Search

The fibrocartilage presented on the joint surface was caused by cartilage injury or degeneration. There is still a lack of effective strategies for fibrocartilage. Here, we hypothesized that the fibrocartilage could be viewed as a raw material for the renewal of hyaline cartilage and proposed a previously unidentified strategy of cartilage regeneration, namely, “fibrocartilage hyalinization.” Cytoskeleton remodeling plays a vital role in modifying the cellular phenotype. We identified that microtubule stabilization by docetaxel repressed cartilage fibrosis and increased the hyaline cartilage extracellular matrix. We further designed a fibrocartilage-targeted negatively charged thermosensitive hydrogel for the sustained delivery of docetaxel, which promoted fibrocartilage hyalinization in the cartilage defect model. Moreover, the mechanism of fibrocartilage hyalinization by microtubule stabilization was verified as the inhibition of Sparc (secreted protein acidic and rich in cysteine). Together, our study suggested that articular fibrocartilage-targeted therapy in situ was a promising strategy for hyaline cartilage repair.

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional

The microneedle (MN) provides a promising strategy for transdermal delivery of exosomes (EXO), in which the therapeutic effects and clinical applications are greatly reduced by the fact that EXO can only partially reach the injury site by passive diffusion. Here, we designed a detachable MN array to deliver EXO modified by a nitric oxide nanomotor (EXO/MBA) for Achilles tendinopathy (AT) healing. With the releasing of EXO/MBA, l-arginine was converted to nitric oxide by NOS or ROS as the driving force. Benefiting from the motion ability and the property of MPC tending to lower pH, EXO could accumulate at the injury site more efficiently. This work demonstrated that EXO/MBA-loaded MN notably suppressed the inflammation of AT, facilitated the proliferation of tendon cells, increased the expression of Col1a, and prevented extracellular matrix degradation, indicating its potential value in enthesiopathy healing and other related biomedical fields.

Stochastic characteristics of wind and photovoltaic (PV) power causes great challenge for power system operations. Distributed energy storage system (DESS) can mediate the intermittent renewable energy. This paper proposes a two-level optimization method for DESS scheduling. Firstly, DESSs are aggregated in a virtual power plan (VPP) and participates the power scheduling as a whole, the power schedules of DESSs are obtained with the proposed two-level optimization method. Secondly, in the upper-level optimization model, a two-stage stochastic unit commitment model is established with considering power uncertainties, and thermal units as well as VPP of DESS are optimized to maximize the power generation of renewable energy. And then, in the lower-level optimization model, an optimization model is proposed to schedule each DESS in order to minimize the total life loss cost of DESSs. Case studies are inducted based on actual data of a provincial power grid. The effectiveness and practicability of the proposed method is verified by the testing results.

In this paper, we investigate covert communications in uplink nonorthogonal multiple access (NOMA) systems, where a private user tries to transmit information covertly with the shield of a public communication link and a warden tries to detect this transmission. In order to confuse the detection of the warden, we adopt channel inversion power control (CIPC) in the public communication link to fully utilize the channel uncertainty. Specifically, we derive the closed-form expressions of the transmission outage probability and the expected detection error probability from the conservative perspective of the private user. Our analysis shows that the expected detection error probability could be enhanced with the increase of the threshold parameter of CIPC. Furthermore, there is a trade-off between the interference introduction and the channel improvement caused by the threshold parameter of CIPC. Therefore, we optimize this parameter to achieve the maximum covert rate, and we find that the maximum covert rate approximates to a constant when the transmit power of public user is large enough.

Single nucleotide polymorphisms (SNPs) are one of the most common markers in mammals. Rapid, accurate, and multiplex typing of SNPs is critical for subsequent biological and genetic research. In this study, we have developed a novel method for multiplex genotyping SNPs in mice. The method involves allele-specific PCR amplification of genomic DNA with two stem-loop primers accompanied by two different universal fluorescent primers. Blue and green fluorescent signals were conveniently detected on a DNA sequencer. We verified four SNPs of 65 mice based on the novel method, and it is well suited for multiplex genotyping as it requires only one reaction per sample in a single tube with multiplex PCR. The use of universal fluorescent primers greatly reduces the cost of designing different fluorescent probes for each SNP. Therefore, this method can be applied to many biological and genetic studies, such as multiple candidate gene testing, genome-wide association study, pharmacogenetics, and medical diagnostics.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder of the myocardium, and pathogenic mutations in the sarcomere genes myosin heavy chain 7 (MYH7) and myosin-binding protein C (MYBPC3) explain 60%&ndash, 70% of observed clinical cases. The heterogeneity of phenotypes observed in HCM patients, however, suggests that novel causative genes or genetic modifiers likely exist. Here, we systemically evaluated RNA-seq data from 28 HCM patients and nine healthy controls with pathogenic variant identification, differential expression analysis, and gene co-expression and protein&ndash, protein interaction network analyses. We identified 43 potential pathogenic variants in 19 genes in 24 HCM patients. Genes with more than one variant included the following: MYBPC3, TTN, MYH7, PSEN2, and LDB3. A total of 2538 protein-coding genes, six microRNAs (miRNAs), and 1617 long noncoding RNAs (lncRNAs) were identified differentially expressed between the groups, including several well-characterized cardiomyopathy-related genes (ANKRD1, FHL2, TGFB3, miR-30d, and miR-154). Gene enrichment analysis revealed that those genes are significantly involved in heart development and physiology. Furthermore, we highlighted four subnetworks: mtDNA-subnetwork, DSP-subnetwork, MYH7-subnetwork, and MYBPC3-subnetwork, which could play significant roles in the progression of HCM. Our findings further illustrate that HCM is a complex disease, which results from mutations in multiple protein-coding genes, modulation by non-coding RNAs and perturbations in gene networks.

MicroRNAs are widely referred to as gene expression regulators for different diseases. The integration between single nucleotide polymorphisms (SNPs) and miRNAs has been associated with both human and animal diseases. In order to gain new insights on the effects of SNPs on miRNA and their related sequences, we steadily characterized a whole mouse genome miRNA related SNPs, analyzed their effects on the miRNA structural stability and target alteration. In this study, we collected 73643859 SNPs across the mouse genome, analyzed 1187 pre-miRNAs and 2027 mature miRNAs. Upon mapping the SNPs, 1700 of them were identified in 702 pre-miRNAs and 609 SNPs in mature miRNAs. We also discovered that SNP densities of the pre-miRNA and mature miRNAs are lower than the adjacent flanking regions. Also the flanking regions far away from miRNAs appeared to have higher SNP density. In addition, we also found that transitions were more frequent than transversions in miRNAs. Notably, 841 SNPs could change their corresponding miRNA’s secondary structure from stable to unstable. We also performed target gain and loss analysis of 163 miRNAs and our results showed that few miRNAs remained unchanged and many miRNAs from wild mice gained target site. These results outline the first case of SNP variations in the mouse whole genome scale. Those miRNAs with changes in structure or target could be of interest for further studies.

Puberty onset is a milestone in sexual development. A tumor suppress gene (TSG) network had been reported to be involved in the regulation of female puberty onset. The observations in rodents and primates showed a potential link between microRNAs and puberty onset. To figure out what miRNAs play roles in this important biological process, profilings of microRNAs in the hypothalamus of female mice from three different pubertal stages, juvenile [postnatal day (P10)], early pubertal (P25) and pubertal (P30) were performed on the Affymetrix GeneChip miRNA 3.0 Arrays, the cerebral cortex (CTX) was used as a control tissue. 20 miRNAs were shown to be differentially expressed in hypothalamus (fold change > 1.5, P < 0.05), but not in CTX during the transition from juvenile to pubertal. Four of them were validated by real-time quantitative RT-PCR (qRT-PCR) method. 1018 genes were predicted as the targets of these miRNAs. Further bioinformatics analysis suggested that these target genes were involved in many important signaling pathways, especially in the cancer related pathways. We also found that about 90% of these target genes were expressed in the hypothalamus, as well as in the immortalized GnRH-producing GT1-7 cells, which provided additional evidence that these miRNAs could be female puberty onset related. Here we present a novel comprehensive data set of miRNA gene expression during the puberty onset; and it provides an important recourse for the future functional characterization of individual miRNAs and their targets in mouse hypothalamus and in GT1-7 cells.

The grid connection of high proportion of renewable energy generation increases the uncertainty of power system. Therefor the flexibility margin of different energy sources needs to be quantified to cope with the uncertainty change and maintain the dynamic balance of power system flexibility. In this paper, firstly, the flexibility characteristics of source, net, load and power and load community (PLC) are analyzed. The dynamic equilibrium relationship among them is briefly introduced. Secondly, taking into full consideration the complex output characteristics of different energy sources and combining their respective flexibility characteristics, a quantitative model of the power source flexibility margin for thermal power, hydro-power, gas power and concentrating solar power was established. A quantitative model of the power source flexibility margin of PV and wind power based on blind number theory was established. Furthermore, the calculation method of theoretical power generation capacity which can reflect different characteristics of output power of various energy sources is presented. The actual output power of each power source in each period is predicted. Finally, a case study shows that the model and method can consider the operating characteristics of different types of power sources, and quickly and accurately quantify the adjustable range of flexibility margins of each power source at different periods of time, which can provide an important basis for evaluating the capacity of renewable energy consumption and the optimal operation of multi-energy power system (MEPS).

Background Dyslipidemia is the major risk factor of cardiovascular disease. Although many genetic factors have been unveiled, large fraction of the phenotypic variance still needs further investigation. Chromosome 1 (Chr 1) harbors multiple gene loci related to blood lipid regulation, nevertheless, it’s challenging to identify the functional genes. Results We constructed a mouse population, chromosome 1 substitution lines (C1SLs), of which Chr 1 differ from recipient C57BL/6J (B6) mouse while others remain the same. Therefore, any phenotype variance between C1SLs and B6 can be easily inferred to Chr 1. In the current study, we assayed plasma lipids and glucose in 13 C1SLs and their recipient strain B6. Through weighted gene co-expression network analysis of the liver transcriptome and “guilty-by-association” study, eight associated modules of plasma lipids and glucose were identified. Further joint analysis of human genome wide association studies revealed 48 candidate blood lipids or glucose regulating genes. In addition, 38 genes on Chr 1 were also uncovered, in which 13 have been functional validated in mouse models. Conclusions These results suggest that C1SLs are ideal mouse models to study the complex traits and identify the candidate genes on Chr 1 with gene co-expression network analysis.

Aiming at the problem that uncertain power sources bring fluctuation to power system and cause lots of wind and photovoltaic curtailment, a short-term optimized operation method of multi-energy power system based on complementary characteristics of power sources is presented. The complementary mechanism of multi-energy power system is established. Based on the complementary mechanism, mathematical models of complementary objectives and complementary demands are established. Define renewable energy complementary power source. To minimize complementary demands, the capacity matching ratio of hydropower in renewable energy complementary power source is determined. According to the complementary objectives, a hierarchical optimal operation strategy for multi-energy power system is proposed. Particle swarm optimization is used to solve the optimization objective function. Taking a provincial power grid in northwest China as an example, the results show that the strategy makes full use of the complementarity of power sources and has the benefit of energy saving.

In the light of wind and photovoltaic curtailment caused by the lack of flexibility in multi-energy power systems, a method for measuring the flexibility margin of power source is proposed. Aiming at the lowest cost of fuel and atmospheric emission control, a coordinated optimal dispatching model of wind, photovoltaic, hydropower and thermal was constructed. Flexibility balance constraints are introduced into the model, and the model is divided into three dispatching layers: non- water renewable energy, hydropower and thermal power. The net load is updated step by step. Heuristic algorithm is used to determine the thermal power unit combination and particle swarm optimization algorithm is improved to optimize the unit output. Taking a provincial power grid in China as an example, the calculation results show that the model and method can not only as far as possible utilize renewable energy, but also reduce system redundancy and environmental pollution.

8-OAM modes each carrying 10 wavelengths with 2.56-Tbit/s aggregated capacity and 10.24-bit/s/Hz spectral efficiency have been transmitted over 50-km specially designed ring-core fiber, using a compact OAM mode sorter and only modular 4×4 MIMO equalization.

MicroRNAs (miRNAs) are endogenous ~22 nt RNAs that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or gene silencing. Although quantitative real-time PCR (qRT-PCR) had been widely used for miRNAs quantification, a multiplex quantification method is demanding. In this study, we successfully detected 2 miRNAs (miR-505-3p and miR-21a-5p) and an internal control (miR-16-5p) with only one reaction based on competitive PCR (cPCR) with high sensitivity. For each miRNA, two stem-loop reverse transcription (RT) primers were designed to produce two different templates: the competitor cDNA and the target cDNA, which had similar sequences except for 3 nucleotides different in length. RNA from a control sample was reverse transcribed with the competitive RT primers of multiple genes. Samples for test were reverse transcribed with target RT primers to obtain target cDNAs. Target cDNA was mixed with competitor cDNA to be used as the template for a multiplex fluorescent cPCR reaction. The cPCR products were separated on polyacrylamide gel electrophoresis with ABI 377 DNA sequencer and each fluorescent peak was quantified by its intensity. In this method, we compared the expression level of miR-505-3p in two tissues (thalamus and tail) between C57BL/6J and C3H/HeJ mice. The results showed that in the thalamus, which had high abundance of miR-505-3p, both cPCR and SYBR Green based qRT-PCR provided a sensitive quantification outcome. However, in the tail, which had extremely low level of miR-505-3p, it could be steadily detected by cPCR even after 8 times dilution with a relatively high sensitivity, while qRT-PCR can’t detect any product only after 2 times dilution. The variation as low as 12.2% between samples could be clarified by cPCR, which could not be accomplished by qRT-PCR. This method enables multiplex, accurate and sensitive quantification of miRNAs with fewer precious RNA samples than qRT-PCR.

Owing to the high throughput and low cost, next generation sequencing has attracted much attention for SNP genotyping application for researchers. Here, we introduce a new method based on three-round multiplex PCR to precisely genotype SNPs with next generation sequencing. This method can as much as possible consume the equivalent amount of each pair of specific primers to largely eliminate the amplification discrepancy between different loci. After the PCR amplification, the products can be directly subjected to next generation sequencing platform. We simultaneously amplified 37 SNP loci of 757 samples and sequenced all amplicons on ion torrent PGM platform; 90.5 % of the target SNP loci were accurately genotyped (at least 15×) and 90.4 % amplicons had uniform coverage with a variation less than 50-fold. Ligase detection reaction (LDR) was performed to genotype the 19 SNP loci (as part of the 37 SNP loci) with 91 samples randomly selected from the 757 samples, and 99.5 % genotyping data were consistent with the next generation sequencing results. Our results demonstrate that three-round PCR coupled with next generation sequencing is an efficient and economical genotyping approach. Graphical Abstract The schematic diagram of three-round PCR.

In this work, a high-performance, low-complexity modulation format identification (MFI) technique is proposed and experimentally demonstrated for coherent optical receivers using features extracted from phase statistics in Stokes space. Numerical simulations as well as long-haul experiments are carried out to validate the proposed MFI scheme. Successful identification is demonstrated among polarization-multiplexed (PM) QPSK, 8PSK, 8QAM, 16QAM, 32QAM and 64QAM signals. Compared with existing modulation identification schemes, the proposed MFI method has an excellent recognition performance with a low computational complexity.

Puberty onset is a complex trait regulated by multiple genetic and environmental factors. In this study, we narrowed a puberty-related QTL region down to a 1.7 Mb region on chromosome X in female mice and inferred miR-505-3p as the functional gene. We conducted ectopic expression of miR-505-3p in the hypothalamus of prepubertal female mice through lentivirus-mediated orthotopic injection. The impact of miR-505-3p on female puberty was evaluated by the measurement of pubertal/reproduction events and histological analysis. The results showed that female mice with overexpression of miR-505-3p in the hypothalamus manifested later puberty onset timing both in vaginal opening and ovary maturation, followed by weaker fertility lying in the longer interval time between mating and delivery, higher abortion rate and smaller litter size. We also constructed miR-505-3p-knockout mice by CRISPR/Cas9 technology. miR-505-3p-knockout female mice showed earlier vaginal opening timing, higher serum gonadotrophin and higher expression of puberty-related gene in the hypothalamus than their WT littermates. Srsf1 proved to be the target gene of miR-505-3p that played the major role in this process. The results of RNA immunoprecipitation sequencing showed that SRSF1 (or SF2), the protein product of Srsf1 gene, mainly bound to ribosome protein (RP) mRNAs in GT1-7 cells. The collective evidence implied that miR-505-3p/SRSF1/RP could play a role in the sexual maturation regulation of mammals.

Single nucleotide polymorphisms (SNPs) are one of the most common markers in mammals. Rapid, accurate, and multiplex typing of SNPs is critical for subsequent biological and genetic research. In this study, we have developed a novel method for multiplex genotyping SNPs in mice. The method involves allele-specific PCR amplification of genomic DNA with two stem-loop primers accompanied by two different universal fluorescent primers. Blue and green fluorescent signals were conveniently detected on a DNA sequencer. We verified four SNPs of 65 mice based on the novel method, and it is well suited for multiplex genotyping as it requires only one reaction per sample in a single tube with multiplex PCR. The use of universal fluorescent primers greatly reduces the cost of designing different fluorescent probes for each SNP. Therefore, this method can be applied to many biological and genetic studies, such as multiple candidate gene testing, genome-wide association study, pharmacogenetics, and medical diagnostics.

Puberty onset is a complex trait regulated by multiple genetic and environmental factors. In this study, we narrowed a puberty related QTL down to a 1.7 Mb region on chromosome X in female mice and inferred miR-505-3p as the functional gene.We conducted ectopic expression of miR-505-3p in the hypothalamus of prepubertal female mice through lentivirus-mediated orthotopic injection. The impact of miR-505-3p on female puberty was evaluated by the measurement of pubertal events and histological analysis. The results showed that female mice with overexpression of miR-505-3p in the hypothalamus manifested later puberty onset timing both in vaginal opening and ovary maturation, followed by weaker fertility lying in the longer interval time between mating and delivery, higher abortion rate and smaller litter size. We also constructed miR-505-3p knockout mice by CRISPR/Cas9 technology. MiR-505-3p knockout female mice showed earlier vaginal opening timing, higher serum gonadotrophin and higher expression of puberty-related gene, as well as its target gene Srsf1 in the hypothalamus than their wild type littermates.Srsf1 was proved to be the target gene of miR-505-3p that played the major role in this process. The results of RIP-seq (RNA Immunoprecipitation-sequencing) showed that SF2, the protein product of Srsf1 gene, mainly bound to ribosome protein (RP) mRNAs in GT1-7 cells. The collective evidence implied that miR-505-3p/SRSF1/RP could play a role in the sexual maturation regulation of mammals.Author summaryThe puberty onset in mammals is a vital biological process that signals the acquisition of reproductive capacity. The initiation of puberty is triggered by the activation of hypothalamic pulsatile GnRH surge. The dysregulation of pubertal development shows relevance to later health risks of type 2 diabetes, cardiovascular disease, breast cancer and other health disorders. Recent progress indicates that a lot of genes play a role in the excitatory or inhibitory regulation of GnRH release. However, the detailed pathway of pubertal timing remains unclear. Our previous studies isolated an X-linked QTL that was associated with the timing of puberty in mice. In this study, we proved that miR-505-3p was a female puberty onset regulator based on data from positional cloning, ectopic expression and knockout mouse models. We also assigned Srsf1 as the functional target gene of miR-505-3p underlying this process. The results of RIP-seq showed that SF2, the protein of Srsf1 gene, preferential bound to ribosome protein (RP) mRNAs in GT1-7 cells. We propose that miR-505-3p/SF2/RP could play a role in the sexual maturation regulation of mammals.

In order to assess the risk of grid frequency deviation caused by power fluctuations in a wind farm more precisely, an annual second-level wind power fluctuation model should be established. Firstly, the annual second-level wind speed considering the spatial correlation in a wind farm is constructed. The annual average wind speed with auto-correlation and satisfying the Weibull distribution is simulated, with which the second-level wind speed incorporating the spatial correlation of wind farm is calculated based on the Kaimal power spectrum in frequency domain. Finally, the wind power fluctuation is determined using the wind speed obtained previously and is utilized to estimate the subsequent frequency deviation. The effectiveness of the generated annual second-level wind power fluctuations is validated via simulations performed in MATLAB/Simulink.

Vitamin A palmitate and vitamin E TPGS, common derivatives of the unstable vitamins A and E, were successfully incorporated into biodegradable gelatin nanofibers via electrospinning. Electron microscopy showed that smooth cylindrical fibers were produced, albeit with a small amount of beading visible for the vitamin-loaded systems. The diameters of the fibers decrease with the addition of vitamins. The presence of the vitamins in the fibers was confirmed by IR spectroscopy, and X-ray diffraction showed them to exist in the amorphous physical form post-electrospinning. The addition of vitamins did not affect the hydrophilic properties of the gelatin nanofibers. Fibers containing vitamin A or E alone showed a sustained release profile over more than 60 hours, and those incorporating both vitamins showed similar release characteristics, except that the extent of release for vitamin A was increased. Antibacterial tests demonstrated that materials loaded with vitamin E were effective in inhibiting the growth of E. coli and S. aureus. The fibers could promote the proliferation of fibroblasts during the early stages of culture, and enhance the expression of collagen-specific genes. In vivo tests determined that the fibers loaded with vitamins have better wound healing performance than a commercially used antiseptic gauze and casting films.

In the smart grid (SG), the active management (AM) mode will be applied for the connection and operation of distributed generation (DG), which means real time control and management of DG units and distribution network devices based on real time measurements of primary system parameters. In this paper, a novel bi-level programming model for distributed wind generation (DWG) planning under AM mode is put forward. The model takes the maximum expectation of net benefit of DWG as the upper level program objective, and takes the minimum expectation of generation curtailment as the lower level program objective. The impact of active management algorithm on improvement of branch power flow and node voltage is taken into account. A hybrid algorithm combining the plant growth simulation algorithm (PGSA) with probabilistic optimal power flow (POPF) algorithm is presented to solve the optimal planning of DWG under AM mode. The case studies have been carried out on a 33-node distribution network, and the results verify the rationality of the planning model and the effectiveness of the proposed method.

Both natural and artificial selection play a critical role in animals’ adaptation to the environment. Detection of the signature of selection in genomic regions can provide insights for understanding the function of specific phenotypes. It is generally assumed that laboratory mice may experience intense artificial selection while wild mice more natural selection. However, the differences of selection signature in the mouse genome and underlying genes between wild and laboratory mice remain unclear. In this study, we used two mouse populations: chromosome 1 (Chr 1) substitution lines (C1SLs) derived from Chinese wild mice and mouse genome project (MGP) sequenced inbred strains and two selection detection statistics: Fst and Tajima’s D to identify the signature of selection footprint on Chr 1. For the differentiation between the C1SLs and MGP, 110 candidate selection regions containing 47 protein coding genes were detected. A total of 149 selection regions which encompass 7.215 Mb were identified in the C1SLs by Tajima’s D approach. While for the MGP, we identified nearly twice selection regions (243) compared with the C1SLs which accounted for 13.27 Mb Chr 1 sequence. Through functional annotation, we identified several biological processes with significant enrichment including seven genes in the olfactory transduction pathway. In addition, we searched the phenotypes associated with the 47 candidate selection genes identified by Fst. These genes were involved in behavior, growth or body weight, mortality or aging, and immune systems which align well with the phenotypic differences between wild and laboratory mice. Therefore, the findings would be helpful for our understanding of the phenotypic differences between wild and laboratory mice and applications for using this new mouse resource (C1SLs) for further genetics studies.