miRNAs derived from milk small extracellular vesicles inhibit porcine epidemic diarrhea virus infection.

Porcine epidemic diarrhea virus (PEDV), a member of the genus Alphacoronavirus in the family Coronaviridae, causes acute diarrhea and/or vomiting, dehydration, and high mortality in neonatal piglets. It has caused huge economic losses to animal husbandry worldwide. Current commercial PEDV vaccines do not provide enough protection against variant and evolved virus strains. No specific drugs are available to treat PEDV infection. The development of more effective therapeutic anti-PEDV agents is urgently needed. Our previous study suggested that porcine milk small extracellular vesicles (sEV) facilitate intestinal tract development and prevent lipopolysaccharide-induced intestinal injury. However, the effects of milk sEV during viral infection remain unclear. Our study found that porcine milk sEV, which was isolated and purified by differential ultracentrifugation, could inhibit PEDV replication in IPEC-J2 and Vero cells. Simultaneously, we constructed a PEDV infection model for piglet intestinal organoids and found that milk sEV also inhibited PEDV infection. Subsequently, in vivo experiments showed that milk sEV pre-feeding exerted robust protection of piglets from PEDV-induced diarrhea and mortality. Strikingly, we found that the miRNAs extracted from milk sEV inhibited PEDV infection. miRNA-seq, bioinformatics analysis, and experimental verification demonstrated that miR-let-7e and miR-27b, which were identified in milk sEV targeted PEDV N and host HMGB1, suppressed viral replication. Taken together, we revealed the biological function of milk sEV in resisting PEDV infection and proved its cargo miRNAs, miR-let-7e and miR-27b, possess antiviral functions. This study is the first description of the novel function of porcine milk sEV in regulating PEDV infection. It provides a better understanding of milk sEV resistance to coronavirus infection, warranting further studies to develop sEV as an attractive antiviral.

The Effect of Clinical Pharmacist Intervention on Renal Function Impairment in Patients with Antimicrobial-Induced Acute Kidney Injury in ICU.

Objective: The purpose of this study was to analyze the improvement effect of clinical pharmacist intervention on renal function impairment in patients with antimicrobial-induced acute kidney injury (AKI). Methods: A total of 145 patients with AKI caused by antibiotics admitted to the ICU department were selected as the research subjects. The patients were divided into the control group (n=57) and the intervention group (n=88) according to whether there were ICU specialist clinical pharmacists involved in clinical treatment. The renal function outcome and infection control were evaluated in the two groups. Results: The proportion of renal function outcome in the intervention group was 88.6%, which was significantly higher than that in the control group. However, there was no statistically significant difference in infection control between the two groups. For the intervention group, the clinical pharmacists adopted three intervention methods: dose adjustment, drug replacement and CRRT treatment, respectively, according to the disease conditions of AKI patients. Among them, dose adjustment and drug replacement were the most frequently used intervention methods. In addition, the proportion of renal function outcome was higher in the group of patients who changed antibiotics and underwent CRRT, which were 93.1% and 100%, respectively. The adjusted-dose group had the highest infection control rate at 82.1%. However, there were no statistically significant differences in renal function outcomes and infection control among the three interventions. Conclusion: Clinical pharmacists participating in the clinical treatment of patients with antimicrobial-induced AKI in ICU can effectively improve the renal function of patients.

GHRH expression plasmid improves osteoporosis and skin damage in aged mice.

The hormone secretion of GHRH-GH-IGF-1 axis in animals was decreased as aging. These hormones play an important role in maintaining bone mass and bone structure, and also affect the normal structure and function of the skin. We used plasmid-based technology to deliver growth hormone releasing hormone (GHRH) to elderly mice. In the current study, 80 and 120 µg/kg pVAX-GHRH plasmid expression plasmid were injected into old mice, the serum GHRH and insulin-like growth factor-1(IGF-1) content were increased within three weeks (P < 0.05). In the groups of 80 and 120 µg/kg plasmid, the content of procollagen type I N-terminal pro-peptide (PINP) in the serum was increased(P < 0.05), and the content of C-terminal telopeptides of type I collagen (CTX-1) in the serum was reduced significantly (P < 0.05). Furthermore, the expression of osteoprotegerin (OPG) and osteocalcin (OCN) in the femur also was increased(P < 0.05). The bone mineral density(BMD)、trabecular bone volume (BV/TV) and trabecular number(Tb.N) of mouse femur were increased significantly (P < 0.05) and trabecular separation(Tb.Sp) was decreased(P < 0.05). There were more trabecular bones in the bone marrow cavity and the trabecular bones are thicker in the groups of 80 and 120 µg/kg plasmid relative to control. The superoxide dismutase (SOD) content in the skin was increased(P < 0.05), and the malondialdehyde (MDA) content was reduced significantly (P < 0.05). Meanwhile, the skin moisture content also increased significantly(P < 0.05). Moreover, the expression of matrix metalloproteinase 3(MMP3) and matrix metalloproteinase 9(MMP9) was decreased in the skin(P < 0.05). The thickness of the dermis and epidermis of the skin had increased significantly(P < 0.05). Skin structure is more dense and complete in the two groups. These results indicate that 80 and 120 µg/kg plasmid-mediated GHRH supplementation can improve osteoporosis and skin aging in aged mice.

The Influence of Long-Term Dietary Intake of Titanium Dioxide Particles on Elemental Homeostasis and Tissue Structure of Mouse Organs.

Background: Titanium dioxide (TiO2), consisting of nanoparticles and sub-microparticles, were widely used as food additive and consumed by people every day, which has aroused a public safety concern. Some studies showed TiO2 can be absorbed by intestine and then distributed to different tissues after oral intake, which is supposed to affect the content of various elements in the body whereas led to tissue damage. However, knowledge gaps still exist in the impact of TiO2 on the disorder of elemental homeostasis. Thus, this study aimed to explore the oral toxicity of TiO2 by assessing its influence on elemental homeostasis and tissues injury. Method: ICR mice were fed with normal feed, TiO2 nanoparticles (NPs)-mixed feed or TiO2 submicron particles (MPs)-mixed feed (1% mass fraction TiO2 NPs or MPs were mixed in commercial pellet diet) for 1, 3, and 6 months. Particles used in this study were characterized. The distribution of Ti and other 23 elements, the correlation among elements, and pathological change in the liver, kidney, spleen and blood cells of the mice was determined. Result: Ti accumulation only appeared in blood cells of mice treated with TiO2 MPs-mixed feed for 6 months, but TiO2 cause 12 kinds of elements (boron, vanadium, iron, cobalt, copper, zinc, selenium, sodium, calcium, magnesium, silicon, phosphorus) content changed in organ tissue. The changed kinds of elements in blood cells (6 elements), liver (7 elements) or kidney (6 elements) were more than in the spleen (1 element). The TiO2 NPs induced more elements changed in blood cells and liver, and the TiO2 MPs induced more elements changed in kidney. Significantly positive correlation between Ti and other elements was found in different organs except the liver. Organ injuries caused by TiO2 NPs were severer than TiO2 MPs. Liver exhibited obvious pathological damage which became more serious with the increase of exposure time, while kidney and spleen had slight damages. Conclusion: These results indicated long-time dietary intake of TiO2 particles could induce element imbalance and organ injury. The liver displayed more serious change than other organs, especially under the treatment with TiO2 NPs. Further research on the oral toxicity of TiO2 NPs should pay more attention to the health effects of element imbalances using realistic exposure methods.

Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers.

G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.

Mapping the Magnetic Field Intensity of Light with the Nonlinear Optical Emission of a Silicon Nanoparticle.

To detect the magnetic component of arbitrary unknown optical fields, a candidate probe must meet a list of demanding requirements, including a spatially isotropic magnetic response, suppressed electric effect, and wide operating bandwidth. Here, we show that a silicon nanoparticle satisfies all these requirements, and its optical magnetism driven multiphoton luminescence enables direct mapping of the magnetic field intensity distribution of a tightly focused femtosecond laser beam with varied polarization orientation and spatially overlapped electric and magnetic components. Our work establishes a powerful nonlinear optics paradigm for probing unknown optical magnetic fields of arbitrary electromagnetic structures, which is not only essential for realizing subwavelength-scale optical magnetometry but also facilitates nanophotonic research in the magnetic light-matter interaction regime.

A space hurricane over the Earth's polar ionosphere.

In Earth's low atmosphere, hurricanes are destructive due to their great size, strong spiral winds with shears, and intense rain/precipitation. However, disturbances resembling hurricanes have not been detected in Earth's upper atmosphere. Here, we report a long-lasting space hurricane in the polar ionosphere and magnetosphere during low solar and otherwise low geomagnetic activity. This hurricane shows strong circular horizontal plasma flow with shears, a nearly zero-flow center, and a coincident cyclone-shaped aurora caused by strong electron precipitation associated with intense upward magnetic field-aligned currents. Near the center, precipitating electrons were substantially accelerated to ~10 keV. The hurricane imparted large energy and momentum deposition into the ionosphere despite otherwise extremely quiet conditions. The observations and simulations reveal that the space hurricane is generated by steady high-latitude lobe magnetic reconnection and current continuity during a several hour period of northward interplanetary magnetic field and very low solar wind density and speed.

Biological Characteristics and Roles of Noncoding RNAs in Milk-Derived Extracellular Vesicles.

Extracellular vesicles (EVs) have diverse roles in the transport of proteins, lipids, and nucleic acids between cells, and they serve as mediators of intercellular communication. Noncoding RNAs (ncRNAs) that are present in EVs, including microRNAs, long noncoding RNAs, and circular RNAs, have been found to participate in complex networks of interactions and regulate a wide variety of genes in animals. Milk is an important source of nutrition for humans and other mammals. Evidence suggests that milk-derived EVs contain abundant ncRNAs, which are stable and can be transported to the offspring and other consumers. Current data suggest a strong link between milk EV ncRNAs and many biological processes, and these ncRNAs have been drawing increasing attention and might play an epigenetic regulatory role in recipients, though further research is still necessary to understand their precise roles. The present review introduces basic information about milk EV ncRNAs, summarizes their expression profiles, biological characteristics, and functions based on current knowledge, and discusses their biological roles, indeterminate issues, and perspectives. Our goal is to provide a deeper understanding of the physiological effects of milk EV ncRNAs on offspring and to provide a reference for future research in this field.

Taurochenodeoxycholic acid mediates cAMP-PKA-CREB signaling pathway.

Taurochenodeoxycholic acid (TCDCA) is one of the main effective components of bile acid, playing critical roles in apoptosis and immune responses through the TGR5 receptor. In this study, we reveal the interaction between TCDCA and TGR5 receptor in TGR5-knockdown H1299 cells and the regulation of inflammation via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding (CREB) signal pathway in NR8383 macrophages. In TGR5-knockdown H1299 cells, TCDCA significantly activated cAMP level via TGR5 receptor, indicating TCDCA can bind to TGR5; in NR8383 macrophages TCDCA increased cAMP content compared to treatment with the adenylate cyclase (AC) inhibitor SQ22536. Moreover, activated cAMP can significantly enhance gene expression and protein levels of its downstream proteins PKA and CREB compared with groups of inhibitors. Additionally, TCDCA decreased tumour necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8 and IL-12 through nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activity. PKA and CREB are primary regulators of anti-inflammatory and immune response. Our results thus demonstrate TCDCA plays an essential anti-inflammatory role via the signaling pathway of cAMP-PKA-CREB induced by TGR5 receptor.

MiR-125b-2 knockout increases high-fat diet-induced fat accumulation and insulin resistance.

Obese individuals are more susceptible to comorbidities than individuals of healthy weight, including cardiovascular disease and metabolic disorders. MicroRNAs are a class of small and noncoding RNAs that are implicated in the regulation of chronic human diseases. We previously reported that miR-125b plays a critical role in adipogenesis in vitro. However, the involvement of miR-125b-2 in fat metabolism in vivo remains unknown. In the present study, miR-125b-2 knockout mice were generated using CRISPR/CAS9 technology, resulting in mice with a 7 bp deletion in the seed sequence of miR-125b-2. MiR-125b-2 knockout increased the weight of liver tissue, epididymal white fat and inguinal white fat. MiR-125b-2 knockout also increased adipocyte volume in HFD-induced obese mice, while there were no significant differences in body weight and feed intake versus mice fed a normal diet. Additionally, qRT-PCR and western blot analysis revealed that the expression of the miR-125b-2 target gene SCD-1 and fat synthesis-associated genes, such as PPARγ and C/EBPα, were significantly up-regulated in miR-125b-2KO mice (P < 0.05). Moreover, miR-125b-2KO altered HFD-induced changes in glucose tolerance and insulin resistance. In conclusion, we show that miR-125b-2 is a novel potential target for regulating fat accumulation, and also a candidate target to develop novel treatment strategies for obesity and diabetes.

Dominant-negative NFKBIA mutation promotes IL-1ß production causing hepatic disease with severe immunodeficiency.

Although IKK-ß has previously been shown as a negative regulator of IL-1ß secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1ß expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1ß secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1ß correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1ß release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1ß secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.

Multiple transpolar auroral arcs reveal insight about coupling processes in the Earth's magnetotail.

A distinct class of aurora, called transpolar auroral arc (TPA) (in some cases called "theta" aurora), appears in the extremely high-latitude ionosphere of the Earth when interplanetary magnetic field (IMF) is northward. The formation and evolution of TPA offers clues about processes transferring energy and momentum from the solar wind to the magnetosphere and ionosphere during a northward IMF. However, their formation mechanisms remain poorly understood and controversial. We report a mechanism identified from multiple-instrument observations of unusually bright, multiple TPAs and simulations from a high-resolution three-dimensional (3D) global MagnetoHydroDynamics (MHD) model. The observations and simulations show an excellent agreement and reveal that these multiple TPAs are generated by precipitating energetic magnetospheric electrons within field-aligned current (FAC) sheets. These FAC sheets are generated by multiple-flow shear sheets in both the magnetospheric boundary produced by Kelvin-Helmholtz instability between supersonic solar wind flow and magnetosphere plasma, and the plasma sheet generated by the interactions between the enhanced earthward plasma flows from the distant tail (less than -100 RE) and the enhanced tailward flows from the near tail (about -20 RE). The study offers insight into the complex solar wind-magnetosphere-ionosphere coupling processes under a northward IMF condition, and it challenges existing paradigms of the dynamics of the Earth's magnetosphere.

Rosamultin Attenuates Acute Hypobaric Hypoxia-Induced Bone Injuries by Regulation of Sclerostin and Its Downstream Signals.

Wang, Xing-Min, Hui Liu, Jian-Yu Li, Jin-Xia Wei, Xia Li, Yong-Liang Zhang, Ling-Zhi Li, and Xi-Zheng Zhang. Rosamultin attenuates acute hypobaric hypoxia-induced bone injuries by regulation of sclerostin and its downstream signals. High Alt Med Biol. 21:273-286, 2020. Background: Rosamultin, one of the compounds extracted from Potentilla anserina L., exhibited significant pharmacological activity against oxidative stress and hypoxic injury in our previous study. However, the effect of rosamultin on bone damage induced by acute hypobaric hypoxia (HH) has not been thoroughly studied. Methods: In this study, we first investigated the protective effect of rosamultin against bone damage in rats following acute exposure to simulated high-altitude hypoxia. Furthermore, we explored the detailed mechanism involved in the regulation of rat bone remodeling by rosamultin in an acute HH environment through analysis of sclerostin expression and the regulation of downstream signaling pathways. Results: Pretreatment with rosamultin significantly reduced HH-induced oxidative stress and inflammation, improved bone metabolic abnormalities, and alleviated the imbalance in bone remodeling in rats exposed to acute HH. Rosamultin markedly downregulated the expression of sclerostin, activated the Wnt/ß-catenin signaling pathway, and enhanced the ratio of osteoprotegerin/receptor activator of nuclear factor kappa B ligand to maintain the balance of bone formation and resorption. Conclusions: Rosamultin attenuates acute HH-induced bone damage and improves abnormal bone remodeling in rats by inhibition of sclerostin expression and activation of the Wnt/ß-catenin signaling pathway.

Multifunctional Water Drop Energy Harvesting and Human Motion Sensor Based on Flexible Dual-Mode Nanogenerator Incorporated with Polymer Nanotubes.

In the world of increasing energy consumption, nanogenerators have shown great potential for energy harvesting and self-powered portable electronics. Herein, a flexible and dual-mode triboelectric nanogenerator (TENG) combining both vertical contact-separation and single electrical modes has been developed to convert environmental mechanical energy into electricity using highly encapsulated and multifunctional strategies. By introducing the polymer melt wetting technique, polymer nanotubes are fabricated on the surface of the TENG, which provides self-cleaning and hydrophobic features beneficial for water drop energy harvesting using the device. In such mechanical energy harvesting, the maximum output power of 0.025 mW and the open-circuit voltage of 41 V can be achieved. By designing the dimensions of the device, the dual-mode TENG is utilized as a self-powered sensor to detect human body motions such as phalanges' movement of fingers. The fabricated dual-mode TENG promotes the development of energy-harvesting and self-powered human motion sensors for artificial intelligent prosthetics, human kinematics, and human body recovery treatment.

Plasmapause surface wave oscillates the magnetosphere and diffuse aurora.

Energy circulation in geospace lies at the heart of space weather research. In the inner magnetosphere, the steep plasmapause boundary separates the cold dense plasmasphere, which corotates with the planet, from the hot ring current/plasma sheet outside. Theoretical studies suggested that plasmapause surface waves related to the sharp inhomogeneity exist and act as a source of geomagnetic pulsations, but direct evidence of the waves and their role in magnetospheric dynamics have not yet been detected. Here, we show direct observations of a plasmapause surface wave and its impacts during a geomagnetic storm using multi-satellite and ground-based measurements. The wave oscillates the plasmapause in the afternoon-dusk sector, triggers sawtooth auroral displays, and drives outward-propagating ultra-low frequency waves. We also show that the surface-wave-driven sawtooth auroras occurred in more than 90% of geomagnetic storms during 2014-2018, indicating that they are a systematic and crucial process in driving space energy dissipation.

Porcine milk exosome miRNAs protect intestinal epithelial cells against deoxynivalenol-induced damage.

Porcine milk exosomes play an important role in mother-infant communication. Deoxynivalenol (DON) is a toxin which causes serious damage to the animal intestinal mucosa. Our previous study showed porcine milk exosomes facilitate mice intestine development, but the effects of these exosomes to antagonize DON toxicity is unclear. Our in vivo results showed that milk exosomes attenuated DON-induced damage on the mouse body weight and intestinal epithelium growth. In addition, these exosomes could reverse DON-induced inhibition on cell proliferation and tight junction proteins (TJs) formation and reduce DON-induced cell apoptosis. In vitro, exosomes up-regulated the expression of miR-181a, miR-30c, miR-365-5p and miR-769-3p in IPEC-J2 cells and then down-regulated the expression of their targeting genes in p53 pathway, ultimately attenuating DON-induced damage by promoting cell proliferation and TJs and by inhibiting cell apoptosis. In conclusion, porcine milk exosomes could protect the intestine against DON damage, and these protections may take place through the miRNAs in exosomes. These results indicated that the addition of miRNA-enriched exosomes to feed or food could be used as a novel preventative measure for necrotizing enterocolitis.

Effect of Moringa oleifera supplementation on productive performance, colostrum composition and serum biochemical indexes of sow.

Moringa oleifera has been considered as a potential functional feed or food, since it contains multiple components beneficial to animal and human. However, little is known about the effects of Moringa oleifera supplementation on productive performances in sows. In the current study, the results showed that dietary Moringa oleifera significantly decreased the farrowing length and the number of stillborn (p < .05), while had an increasing trend in the number of live-born (0.05 < p < .10). Furthermore, 8% Moringa oleifera supplementation significantly elevated protein levels in the colostrum (p < .05); 4% Moringa oleifera lowed serum urea nitrogen of sows after 90 days of gestation (p < .05) and significantly decreased serum glucose on 10 days of lactation (p < .05). Both groups showed significant elevation in serum T-AOC activity (p < .05). The serum malondialdehyde (MDA) of sows declined significantly in 4% Moringa oleifera addition group (p < .05). 8% Moringa oleifera meal significantly elevated serum CAT activity after 60 days of gestation (p < .05), while decreased the serum MDA level and increased the serum GSH-Px activity of sows at 10 days of lactation (p < .05). Of piglets, both two dosages of Moringa oleifera supplementation essentially reduced the serum urea nitrogen (p < .05), and 4% Moringa oleifera meal increased serum total protein (p < .05). In addition, piglets that received 8% Moringa oleifera had the highest serum CAT and SOD activities among all groups (p < .05). The present study indicated that Moringa oleifera supplementation could enhance the reproduction performances, elevate protein levels in the colostrum and improve the serum antioxidant indices in both sows and piglets.