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N6-methyladenosine (m6A) modification plays a pivotal role in cell fate determination. Previous studies show that eliminating m6A using Mb1-Cre dramatically impairs B cell development. However, whether disturbing m6A modification at later stages affects B cell development and function remains elusive. Here, we deleted m6A methyltransferase Mettl3 from the pro-B stage on using Cd19-Cre (Mettl3 cKO) and found that the frequency of total B cells in peripheral blood, peritoneal cavity, and liver is comparable between Mettl3 cKO mice and wild-type (WT) littermates, while the percentage of whole splenic B cells slightly increases in Mettl3 cKO individuals. The proportion of pre-pro-B, pro-B, pre-B, immature, and mature B cells in the bone marrow were minimally affected. Loss of Mettl3 resulted in increased apoptosis but barely affected B cells’ proliferation and IgG production upon LPS, CD40L, anti-IgM, or TNF-α stimulation. Different stimuli had different effects on B cell activation. In addition, B cell-specific Mettl3 knockout had no influence on the pro-fibrogenic activity of B cells in liver fibrosis, evidenced by comparable fibrosis in carbon tetrachloride- (CCl4-) treated Mettl3 cKO mice and WT controls. In summary, our study demonstrated that deletion of Mettl3 from the pro-B stage on has minimal effects on B cell development and function, as well as profibrogenic activity of B cells in liver fibrosis, revealing a stage-specific dependence on Mettl3-mediated m6A of B cell development.

The MYB (v-MYB avian myeloblastosis viral oncogene homolog) transcription factor (TF) family has numerous members with complex and diverse functions, which play an indispensable role in regulating the response of plants to stress. In this study, a new 1R-MYB TF gene was obtained from Fragaria vesca (a diploid strawberry) by cloning technology and given a new name, FvMYB114. According to the subcellular localization results, FvMYB114 protein was a nuclear localization protein. Overexpression of FvMYB114 greatly enhanced the adaptability and tolerance of Arabidopsis thaliana to salt and low temperature. Under salt and cold stress, the transgenic plants had greater proline and chlorophyll contents and higher activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) than the wild-type (WT) and unloaded-line (UL) A. thaliana. However, malondialdehyde (MDA) was higher in the WT and UL lines. These results suggested that FvMYB114 may be involved in regulating the response of A. thaliana to salt stress and cold stress. FvMYB114 can also promote the expression of genes, such as the genes AtSOS1/3, AtNHX1 and AtLEA3 related to salt stress and the genes AtCCA1, AtCOR4 and AtCBF1/3 related to cold stress, further improving the tolerance of transgenic plants to salt and cold stress.

During underwater acoustic detection, the positioning accuracy of the bionic cilia MEMS vector hydrophone is affected by its own sensitivity. MEMS vector hydrophone operate in different temperature environments, so studies on the environmental temperature and the sensitivity of the MEMS vector hydrophone are of great significance. In this paper, based on the sensitivity of the MEMS vector hydrophone at room temperature (22°C), its sensitivity variation is studied within the temperature range of 0–40°C. The relationship between the temperature and the piezoresistor in the MEMS vector hydrophone is theoretically analyzed, and it is concluded that the sensitivity change is within ±0.6dB. The sensitivity change of MEMS vector hydrophone is proved to be within ±0.3 dB via COMSOL 5.4 simulation software, and the MEMS vector hydrophone is verified experimentally by the hydrophone temperature characteristic testing system. The results show that the variation of the sensitivity is within ±0.5 dB, which is basically consistent with the theoretical analysis results and simulation results. It can be said that under normal non-extreme ambient temperature, the operating temperature has little effect on the sensitivity of the MEMS vector hydrophone.

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CBF transcription factors (TFs) are key regulators of plant stress tolerance and play an integral role in plant tolerance to adverse growth environments. However, in the current research situation, there are few reports on the response of the CBF gene to Begonia stress. Therefore, this experiment investigated a novel CBF TF gene, named MbCBF2, which was isolated from M. baccata seedlings. According to the subcellular localization results, the MbCBF2 protein was located in the nucleus. In addition, the expression level of MbCBF2 was higher in new leaves and roots under low-temperature and high-salt induction. After the introduction of MbCBF2 into Arabidopsis thaliana, the adaptability of transgenic A. thaliana to cold and high-salt environments was significantly enhanced. In addition, the high expression of MbCBF2 can also change many physiological indicators in transgenic A. thaliana, such as increased chlorophyll and proline content, superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activity, and reduced malondialdehyde (MDA) content. Therefore, it can be seen from the above results that MbCBF2 can positively regulate the response of A. thaliana to low-temperature and osmotic stress. In addition, MbCBF2 can also regulate the expression of its downstream genes in transgenic lines. It can not only positively regulate the expression of the downstream key genes AtCOR15a, AtERD10, AtRD29a/b and AtCOR6.6/47, related to cold stress at low temperatures, but can also positively regulate the expression of the downstream key genes AtNCED3, AtCAT1, AtP5CS, AtPIF1/4 and AtSnRK2.4, related to salt stress. That is, the overexpression of the MbCBF2 gene further improved the adaptability and tolerance of transgenic plants to low-temperature and high-salt environments.

CBF transcription factors (TFs) are key regulators of plant stress tolerance and play an integral role in plant tolerance to adverse growth environments. However, in the current research situation, there are few reports on the response of the CBF gene to Begonia stress. Therefore, this experiment investigated a novel CBF TF gene, named

In the life cycle of apple, it will suffer a variety of abiotic stresses, such as iron stress and salt stress. bHLH transcription factors (TFs) play an indispensable role in the response of plants to stress. In this study, a new bHLH gene named MxbHLH18 was separated from Malus xiaojinensis. According to the results of subcellular localization, MxbHLH18 was localized in the nucleus. Salt stress and iron stress affected the expression of MxbHLH18 in Malus xiaojinensis seedlings to a large extent. Due to the introduction of MxbHLH18, the resistance of Arabidopsis thaliana to salt, high iron and low iron was significantly enhanced. Under the environmental conditions of high iron and low iron, the overexpression of MxbHLH18 increased many physiological indexes of transgenic Arabidopsis compared to wild type (WT), such as root length, fresh weight and iron content. The high level expression of MxbHLH18 in transformed Arabidopsis thaliana can not only increased the content of chlorophyll and proline, as well as increasing the activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT); it also reduced the content of malondialdehyde (MDA), which was more obvious under high salt conditions. In addition, the relative conductivity, H2O2 content and O2− content in transgenic Arabidopsis decreased under salt stress. Meanwhile, MxbHLH18 can also regulate the expression of downstream genes associated with salt stress (AtCBF1/2/3, AtKIN1 and AtCOR15a/b) and iron stress (AtIRT1, AtFRO2, AtNAS2, ATACT2, AtZIF1 and AtOPT3). Therefore, MxbHLH18 can actively promote the adaptability of plants to the growth environment of salt and low and/or iron.

In the life cycle of apple, it will suffer a variety of abiotic stresses, such as iron stress and salt stress. bHLH transcription factors (TFs) play an indispensable role in the response of plants to stress. In this study, a new

CBFs play a crucial role when plants are in adverse environmental conditions for growth. However, there are few reports on the role of CBF gene in stress responses of Malus plant. In this experiment, a new CBF TF was separated from M. baccata which was named MbCBF1. MbCBF1 protein was found to be localized in the nucleus after subcellular localization. Furthermore, the expression of MbCBF1 was highly accumulated in new leaves and roots due to the high influence of cold and high salt in M. baccata seedlings. After introducing MbCBF1 into A. thaliana, transgenic A. thaliana can better adapt to the living conditions of cold and high salt. The increased expression of MbCBF1 in A. thaliana also increased the contents of proline, remarkablely improved the activities of SOD, POD and CAT, but the content of MDA was decreased. Although the chlorophyll content also decreased, it decreased less in transgenic plants. In short, above date showed that MbCBF1 has a positive effect on improving A. thaliana cold and high salt tolerance. MbCBF1 can regulate the expression of its downstream gene in transgenic lines, up-regulate the expression of key genes COR15a, RD29a/bandCOR6.6/47 related to low temperature under cold conditions and NCED3, CAT1, P5CS1, RD22, DREB2A,PIF1/4, SOS1 and SnRK2.4 related to salt stress under high salt conditions, so as to further improve the adaptability and tolerance of the transgenic plants to low temperature and high salt environment.

The MYB transcription factor (TF) family is one of the largest transcription families in plants, which is widely involved in the responses of plants to biotic and abiotic stresses, as well as plant growth, development, and metabolic regulation. In the present study, a new MYB TF gene, MbMYB108, from Malus baccata (L.) Borkh, was identified and characterized. The open reading frame (ORF) of MbMYB108 was found to be 903 bp, encoding 300 amino acids. Sequence alignment results and predictions of the protein structure indicated that the MbMYB108 protein contained the conserved MYB domain. Subcellular localization showed that MbMYB108 was localized to the nucleus. The expression of MbMYB108 was enriched in young and mature leaves, and was highly affected by cold and drought treatments in M. baccata seedlings. When MbMYB108 was introduced into Arabidopsis thaliana, it greatly increased the cold and drought tolerances in the transgenic plant. Increased expression of MbMYB108 in transgenic A. thaliana also resulted in higher activities of peroxidase (POD) and catalase (CAT), higher contents of proline and chlorophyll, while malondialdehyde (MDA) content and relative conductivity were lower, especially in response to cold and drought stresses. Therefore, these results suggest that MbMYB108 probably plays an important role in the response to cold and drought stresses in A. thaliana by enhancing the scavenging capability for reactive oxygen species (ROS).

Undesirable drug-drug interactions (DDIs) may lead to serious adverse side effects when more than two drugs are administered to a patient simultaneously. One of the most common DDIs is caused by unexpected inhibition of a specific human cytochrome P450 (CYP450), which plays a dominant role in the metabolism of the co-administered drugs. Therefore, a unified and reliable method for predicting the potential inhibitors of CYP450 family is extremely important in drug development. In this work, graph convolutional neural network (GCN) with attention mechanism and 1-D convolutional neural network (CNN) were used to extract the features of CYP ligands and the binding sites of CYP450 respectively, which were then combined to establish a unified GCN-CNN (GCNN) model for predicting the inhibitors of 5 dominant CYP isoforms, i.e., 1A2, 2C9, 2C19, 2D6, and 3A4. Overall, the established GCNN model showed good performances on the test samples and achieved better performances than the recently proposed iCYP-MFE model by using the same datasets. Based on the heat-map analysis of the resulting molecular graphs, the key structural determinants of the CYP inhibitors were further explored.

The MYB transcription factor (TF) family is one of the largest transcription families in plants, which is widely involved in the responses of plants to biotic and abiotic stresses, as well as plant growth, development, and metabolic regulation. In the present study, a new MYB TF gene

Activation of hepatic stellate cells (HSCs) is a central driver of liver fibrosis. Previous investigations have identified various altered epigenetic landscapes during the cellular progression of HSC activation. N6-methyladenosine (m

The grape (Vitis vinifera L.) not only has a long history of cultivation, but also has rich nutritional value and high economic value. However, grapes often face many threats in the growth process. For example, low temperature and salt stress restrict the growth status, yield, and geographical distribution of grapes. WRKY, as one of the largest transcription factor (TF) families in plants, participates in the response of plants to stress. VvWRKY28, a new zinc finger type transcriptional regulator gene, was isolated from Beichun (V. vinifera × V.amurensis) in this study. From the subcellular localization results, it can be concluded that VvWRKY28 was localized in the nucleus. The expression of VvWRKY28 was enriched in leaves (young and mature leaves), and cold and high salt conditions can induce high expression of VvWRKY28. After being transferred into Arabidopsis, VvWRKY28 greatly improved the tolerance of Arabidopsis to low temperature and high salt and also changed many physiological and biochemical indicators of transgenic Arabidopsis to cope with cold and high salt stimulation. The content of malondialdehyde (MDA) was decreased, but for chlorophyll and proline, their content increased, and the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were improved. In addition, under cold stress, binding with cis-acting elements promotes the expression of downstream genes related to cold stress (RAB18, COR15A, ERD10, PIF4, COR47, and ICS1). Moreover, it also plays an active role in regulating the expression of genes related to salt stress (NCED3, SnRK2.4, CAT2, SOD1, SOS2, and P5CS1) under salt stress. Therefore, these results provide evidence that VvWRKY28 may play a role in the process of plant cold and salt stress tolerance.

Background Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. Methods In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis. Results We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. Conclusion In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.

Background: Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterised by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties, and transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. Methods: In the current study, a well-established Concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord MSC (hUC-MSC) on fulminant hepatitis.Results: We showed that hUC-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA-sequencing of liver tissues and human T cells co-cultured with hUC-MSCs showed that NF-κB signaling and glycolysis are two main pathways involved in mediating the protective role of hUC-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. Conclusion: In summary, our data confirmed the potent therapeutic role of MSCs-derived from human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of hUC-MSCs on T cell immunity.

Hepatic specification and functional maturation are tightly controlled throughout development. N6-methyladenosine (m

Graphical abstract, Caspase-6 participates in a series of neurodegenerative pathways, and has aroused widespread attentions as a promising molecular target for the treatment of neurodegeneration. Caspase-6 is a homodimer with 6 central-stranded β-sheets and 5 α-helices in each monomer. Previous crystallographic studies suggested that the 60′s, 90′s and 130′s helices of caspase-6 undergo a distinctive conformational transition upon substrate binding. Although the caspase-6 structures in apo and active states have been determined, the conformational transition process between the two states remains poorly understood. In this work, perturbation-response scanning (PRS) combined with targeted molecular dynamics (TMD) simulations was employed to unravel the atomistic mechanism of the dynamic conformational transitions underlying the substrate-induced activation process of caspase-6. The results showed that the conformational transition of caspase-6 from apo to active states is mainly characterized by structural rearrangements of the substrate-binding site as well as the conformational changes of 60′s and 130′s extended helices. The H-bond interactions between L1, 130′s helix and 90′s helix are proved to be key determinant factors for substrate-induced conformational transition. These findings provide valuable insights into the activation mechanism of caspase-6 as well as the molecular design of caspase-6 inhibitors.

The synthesis of Metal-organic Frameworks (MOFs) and their evaluation for various applications is one of the largest research areas within materials sciences and chemistry. Here, the use of MOFs in biomaterials and implants is summarized as narrative review addressing primarely the Tissue Engineering and Regenerative Medicine (TERM) community. Focus is given on MOFs as bioactive component to aid tissue engineering and to augment clinically established or future therapies in regenerative medicine. A summary of synthesis methods suitable for TERM laboratories and key properties of MOFs relevant to biomaterials is provided. The use of MOFs is categorized according to their targeted organ (bone, cardio-vascular, skin and nervous tissue) and whether the MOFs are used as intrinsically bioactive material or as drug delivery vehicle. Further distinction between in vitro and in vivo studies provides a clear assessment of literature on the current progress of MOF based biomaterials. Although the present review is narrative in nature, systematic literature analysis has been performed, allowing a concise overview of this emerging research direction till the point of writing. While a number of excellent studies have been published, future studies will need to clearly highlight the safety and added value of MOFs compared to established materials for clinical TERM applications. The scope of the present review is clearly delimited from the general ‘biomedical application’ of MOFs that focuses mainly on drug delivery or diagnostic applications not involving aspects of tissue healing or better implant integration.

A self-contained MEMS vector hydrophone with a scalar–vector integrated design is proposed in this paper. Compared with traditional MEMS vector hydrophones, this design solves the problem of ambiguity in the port and starboard during orientation, and also realizes the self-contained storage of acoustic signals. First, the sensor principle and structural design of the self-contained MEMS hydrophone are introduced, and then the principle of the combined beamforming algorithm is given. In addition to this, the amplitude and phase calibration method based on the self-contained MEMS vector hydrophone is proposed. Then, the sensitivity and phase calibrations of the sensor are carried out in the standing wave tube. The sensitivity of the vector channel is −182.7 dB (0 dB@1 V/μPa) and the sensitivity of the scalar channel is −181.8 dB (0 dB@1 V/μPa). Finally, an outdoor water experiment was carried out. The experimental results show that the self-contained MEMS vector hydrophone can accurately pick up and record underwater acoustics information. It realizes the precise orientation of the target by combining beamforming algorithms. The direction of arrival (DOA) error is within 5° under the outdoor experimental conditions with an SNR of 13.67 dB.

The polyurethane-encapsulated lateral line-inspired MEMS vector hydrophone has problems such as low-frequency sensitivity (10–80 Hz) loss and narrow working bandwidth. In order to eliminate these two problems, a new encapsulation with a stainless steel mesh cap structure was proposed. This paper first verified the sensitivity loss and narrow working bandwidth of the polyurethane encapsulation through experiments and simulations, analyzed the impact of the perforation rate, thickness, and aperture of the stainless steel mesh cap structure on the vector hydrophone through simulation, and finally made 8 types of stainless steel mesh cap with different apertures was tested experimentally. Finally, the experimental results show that the sensitivity of the stainless steel mesh encapsulation in the low frequency range (10–80 Hz) is improved by an average of 12 dB than that of the polyurethane encapsulation, and the working bandwidth has been increased from 10–210 Hz to 10–667 Hz.

The traditional design of cilium MEMS vector hydrophone (CVH) usually adds attachment to the cilium to increase the force-bearing area of the cilium, which improves the sensitivity of CVH but also greatly reduces the inherent frequency of hydrophone, and brings heavier burden to the cross-beam. Based on the radiation noise of ships that is generally below 1 kHz, this article designs a sculpture-shape cilium MEMS vector hydrophone (SCVH). Compared to traditional CVH, it enhances the sensitivity of hydrophone, increases the resolution of weak signal, and reaches the working frequency band of 1 kHz. In this paper, the stress analysis of cantilever beam is carried out, and then the appropriate size of SCVH is determined by simulation analysis. Finally, the sensitivity and directivity experiments in standing wave tube are carried out. The experimental results show that the sensitivity of SCVH at 1 kHz reaches -184.2 dB (0 dB = 1 V/μPa), 13.1 dB higher than traditional CVH. The working frequency band of SCVH is 20 Hz-1kHZ, and the depth of “8”-shaped directivity concave point is larger than 30 dB.

Ciliary MEMS vector hydrophone (CVH) has excellent performance in low-frequency detection, however, there is still the problem of poor sensitivity in some applications. A cap-shaped ciliary vector hydrophone (CCVH) is proposed in this paper. The microstructure not only ensures the working bandwidth of the hydrophone, but also increases the sensitivity. A single integration process is adopted to complete the pasting of the cap-shaped cilia and the cantilever beam, requiring no complicated secondary cilia integration process. Firstly, a mathematical model is established for theoretical derivation, and then the principle is verified via COMSOL simulation. Finally, test results show that the sensitivity of CCVH can reach −182.7 dB at 1 kHz (1 kHz, 0 dB@1 V/µPa). Compared with the CVH, the sensitivity has increased by 14.4 dB. Concave point depth of 8-shaped directivity is beyond 30 dB, which indicates that CCVH has an excellent ability to detect underwater ship noise.

In view of the problem that the increased difficulty of underwater moving targets detection caused by the development of acoustic stealth technology, a beaded cilia MEMS vector hydrophone (BCVH) is proposed in this paper. Compared with previous cilia structures, it can enlarge the receiving area of acoustic wave to improve sensitivity without the introduction of additional structures. Meanwhile, the introduction of additional mass and the loss of working frequency band are reduced, and the structure is manufactured at one time. In this paper, the design scheme and optimal size of BCVH are determined via theoretical analysis and simulation, then vector hydrophone calibration system is used to verify it. The experimental results show that the sensitivity of BCVH reaches −183.3 dB (@1kHz, 0 d B = 1 V / μ P a ), 13.7 dB higher than bionic cilia MEMS vector hydrophone (CVH). Moreover, the depth of concave point of BCVH is more than 30 dB, which has a good directivity.

With the acceleration of global aging, the service of the aged has been widely concerned by the whole society. The traditional service mode has been challenged, and it is difficult to meet the needs of the aged. In order to provide better services for the aged, the construction of emotional intelligent service based on Internet of things is proposed in this article. First, the framework is introduced, and the architecture of the whole system is given. Second, the key technologies of emotional intelligence and Internet of things are described, which mainly include affective computing and data collection of Internet of things. Third, the implementation of the software and hardware is given, and the core functional modules are analyzed. As a whole, there are two main contributions of this article. One is to give the framework of emotional intelligence service system for the aged based on Internet of things, and the other is to analyze the emotional state and the physical data of the aged so that the early-warning and intelligent services can be provided for them.