumor metastasis is one of the important factors leading to the death of patients, but the specific mechanism of breast cancer metastasis is not very clear at present. Our study showed that overexpression of TIMELESS could significantly inhibit the invasion and metastasis of breast cancer cells ZR-75-30 and the assembly of F-actin protein. On the contrary, knockdown of TIMELESS promoted the invasion and metastasis of breast cancer cells. Further study revealed that TIMELESS overexpression decreased the mRNA and protein levels of MMP9. Furthermore, TIMELESS could interact with p65, leading to repress the association of p65 and its acetyltransferase CBP and down-regulating the acetylation level of p65, which inhibited the activation of NF-κB signal pathway. In conclusion, our research showed that TIMELESS may repress the invasion and metastasis of breast cancer cells via inhibiting the acetylation of p65, inhibiting the activation of NF-κB, thus down-regulating the expression of MMP9, and then inhibiting the invasion and metastasis of breast cancer cells.

Adenosine-to-inosine RNA editing in neurological development and disease.

Adenosine-to-inosine (A-to-I) editing is one of the most prevalent post-transcriptional RNA modifications in metazoan. This reaction is catalysed by enzymes called adenosine deaminases acting on RNA (ADARs). RNA editing is involved in the regulation of protein function and gene expression. The numerous A-to-I editing sites have been identified in both coding and non-coding RNA transcripts. These editing sites are also found in various genes expressed in the central nervous system (CNS) and play an important role in neurological development and brain function. Aberrant regulation of RNA editing has been associated with the pathogenesis of neurological and psychiatric disorders, suggesting the physiological significance of RNA editing in the CNS. In this review, we discuss the current knowledge of editing on neurological disease and development.

[Research and Thinking of International Coordination Documents for Medical Device Labeling].

OBJECTIVE: To further improve the regulation of medical device Introduction for Use (IFU) and improve the quality of medical device Introduction for Use (IFU). METHODS: Summarize domestic regulatory experience and deficiencies through literature research, and introduce the international experience gathered from the IMDRF coordination document Principles of Labelling for Medical Devices and IVD Medical Devices. RESULTS: The IMDRF international coordination document categorizes ten chapters to define and summarize the basic principles that medical device instructions and labels should contain. CONCLUSIONS: According to the current status of medical device specification supervision and drawing on international supervision experience, improvement suggestions are proposed in terms of refining the IFU requires to improve the quality of the instructions, e.g. dynamic adjustment of IFU management requirements, strengthen the management of IFU for home used medical devices, and improving the standardization and rationality of medical device IFU content. We should continue to maintain effective management of medical device IFU.

The zinc finger protein Zfpm1 modulates ventricular trabeculation through Neuregulin-ErbB signalling.

Ventricular trabeculation is one essential step for generating a functionally competent ventricular wall, while how the early trabeculae carneae forms and subsequently develops into mature chambers is poorly understood. We found that in zebrafish zfpm1-/- juvenile, cardiac function is significantly compromised, with hearts exhibiting deformed trabecular meshwork. To elucidate the mechanisms of Zfpm1 function in cardiac trabeculation, we analyzed zfpm1 mutant hearts more closely and found that loss of Zfpm1 activity resulted in over-activation of Neuregulin-ErbB signalling and abnormally elevated cardiomyocyte proliferation during cardiac trabeculae growth and modeling stages. These results implicate Zfpm1 plays a pivotal role in coordinating trabeculae patterning and growth.

Circadian protein BMAL1 promotes breast cancer cell invasion and metastasis by up-regulating matrix metalloproteinase9 expression.

BACKGROUND: Metastasis is an important factor in the poor prognosis of breast cancer. As an important core clock protein, brain and muscle arnt-like 1 (BMAL1) is closely related to tumorigenesis. However, the molecular mechanisms that mediate the role of BMAL1 in invasion and metastasis remain largely unknown. In this study, we investigated the BMAL1 may take a crucial effect in the progression of breast cancer cells. METHODS: BMAL1 and MMP9 expression was measured in breast cell lines. Transwell and scratch wound-healing assays were used to detect the movement of cells and MTT assays and clonal formation assays were used to assess cells' proliferation. The effects of BMAL1 on the MMP9/NF-κB pathway were examined by western blotting, co-immunoprecipitation and mammalian two-hybrid. RESULTS: In our study, it showed that cell migration and invasion were significantly enhanced when overexpressed BMAL1. Functionally, overexpression BMAL1 significantly increased the mRNA and protein level of matrix metalloproteinase9 (MMP9) and improved the activity of MMP9. Moreover, BMAL1 activated the NF-κB signaling pathway by increasing the phosphorylation of IκB and promoted human MMP9 promoter activity by interacting with NF-kB p65, leading to increased expression of MMP9. When overexpressed BMAL1, CBP (CREB binding protein) was recruited to enhance the activity of p65 and further activate the NF-κB signaling pathway to regulate the expression of its downstream target genes, including MMP9, TNFα, uPA and IL8, and then promote the invasion and metastasis of breast cancer cells. CONCLUSIONS: This study confirmed a new mechanism by which BMAL1 up-regulated MMP9 expression to increase breast cancer metastasis, to provide research support for the prevention and treatment of breast cancer.

Dynamics of Zebrafish Heart Regeneration Using an HPLC-ESI-MS/MS Approach.

Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. To characterize protein dynamics during heart regeneration, we employed an HPLC-ESI-MS/MS (mass spectrometry) approach. Myocardium tissues were taken from sham-operated fish and ventricle-resected sample at three different time points (2, 7, and 14 days); dynamics of protein expression were analyzed by an ion-current-based quantitative platform. More than 2000 protein groups were quantified in all 16 experiments. Two hundred and nine heart-regeneration-related protein groups were quantified and clustered into six time-course patterns. Functional analysis indicated that multiple molecular function and metabolic pathways were involved in heart regeneration. Interestingly, Ingenuity Pathway Analysis revealed that P53 signaling was inhibited during the heart regeneration, which was further verified by real-time quantitative polymerase chain reaction (Q-PCR). In summary, we applied systematic proteomics analysis on regenerating zebrafish heart, uncovered the dynamics of regenerative genes expression and regulatory pathways, and provided invaluable insight into design regenerative-based strategies in human hearts.

The Sec domain protein Scfd1 facilitates trafficking of ECM components during chondrogenesis.

Chondrogenesis in the developing skeleton requires transformation of chondrocytes from a simple mesenchymal condensation to cells with a highly enriched extracellular matrix (ECM). This transition is in part accomplished by alterations in the chondrocyte protein transport machinery to cope with both the increased amount and large size of ECM components. In a zebrafish mutagenesis screen to identify genes essential for cartilage development, we uncovered a mutant that disrupts the gene encoding Sec1 family domain containing 1 (scfd1). Homozygous scfd1 mutant embryos exhibit a profound craniofacial abnormality caused by a failure of chondrogenesis. Loss of scfd1 was found to hinder ER to Golgi transport of ECM proteins and is accompanied with activation of the unfolded protein response in chondrocytes. We further demonstrate a conserved role for Scfd1 in differentiation of mammalian chondrocytes, in which loss of either SCFD1 or STX18, a SLY1 interacting t-SNARE, severely impair transport of type II collagen. These results show that the existence of a specific export pathway, mediated by a complex containing SCFD1 and STX18 that plays an essential role in secretion of large ECM proteins during chondrogenesis.

CircRNAs as biomarkers of cancer: a meta-analysis.

BACKGROUND: The expression of circular RNA (circRNA) may affect tumor progression. However, there have been no systemic meta-analysis for cancer diagnosis by using circRNAs in clinical till now. Herein, we aimed to collect and examined all the evidence on the potential role of circRNA as novel biomarker in human cancers. METHODS: A comprehensive search strategy was used to search relevant literatures in the databases of PubMed, Embase, and the Web of Science from 2015 to August 2017. The correlation between circRNA expression and the diagnostic accuracy of tumor markers was analyzed. The methodological quality of each study was assessed by quality assessment for the diagnostic accuracies of the eligible studies (QUADAS-2). Statistical analysis was performed by applying the STATA (version 12.0) software. RESULTS: The present meta-analysis included 1752 patients with circRNA expression data of tumor and paired adjacent non-tumorous tissues from 17 publications (19 studies). The pooled sensitivity, specificity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), and diagnostic OR (DOR) with their 95% confidential intervals (95%CIs), and AUC values were 0.72 (0.67-0.76), 0.74 (0.69-0.78), 2.80 (2.40-3.10), 0.38 (0.33-0.44), 7.00 (6.00-9.00), and 0.79, respectively. Subgroup analyses showed that the expression of circRNA in tissues of hepatocellular carcinoma (HCC) group was more prone to be detected than other tumor types, with a high values of the specificity, DOR, and AUC. CONCLUSIONS: circRNAs might be suitable as diagnostic biomarkers for tumors, especially in HCC diagnosis. Further prospective studies on the diagnostic value of circRNAs from the different tumors are needed in the future.

Preventive effect of human umbilical cord mesenchymal stem cells on skin aging in rats.

The irreversibility of aging makes anti-aging become an important research direction in the field of medical research. As the most direct manifestation of human aging, skin aging has been paid more and more attention. Stem cells have been used as a basis for anti-aging studies in skin, of which adipose-derived mesenchymal stem cells are more commonly used. In this study, human umbilical cord mesenchymal stem cells were used, and human umbilical cord mesenchymal stem cells were intervened while making a skin aging model, which was planned to reduce the process of preventing skin aging in the study method. At the end of the experiment, rat skin and serum were taken for relevant data detection. The results showed that the contents of EGF and VEGF in serum and skin tissue of rats increased and the content of MDA decreased after the application of human umbilical cord mesenchymal stem cells. At the same time, hUCMSC intervention increased skin thickness, increased dermal vessels, increased type I collagen type III collagen mRNA expression, and decreased MMP-1 content in rats. The results showed that hUCMSC could prevent skin aging in rats.

Casein-based hydrogels: Advances and prospects.

Casein-based hydrogels (Casein Gels) possess advantageous properties, including mechanical strength, stability, biocompatibility, and even adhesion, conductivity, sensing capabilities, as well as controlled-releasing behavior of drugs. These features are attributed to their gelation methods and functionalization with various polymers. Casein Gels is an important protein-based material in the food industry, in terms of dairy and functional foods, biological and medicine, in terms of carrier for bioactive and sensitive drugs, wound healing, and flexible sensors and wearable devices. Herein, this review aims to highlight the importance of the features mentioned above via a comprehensive investigation of Casein Gels through multiple directions and dimensional applications. Firstly, the composition, structure, and properties of casein, along with the gelation methods employed to create Casein Gels are elaborated, which serves as a foundation for further exploration. Then, the application progresses of Casein Gels in dairy products, functional foods, medicine, flexible sensors and wearable devices, are thoroughly discussed to provide insights into the diverse fields where Casein Gels have shown promise and utility. Lastly, the existing challenges and future research trends are highlighted from an interdisciplinary perspective. We present the latest research advances of Casein Gels and provide references for the development of multifunctional biomass-based hydrogels.

Notoginseng leaf triterpenes promotes angiogenesis by activating the Nrf2 pathway and AMPK/SIRT1-mediated PGC-1/ERα axis in ischemic stroke.

Notoginseng leaf triterpenes (PNGL), derived from the dried stems and leaves of P. notoginseng, is a phytoestrogen that exerts many neuroprotective effects in vivo and in vitro of ischemic stroke. However, its impact on neurological restoration specifically in relation to angiogenesis following ischemic stroke remains unexplored. The aim of this study was to assess the effects of PNGL on angiogenesis subsequent to ischemic stroke. Male Sprague-Dawley rats were utilized in this study and were subjected to middle cerebral artery occlusion/reperfusion (MCAO/R). Post-ischemia, PNGL were administered through intraperitoneal (i.p.) injection. The high-performance liquid chromatography (HPLC) fingerprinting, triphenyltetrazolium chloride (TTC) staining, immunofluorescent staining, network pharmacology and western blot analyses were assessed to determine the therapeutical effect and molecular mechanisms of PNGL on cerebral ischemia/reperfusion injury. Our findings demonstrate that PNGL effectively reduced infarct volume, enhanced cerebral blood flow, and induced angiogenesis in rats subjected to MCAO/R. Notably, PNGL also facilitated neuronal proliferation and migration in HUMECs in vitro. The proangiogenic effects of PNGL were found to be linked to the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the AMPK/SIRT1-mediated PGC-1/ERα axis, as well as the activation of neurological function. Our study provides evidence that PNGL hold promise as an active ingredient of inducing proangiogenic effects, potentially through the activation of the Nrf2 pathway and the AMPK/SIRT1-mediated PGC-1/ERα axis. These findings contribute to the understanding of novel mechanisms involved in the restoration of neurological function following PNGL treatment for ischemic stroke.