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The proliferation and differentiation of pre-adipocytes are regulated by microRNAs (miRNAs) and other factors. In this study, the potential functions of bta-miR-6517 in the regulation of pre-adipocyte proliferation and differentiation were explored. The qRT-PCR, oil red O staining and CCK-8 assay were used to evaluate the role of bta-miR-6517. Further, the target gene of bta-miR-6517 was identified using bioinformatics analysis, dual-luciferase reporter system and qRT-PCR system. The results found that the overexpression of bta-miR-6517 promoted the expression of proliferation marker genes and substantially increased the adipocyte proliferation vitality in the CCK-8 assay, whereas suppressing of bta-miR-6517 had the opposite effect. Overexpression bta-miR-6517 suppressed the expression of adipogenic genes, which inhibited lipid accumulation, whereas suppressing of bta-miR-6517 had the opposite effect. Furthermore, the dual-fluorescent reporter experiment results demonstrated that bta-miR-6517 directly targeted phosphofructokinase, liver type (PFKL). When bta-miR-6517 was either overexpressed or suppressed, it negatively regulated PFKL. In conclusion, we observed that bta-miR-6517 promoted adipocyte proliferation and inhibited differentiation by targeting PFKL.

An amorphous niobium polysulfide based nanocomposite with electronic/ionic conductive networks is prepared and further employed as a cathode for all-solid-state lithium batteries, exhibiting superior long-term cycling stability as well as high reversible capacity.

To investigate the effect of surface coating materials on the humidity stability of aluminum (Al) nanopowders, three kinds of core–shell structure Al nanopowders with an Al2O3 passivation coating, carbon coating, and plasticizer dioctyl sebacate (DOS) coating were prepared through laser-induction complex heating method. After one year’s storage at 95% relative humidity, their thermal properties were tested through differential scanning calorimeter (DSC) and thermal gravimeter (TG) analysis. The results show that the thermal properties of Al2O3-passivated Al nanopowders are entirely lost under high humidity because the Al2O3 passivation coating is very sensitive to moisture. The thermal properties of carbon-coated Al nanopowders are not well-protected under a high humidity due to the uneven thickness and structural defects of carbon coatings. However, the thermal enthalpy of DOS-coated Al nanopowders remains at 3.56 KJ/g under high humidity, which indicates that an organic DOS coating with a hydrophobic nature has an excellent protective effect on the thermal properties of the Al nanopowders. Given the good forming performance of organic DOS coatings and other components of propellants, DOS-coated Al nanopowders are a kind of energetic material with potential application value.

The disease caused by SARS-CoV-2 infection threatens human health. In this study, we used high-pressure homogenization technology not only to efficiently drive the bacterial membrane to produce artificial vesicles but also to force the fusion protein ClyA-receptor binding domain (RBD) to pass through gaps in the bacterial membrane to increase the contact between ClyA-RBD and the membrane. Therefore, the load of ClyA-RBD on the membrane is substantially increased. Using this technology, we constructed a "ring-like" bacterial biomimetic vesicle (BBV) loaded with polymerized RBD (RBD-BBV). RBD-BBVs injected subcutaneously can accumulate in lymph nodes, promote antigen uptake and processing, and elicit SARS-CoV-2-specific humoral and cellular immune responses in mice. In conclusion, we evaluated the potential of this novel bacterial vesicle as a vaccine delivery system and provided a new idea for the development of SARS-CoV-2 vaccines.

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.

pH sensing plays a key role in the life sciences as well as the environmental, industrial, and agricultural fields. Carbon nanodots (C-dots) with small size, low toxicity, and excellent stability hold great potential in pH sensing as nanoprobes due to their intrinsic pH-sensitive photoluminescence (PL). Nonetheless, the undesirable sensitivity and response range of C-dot PL toward pH cannot meet the requirements of practical applications, and the unclear pH-sensitive PL mechanism makes it difficult to control their pH sensitivity. Herein, the quantitative correlation of pH-sensitive PL with specific surface structures of C-dots is uncovered for the first time, to our best knowledge. The association of carboxylate and H+ increases the ratio of nonradiation to radiation decay of C-dots through excited-state proton transfer, resulting in the decrease of PL intensity. Meanwhile, the dissociation of α-H in β-dicarbonyl forming enolate increases the extent of delocalization of the C-dots conjugated system, which induces the PL broadening to the red region and a decreasing intensity. Based on the understanding of the pH-sensitive PL mechanism, the pH-sensitive PL of C-dots can be switched by quantitative modulation of carboxyl and β-dicarbonyl groups to achieve a desirable pH response range with high sensitivity. This work contributes to a better understanding of the pH-sensitive PL of C-dots and therefore presents an effective strategy for controllably tuning their pH sensitivity, facilitating the rational design of C-dot-based pH sensors.

Fluorescence quenching of carbon nanodots by metal ions has been extensively applied for the determination of oligonucleotides, proteins, small molecules and metal ions. However, the problem of poor selectivity originating from the coordination of surface oxygen-containing groups to many kinds of metal ions has limited the prosperity of carbon nanodots in detection field. Herein, the specific recognition of carbon nanodots to Hg2+ is controlled by rational regulation of the surface structure of carbon nanodots. Passivation of the surface carboxyl and hydroxyl groups plays a decisive role in inhibiting the binding of metal ions with carbon nanodots. Upon the attachment of Hg2+ specific recognition unit, carbon nanodots exhibited a high selectivity to Hg2+. This work facilitates to rationally design the surface structure of carbon nanodots to obtain the desirable selective recognition ability.

Identification of a suitable nonhuman primate (NHP) model of COVID-19 remains challenging. Here, we characterized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in three NHP species: Old World monkeys Macaca mulatta (M. mulatta) and Macaca fascicularis (M. fascicularis) and New World monkey Callithrix jacchus (C. jacchus). Infected M. mulatta and M. fascicularis showed abnormal chest radiographs, an increased body temperature and a decreased body weight. Viral genomes were detected in swab and blood samples from all animals. Viral load was detected in the pulmonary tissues of M. mulatta and M. fascicularis but not C. jacchus. Furthermore, among the three animal species, M. mulatta showed the strongest response to SARS-CoV-2, including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues. Collectively, these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M. mulatta as the most suitable for modeling COVID-19.

Multiple drug-targeting strategies have been applied to drug development in order to reduce the toxic side effects of the traditional chemotherapy while enhancing its anti-tumor efficacy. Various peptides, proteins and antibodies are usually used to conjugate cytotoxic agents via acting as drug delivery vehicles. In our previous studies, we identified that peptides displayed their efficacious functions to deliver small molecules or oligo DNA to the target sites through ligand-receptor interactions and quick internalization. In our present study, we attempt to synthesize serial drug conjugates via coupling these compounds to peptide or protein vehicles. Tye1001, one of these conjugates, displayed similar potent anti-proliferation activities in lymphoma cells and many other cancer cells compared to the small molecule itself. In particular, this conjugate significantly enhanced its potent anti-tumor efficacy in xenografts. Meanwhile, this conjugate has much less toxic side effects. In our in vivo assays, the similar results were also observed in multiple other tumors such as gastric cancer and leukemia. Our findings provide a more potential druggable opportunity in the clinical applications of cancer patients and the treatment of different types of cancers. Citation Format: Lichun Sun, Mengli Yang, Haihua Xiao, Yuan Tian, Natalya Vasilevich, Joseph Fuselier, David Coy. The targeting drug conjugate Tye1001 displayed its potent anti-tumor efficacy in lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4957.

Triple-negative breast cancer (TNBC) with estrogen receptor (ER), progesterone receptor (PR) and HER2 (c-erbB-2, neu) being negatively expressed in patient cancer tissues displayed its unique clinical pathological difference from other types of breast cancers. TNBC is more common in younger patients and more likely to have a family history of breast cancer. TNBCs more likely have poor prognosis and postsurgical recurrence, with strong invasiveness and metastasis. However, there is lack of effective and TNBC-targeting drugs. The non-typical CDK16 was found highly expressed in TNBCs and clearly associated with prognosis and survival of patients. CDK16 could promote the progression and metastasis of TNBC by phosphorylating PRC1. Knockdown of CDK16 could significantly suppress tumor growth and metastasis. Furthermore, in our studies, rebastinib acting as a CDK16 inhibitor displayed its strong suppression of TNBC tumor growth in a dose-dependent manner, indicating rebastinib or its analogs could be druggable and likely used to treat TNBC patients. Citation Format: Haihua Xiao, Huangyu Jiang, Kunxian Feng, Mengli Yang, Jinping Yang, Chengfang Jian, Yuan Tian, Natalya Vasilevich, Lichun Sun. The application of CDK16 inhibitors in the treatment of triple-negative breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5345.

Fibroblast growth factor (FGF) family genes are a class of polypeptide factors with similar structures that play an important role in regulating cell proliferation and differentiation, nutritional metabolism, and neural activity. In previous studies, the FGF gene has been widely studied and analyzed in many species. However, the systematic study of the FGF gene in cattle has not been reported. In this study, 22 FGF genes distributed on 15 chromosomes were identified in the Bos taurus genome and clustered into seven subfamilies according to phylogenetic analysis and conservative domains. Collinear analysis showed that the bovine FGF gene family was homologous to Bos grunniens, Bos indicus, Hybrid-Bos taurus, Bubalus bubalis, and Hybrid-Bos indicus, and tandem replication and fragment replication were the key driving forces for the expansion of the gene family. Tissue expression profiling showed that bovine FGF genes were commonly expressed in different tissues, with FGF1, FGF5, FGF10, FGF12, FGF16, FGF17, and FGF20 being highly expressed in adipose tissue. In addition, real-time fluorescence quantitative PCR (qRT-PCR) detection showed that some FGF genes were differentially expressed before and after adipocyte differentiation, indicating their diverse role in the formation of lipid droplets. This study made a comprehensive exploration of the bovine FGF family and laid a foundation for further study on the potential function in the regulation of bovine adipogenic differentiation.

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids. Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein. Moreover, histones enhance cell–cell fusion. Finally, treatment with an inhibitor of NETosis, histone H3 or H4, or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model. These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

New SARS-COV-2 vaccine strategies are still urgently needed, especially for emerging virus mutations and variants. In this study, we focused on analyzing the antigenicity and vaccine potency of linear peptide epitopes located in receptor binding motif (RBM) of spike (S) protein. Nine 12 to 16-mer overlapping peptides (P1-P9) were synthesized chemically and coupled to carrier protein KLH for the immunization in mice. Four of identified peptides were further engineered to present on the surface of recombinant Hepatitis B core antigen (HBcAg) virus-like particles (VLPs) respectively. Antisera obtained from VLPs -immunized mice demonstrated strong reactivity and affinity to S1 protein or inactivated virus and neutralizing activity against virus infection in vitro. This study indicates that recombinant VLPs empower peptides which display underprivileged antigenicity in native protein to elicit high levels of neutralizing antibody, providing potential epitope candidates and an effective delivery strategy for the development of a multi-epitope vaccine., Graphical Abstract Nine peptides (P1-P9) which cover the whole sequence of RBM of SARS-COV-2 spike protein were synthesized chemically and coupled to KLH for the immunization in mice. Among these peptides, P2, P3, P4 and P6 showed neutralizing protection against virus infection in a cell assay. The four peptides were further engineered to present on the surface of recombinant Hepatitis B core antigen (HBcAg) virus-like particles (VLPs) respectively. HBcAg-P6 VLPs dramatically elevated specific IgG level, and the antiserum demonstrated a strong reactivity and affinity to S1 protein or inactivated virus and neutralizing activity against virus infection in vitro.Unlabelled Image

Since the initial outbreak in late 2019, coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has evolved into a global pa...

The microstructures and mechanical properties of as-extruded Mg-Ho-Zn alloys with various Ho/Zn ratios have been investigated. The grain size is refined with increasing Ho addition. The presence of second phase in the alloys, i.e., long-period stacking ordered (LPSO) phase and W-phase, is dependent on the Ho/Zn ratio. The strength of the alloys decreased as the test temperature was increased. Among the experimental alloys, the alloy containing LPSO-phase exhibited the best comprehensive mechanical properties at both room and high temperatures, due to the high plasticity and good thermal stability of the LPSO-phase. Related mechanisms were analyzed via metallographic and fractographic examination and then discussed. A schematic diagram was established to further reflect the different roles of W-phase and LPSO-phase in the fracture behavior of the alloys.

The functional groups and π-electron system of carbon dots (C-dots) were carefully controlled by several innovative chemical methods, without any changes in size, to unravel the relationship between the surface structure and photoluminescence (PL). The results of experiments and theoretical calculations reveal that the PL of C-dots is related to the surface state. The energy gap is determined by the coupling of the π-electron system and carbonyl group, and the quantum yield (QY) is dependent on the carbonyl group. The carbonyl group is the main factor increasing the ratio of nonradiation to radiation recombination, thereby leading to the low QY of C-dots. This work provides a strategy for effectively tuning the structure of C-dots, giving rise to the tunable PL emission wavelength and highly desirable QY, which enables us to further unravel the PL mechanism.

In this work, the microstructures and mechanical properties of as-cast Mg-xHo-2Zn (x = 4, 6 and 8 wt%) alloys have been studied by using optical microscope (OM), X-ray diffraction (XRD), scanning electron microscope (SEM), transmission electron microscopy (TEM) and tensile test at different temperatures. The Ho element exhibits an influence on the grain refinement of the alloys. Increasing Ho content promotes the formation of long period stacking ordered (LPSO) structure, which changes the mechanical properties of the alloys. As a consequence, the strength of the alloy rises with the increase of Ho addition at room temperature and elevated temperature. However, the elongation of the alloy increases at room temperature but slightly decreases at high temperature when the Ho addition increases. These results are explained from morphology evolution of W-phase and the presence of LPSO phase in different alloys.

The specificity of sperm–egg recognition is crucial to species independence, and two proteins (Izumo1 and JUNO) are essential for gamete adhesion/fusion in mammals. However, hybridization, which is very common in turtles, also requires specific recognition of sperm–egg binding proteins. In this study, we discovered that natural selection plays an important role in the codon usage bias of Tu-Izumo1 and Tu-JUNO. Positively selected sites and co-evolutionary analyses between Tu-Izumo1 and Tu-JUNO have been previously reported, and we confirm these results in a larger analysis containing 25 turtle species. We also showed that Tu-JUNO is expressed on the oocyte surface and that Tu-Izumo1 and Tu-JUNO interact with each other directly in different species hybridization combinations. Co-immunization assays revealed that this interaction is evolutionarily conserved in turtles. The results of avidity-based extracellular interaction screening between Tu-Izumo1 and Tu-JUNO for sperm–oocyte binding pairs (both within and across species) likely suggest that the interaction force between Izumo1 and JUNO has a certain correlation in whether the turtles can hybridize. Our results lay a theoretical foundation for the subsequent development of techniques to detect whether different turtle species can interbreed, which would provide the molecular basis for breeding management and species protection of turtles.

We sequenced the entire mitochondrial genome of Melanocorypha mongolica for the first time. The mitogenome is 17,358 bp in length, which includes 13 protein-coding genes, 22 tRNA genes, 2 ribosomal RNA (rRNA) genes, the control region (CR1), and the control region 2 (CR2). Gene order follows a pattern similar to those of Eurasian Skylark. Using mitochondrial genomes of Melanocorypha mongolica and other seven reference birds in Sylvioidea, we preformed Bayesian analysis based on concatenated protein-coding genes. The results reveal that Alaudidae and Acroccphalidae are clustered together, which is sister to the branches included Sylviidae and Leiothrichidae. Further sequencing of mitochondrial genomes in Alaudidae is useful to advance phylogenetic relationship of species in the family.

Ozobranchus jantseanus is the largest metazoan known to survive in liquid nitrogen without pretreatment to date; however, the mechanism underlying this tolerance remains unclear. In this study, the first analyses of histological and morphological changes in normal, frozen, and dehydrated states were performed. Adults survived after direct placement in liquid nitrogen for 96 h, with a survival rate of approximately 86.7%. The leech could withstand rapid desiccation and its survival rate after rehydration was 100% when its water loss was below about 84.8%. After freezing, desiccation, and ethanol dehydration, the leech immediately formed a hemispherical shape. Particularly during drying, an obvious transparent glass-like substance was observed on surface. Scanning electron microscopy revealed many pores on the surface of the posterior sucker, creating a sponge-like structure, which may help to rapidly expel water, and a hemispherical shape may protect the internal organs by contraction and folding reconstruction in the anterior–posterior direction. A substantial amount of mucopolysaccharides on the surface and acid cells and collagen fibers in the body, all of which contained substantial polysaccharides, may play a key protective role during freezing. Our results indicate that the resistance of leeches to ultra-low temperatures can be explained by cryoprotective dehydration/vitrification strategies. This article has an associated First Person interview with the first author of the paper., Summary: The freeze tolerance mechanism of Ozobranchus jantseanus, the largest metazoan animal requiring no pretreatment that can survive in ultra-low temperature, was first studied from the perspective of morphology.

Background and Aims Gastrointestinal (GI) manifestations have been increasingly reported in Coronavirus Disease 2019 (COVID-19) patients. However, the roles of the GI tract in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are not fully understood. We investigated how the GI tract is involved in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19. Methods Our previously established nonhuman primate (NHP) model of COVID-19 was modified in this study to test our hypothesis. Rhesus monkeys were infected with an intragastric or intranasal challenge with SARS-CoV-2. Clinical signs were recorded after infection. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Host responses to SARS-CoV-2 infection were evaluated by examining inflammatory cytokines, macrophages, histopathology and mucin barrier integrity. Results Intranasal inoculation with SARS-CoV-2 led to infections and pathological changes not only in respiratory tissues but also in digestive tissues. Expectedly, intragastric inoculation with SARS-CoV-2 resulted in the productive infection of digestive tissues and inflammation in both the lung and digestive tissues. Inflammatory cytokines were induced by both types of inoculation with SARS-CoV-2, consistent with the increased expression of CD68. Immunohistochemistry and alcian blue/periodic acid-Schiff (AB-PAS) staining showed decreased Ki67, increased cleaved caspase 3 and decreased numbers of mucin-containing goblet cells, suggesting that the inflammation induced by these two types of inoculation with SARS-CoV-2 impaired the GI barrier and caused severe infections. Conclusions Both intranasal and intragastric inoculation with SARS-CoV-2 caused pneumonia and GI dysfunction in our rhesus monkey model. Inflammatory cytokines are possible connections for the pathogenesis of SARS-CoV-2 between the respiratory and digestive systems., Graphical abstract

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ∼16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ~16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.