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Abstract This study reports on the immunogenicity and biodistribution of H5 hemagglutinin (HA)-based self-amplifying (sa) mRNA vaccines in mice. Four sa-mRNA vaccines encoding either a secreted full-length HA, a secreted HA head domain, a secreted HA stalk domain, or a full-length membrane-anchored HA were investigated. All vaccines elicited an adaptive immune response. However, the full-length HA sa-RNA vaccines demonstrated superior performance compared to head and stalk domain vaccines. The antibody titers positively correlated with the vaccine dose. Cellular immune responses and antigen-specific IgA antibodies in the lungs were also observed. The comparison of the sa-mRNA vaccines encoding the secreted and membrane-anchored full-length HA revealed that anchoring of the HA to the membrane significantly enhanced the antibody and cellular responses. In addition to the injection site, the intramuscularly injected sa-mRNA-LNPs were also detected in the draining lymph nodes, spleen, and to a lesser extent, in the lung, kidney, liver, and heart.

Extracellular vesicles (EVs) contain microRNAs (miRNAs), which are important regulators of embryonic development. Nevertheless, little is known about the precise molecular processes controlling blastocyst development and quality. In a previous study, we identified bta-miR-665 as one of the miRNAs more abundantly present in extracellular vesicles of embryo-conditioned culture media of blastocysts compared to degenerate ones. Here, we investigated the effect and regulatory roles of bta-miR-665 in blastocyst development by supplementation of bta-miR-665 mimics or inhibitors to the culture media. Supplementation of bta-miR-665 mimics improved cleavage and blastocyst rate (P < 0.01), and blastocyst quality as indicated by increased inner cell mass rates and reduced apoptotic cell ratios (P < 0.01). Furthermore, supplementation of bta-miR-665 inhibitors had the opposite effect on these phenotypes. Low input transcriptome analysis and RT-qPCR revealed that bta-miR-665 acts on genes linked to microtubule formation and apoptosis/cell proliferation. These insights not only elucidate the important role of bta-miR-665 in embryo development, but also underscore its potential in improving reproductive efficiency in bovine embryo culture.

Abstract Osteoporosis is characterized by decreased bone mass, microarchitectural deterioration, and increased bone fragility. High-fat diet (HFD)-induced obesity also results in bone loss, which is associated with an imbalanced gut microbiome. However, whether HFD-induced obesity or HFD itself promotes osteoclastogenesis and consequent bone loss remains unclear. In this study, we developed HFD-induced obesity (HIO) and non-obesity (NO) mouse models to evaluate the effect of HFD on bone loss. NO mice were defined as body weight within 5% of higher or lower than that of chow diet fed mice after 10 weeks HFD feeding. NO was protected from HIO-induced bone loss by the RANKL /OPG system, with associated increases in the tibia tenacity, cortical bone mean density, bone volume of cancellous bone, and trabecular number. This led to increased bone strength and improved bone microstructure via the microbiome-short-chain fatty acids (SCFAs) regulation. Additionally, endogenous gut-SCFAs produced by the NO mice activated free fatty acid receptor 2 and inhibited histone deacetylases, resulting in the promotion of Treg cell proliferation in the HFD-fed NO mice; thereby, inhibiting osteoclastogenesis, which can be transplanted by fecal microbiome. Furthermore, T cells from NO mice retain differentiation of osteoclast precursors of RAW 264.7 macrophages ex vivo. Our data reveal that HFD is not a deleterious diet; however, the induction of obesity serves as a key trigger of bone loss that can be blocked by a NO mouse-specific gut microbiome.

The synthesis method of logic circuits based on the RRAM (Resistive Random Access Memory) devices is of great concern in recent years. Inspired by the CMOS-like RRAM based logic gates, this work proposes a NMOS-like RRAM gate family. The advantages of the proposed NMOS-like RRAM gates include: (1) all the gate circuits are array-implementable; (2) the gate family is logic complete; (3) the NOR, AND and NOT gates only consume single cycle respectively in the computation phase; (4) the gate circuits save half number of RRAM devices compared with the CMOS-like RRAM based counterparts. Furthermore, the synthesis method of logic circuits based on the NMOS-like RRAM gates is proposed and discussed. The single-cycle NMOS-like RRAM gates are utilized in priority under the constraints of the logic block. The features of the proposed synthesis method are: (1) it generates the high-performance logic circuits because the NMOS-like RRAM based gates work in parallel; (2) the logic block based on the proposed NMOS-like gates can be realized in the RRAM array; (3) the large-scale logic functions can be implemented by cascading the logic blocks. The in-array full-adder circuit generated by the proposed synthesis method only consumes three cycles in minimum, which outperforms the previous RRAM based counterpart. The synthesis results on the benchmark circuits show that the proposed synthesis method is able to generate the high-performance circuit in RRAM arrays for arbitrary logic functions.

The iMemComp (Intelligent memristive computing) gates are a family of logic gates based on the RRAM (Resistive Random Access Memory) devices. It has potential advantage for the design of high-performance logic circuits, because the iMemComp NAND, AND, NOT, and transmission gates only consume single cycle, respectively. However, the original two-input iMemComp OR gate, which requires three cycles, is a relatively slow gate. It decreases the performance of some logic circuits. This work proposes an improved iMemComp OR gate with only one cycle and three RRAM cells. Both the circuit performance and area consumption of the full-adder and LFSR circuits are improved by the application of the proposed OR gate. Furthermore, we propose a general synthesis method of logic circuits based on the improved logic gate. The synthesis results show that the circuits generated from the proposed synthesis method outperform the previous RRAM based counterparts for most cases of the MCNC benchmark circuits.

The polymorphic gates are the circuit cells that deliver different functions with the different external input, supply voltage or temperature. It is an effective method to resist the reverse engineering attacks, for the attackers cannot distinguish the correct function based on the netlist of the circuit. The researchers have found out that the RRAM based Look-Up Table (LUT) has higher performance and less area, comparing with the CMOS based counterparts. However, the attackers can tell the functions of the previous proposed RRAM based LUTs by measuring the resistance states of the RRAM cells. This work proposes an RRAM based polymorphic gate, which implements 16 basic logic functions with 8 RRAM cells in 4 working cycles. Furthermore, the multi-input LUT scheme is proposed based on the polymorphic gate. It is difficult for the attackers to distinguish the circuit function, because the function of the LUT is determined by the applied voltages and the resistance states of the RRAM devices, and the n-input LUT circuit is implemented with the constant area regardless of the number of inputs.

An in-array build-in self-test (BIST) scheme is proposed for the embedded resistive random access memory (RRAM) array. The BIST circuit consists of the linear-feedback-shift-register (LFSR)- based pattern generator and the multi-input signature register (MISR)-based response compactor, and both the n-stage LFSR and MISR are implemented by n + 2 in-array RRAM cells. The proposed LFSR/MISR circuit has better performance than the IMPLY-based counterpart, due to the application of the proposed three-cycle XOR gate and two-cycle shift gate with the in-array RRAM cells. And it is more area efficient comparing with the memristor ratioed logic (MRL)-based counterpart. The proposed n-stage LFSR/MISR circuit is tested by the scan chain method. The test method only has the linear time complexity. For the best of our knowledge, it is the first attempt to design the in-array BIST circuit for the RRAM array.

In conventional HfO2-based resistive random access memory (RRAM), SiO2 is usually adopted as side wall spacer (low-k spacer) to define the device feature size. It is found that the forming voltage of the conventional HfO2 RRAM with SiO2 spacer rises when the device size is scaling down from 16.0 μm2 to 0.16 μm2, which is detrimental for application of high density HfO2-based RRAM. In this study, a high permittivity side wall spacer (high-k spacer) Ta2O5 is introduced to replace SiO2 spacer. The Ta2O5 side wall effectively suppress the forming voltage rising issues during RRAM device scaling without introducing costly processing steps. Moreover, compared to the conventional HfO2-based RRAM, the side wall enhanced device exhibits faster switching speed, smaller operation voltage, and higher reliabilities, including endurance and retention. As a result, the use of Ta2O5 side wall significantly enhances the overall switching characteristics of the HfO2-based RRAM device.