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As viral genomic imprints in host genomes, endogenous viral elements (EVEs) shed light on the deep evolutionary history of viruses, ancestral host ranges, and ancient viral-host interactions. In addition, they may provide crucial information for calibrating viral evolutionary timescales. In this study, we conducted a comprehensive in silico screening of a large data set of available mammalian genomes for EVEs deriving from members of the viral family Flaviviridae, an important group of viruses including well-known human pathogens, such as Zika, dengue, or hepatitis C viruses. We identified two novel pestivirus-like EVEs in the reference genome of the Indochinese shrew (Crocidura indochinensis). Homologs of these novel EVEs were subsequently detected in vivo by molecular detection and sequencing in 27 shrew species, including 26 species representing a wide distribution within the Crocidurinae subfamily and one in the Soricinae subfamily on different continents. Based on this wide distribution, we estimate that the integration event occurred before the last common ancestor of the subfamily, about 10.8 million years ago, attesting to an ancient origin of pestiviruses and Flaviviridae in general. Moreover, we provide the first description of Flaviviridae-derived EVEs in mammals even though the family encompasses numerous mammal-infecting members. This also suggests that shrews were past and perhaps also current natural reservoirs of pestiviruses. Taken together, our results expand the current known Pestivirus host range and provide novel insight into the ancient evolutionary history of pestiviruses and the Flaviviridae family in general. ispartof: MOLECULAR BIOLOGY AND EVOLUTION vol:39 issue:10 ispartof: location:United States status: published

Hepatitis C virus (HCV; genus Hepacivirus) represents a major public health problem, infecting about three per cent of the human population. Because no animal reservoir carrying closely related hepaciviruses has been identified, the zoonotic origins of HCV still remain unresolved. Motivated by recent findings of divergent hepaciviruses in rodents and a plausible African origin of HCV genotypes, we have screened a large collection of small mammals samples from seven sub-Saharan African countries. Out of 4,303 samples screened, eighty were found positive for the presence of hepaciviruses in twenty-nine different host species. We, here, report fifty-six novel genomes that considerably increase the diversity of three divergent rodent hepacivirus lineages. Furthermore, we provide strong evidence for hepacivirus co-infections in rodents, which were exclusively found in four sampled species of brush-furred mice. We also detect evidence of recombination within specific host lineages. Our study expands the available hepacivirus genomic data and contributes insights into the relatively deep evolutionary history of these pathogens in rodents. Overall, our results emphasize the importance of rodents as a potential hepacivirus reservoir and as models for investigating HCV infection dynamics. ispartof: VIRUS EVOLUTION vol:7 issue:1 ispartof: location:England status: published

Hepatitis C virus (HCV; genus Hepacivirus) represents a major public health problem, infecting about 3 % of the human population (± 185,000,000 people). Because no plausible animal reservoir carrying closely related hepaciviruses has been identified, the zoonotic origins of HCV still remain elusive. Motivated by recent findings of divergent hepaciviruses in rodents and a plausible African origin of HCV genotypes, we have screened a comprehensive collection of small mammals samples from seven sub-Saharan African countries. Out of 4,303 samples screened, 80 were found positive for the presence of hepaciviruses in 29 different host species. We here report 56 novel genomes that considerably increase the diversity of three divergent rodent hepacivirus lineages, which previously were almost exclusively represented by New World and European hepaciviruses. Further-more, we provide undisputable evidence for hepacivirus co-infections in rodents, which remarkably, we exclusively but repeatedly found in four sampled species of brush-furred mice. We also point at hepacivirus co-infections indirectly in different animal hosts by demonstrating evidence for recombination within specific host lineages. Our study considerably expands the available hepacivirus genomic data and elucidates the relatively deep evolutionary history that these pathogens have in rodents compared to other mammalian hosts. Overall, our results emphasize the importance of rodents as a potential hepacivirus reservoir and as models for investigating HCV infection dynamics.

After spinal cord injury (SCI), the disruption of blood-spinal cord barrier by activation of the endothelin (ET) system is a critical event leading to leukocyte infiltration, inflammatory response and oxidative stress, contributing to neurological disability. In the present study, we showed that blockade of ET receptor A (ETAR) and/or ET receptor B (ETBR) prevented early inflammatory responses directly via the inhibition of neutrophil and monocyte diapedesis and inflammatory mediator production following traumatic SCI in mice. Long-term neurological improvement, based on a series of tests of locomotor performance, occurred only in the spinal cord‑injured mice following blockade of ETAR and ETBR. We also examined the post‑traumatic changes of the micro-environment within the injured spinal cord of mice following blockade of ET receptors. Oxidative stress reflects an imbalance between malondialdehyde and superoxide dismutase in spinal cord‑injured mice treated with vehicle, whereas blockade of ETAR and ETBR reversed the oxidation state imbalance. In addition, hemeoxygenase-1, a protective protease involved in early SCI, was increased in spinal cord‑injured mice following the blockade of ETAR and ETBR, or only ETBR. Matrix metalloproteinase-9, a tissue-destructive protease involved in early damage, was decreased in the injured spinal cord of mice following blockade of ETAR, ETBR or a combination thereof. The findings of the present study therefore suggested an association between ETAR and ETBR in regulating early pathogenesis of SCI and determining the outcomes of long‑term neurological recovery.

Increasing evidence indicates that diabetes-mediated renal interstitial fibrosis through extracellular matrix (ECM) protein accumulation is an important event in the development of diabetic kidney disease (DKD), however, the underlying mechanism remains unclear. In the current study, it was observed that high levels of glucose (HG) time‑ and dose-dependently increased the production of the ECM protein, fibronectin (FN), in primary rat mesangial cells. Inhibition of the Rho pathway blocked HG‑induced FN upregulation. HG‑induced RhoA activation was prevented by inhibiting caveolae with filipin III or caveolin‑1 siRNA and rescued by exogenous caveolin‑1. HG also increased caveolin-1/Src association and activated Src kinase, whereas the inhibition of Src blocked RhoA activation and FN upregulation. Src-mediated phosphorylation of caveolin‑1 on Y14 has also been implicated in signaling responses. Overexpression of the nonphosphorylatable caveolin‑1 Y14A mutant prevented the HG‑induced RhoA activation and FN upregulation. In conclusion, HG‑induced FN upregulation requires caveolae and caveolin‑1 to interact with RhoA and Src kinases. Interference with Src/caveolin-1/RhoA signaling may provide novel mechanistic targets for the treatment of DKD.

The efficacy of pulsed ultraviolet light (PUV) and high hydrostatic pressure (HHP) on the IgE binding to the almond extracts was studied using sodium dodecyl sulfate polyacrylamide-gel electrophoresis, Western blot, and enzyme-linked immunosorbent assay (ELISA) probed with human plasma containing IgE antibodies to almond allergens and a polyclonal antibody against almond major protein. Crude almond protein extracts were treated with PUV (3 pulses/s, 10 cm from lamp) for 0.5, 1, 2, 3, 4, 6, 7, and 10 min. In comparison, boiling treatments were also carried out. The HHP treatments were conducted at 600 MPa for 5, 15, and 30 min at three temperatures of 4 °C, 21 °C, and 70 °C. Western blots and indirect ELISA demonstrated a reduction in the levels of allergens and IgE binding in PUV-treated extracts at 7 min, which was found to be the optimal time for PUV exposure. Boiling was not as effective as PUV in reducing the overall IgE-binding of the almond extracts. Unlike PUV, HHP did not affect the allergen levels and IgE binding under the conditions tested.

Germinal center lymphoma is a heterogeneous human lymphoma entity. Here we report that constitutive activity of SHP2 (PTPN11) and its downstream kinase ERK is essential for the viability of germinal center lymphoma cells and disease progression. Mechanistically, SHP2/ERK inhibition impedes c-Myc transcriptional activity, which results in the repression of proliferative phenotype signatures of germinal center lymphoma. Furthermore, SHP2/ERK signaling is required to maintain the CD19/c-Myc loop, which preferentially promotes survival of a distinct subtype of germinal center lymphoma cells carrying the MYC/IGH translocation. These findings demonstrate a critical function for SHP2/ERK signaling upstream of c-Myc in germinal center lymphoma cells and provide a rationale for targeting SHP2 in the therapy of germinal center lymphoma.

Our aim is to elucidate the effects of osteoproteogerin (OPG) on cartilage destruction in rats as a model of collagen-induced arthritis (CIA). To establish the CIA model, Sprague Dawley rats were injected with bovine type II collagen solution subcutaneously via the tails. Adenovirus-mediated OPG (Ad-OPG) was then injected intra-articularly either at the beginning of CIA (early OPG treatment) or one week after CIA establishment (late OPG treatment); vehicle or Ad-green fluorescent protein were injected as controls. The rats were killed 4 weeks after treatment. Ankle-joint sections were obtained for histology. Serum samples were collected for enzyme-linked immunosorbent assay. Safranin O staining showed that proteoglycan loss was inhibited in the early and late Ad-OPG groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining revealed that both early and late Ad-OPG treatments significantly prevented chondrocyte apoptosis in CIA rats. Furthermore, disintegrin and metalloproteinase with thrombospondin motif−5 expression decreased remarkably in the early and late OPG treatment groups. However, the cartilage destruction score, cartilage oligomeric matrix protein level and caspase-3 expression were only decreased in the early Ad-OPG treatment group. Additionally, ankle-joint swelling and the interleukin-1β expression level in CIA rats were not notably altered by Ad-OPG treatment. Taken together, our results suggest that early Ad-OPG treatment has potent protective effects against cartilage destruction during rheumatoid arthritis progression, mainly by reducing proteoglycan loss and chondrocyte apoptosis.

In this study, the complete mitochondrial genome of Inez’s red-backed vole Caryomys inez was sequenced and analyzed as the first species in genus Caryomys. The complete mitochondrial genome of C. inez is 16,354 bp in length and shows a typical vertebrate pattern with 13 PCGs, 22 tRNAs, 2 rRNAs and 2 non-coding regions. To gain a clear phylogenetic position of C. inez, a ML phylogenetic tree was constructed based on 12 PCGs on H-strand from 23 rodent species except for ND6 gene which is on L-strand. As a result, C. inez is clustered with genera Eothenomys and Myodes, showing their close phylogenetic relationships. The present study may facilitate further investigation of the taxonomic studies and phylogenetic analyses of the genus Caryomys.

Following spinal cord trauma, mitochondrial dysfunction associated with increased oxidative stress is a critical event leading to leukocyte inflammatory responses, neuronal cell death and demyelination, contributing to permanent locomotor and neurological disability. The present study demonstrated that the mitochondrial enhancer N-acetylcysteine (NAC) may restore redox balance via enhancement of mitochondrial respiratory activity following traumatic spinal cord injury (SCI). In addition, NAC ameliorates oxidative stress-induced neuronal loss, demyelination, leukocyte infiltration and inflammatory mediator expression and improves long-term locomotor function. Furthermore, neuronal survival and neurological recovery are significantly correlated with increased mitochondrial bioenergetics in SCI following treatment with NAC. Therefore, NAC may represent a potential therapeutic agent for preserving mitochondrial dynamics and integrity following traumatic SCI.

In order to select proper revetment plant to apply in the rock slope protection, we used Cynodon dactylon as control to investigate the effect of cold stress on two wild revetment plants (Pogonatherum paniceum and Eriophorum comosum) in current study. With the dropping of temperature (0°C, -5°C, -10°C, -15°C, -20°C), the content of soluble sugar, soluble protein, and free proline in these three plants rose first, and then decreased. Meanwhile, the chlorophyll content declined, but the electrolyte osmotic rate increased. Under the five different temperatures, the content of soluble sugar and soluble protein were highest (P < 0.05) in E. comosum, the lowest (P < 0.05) in C. dactylon, and P. paniceum in the middle. The free proline contents in E. comosum was similar to P. paniceum at -15°C, and -20°C, but both of them were significant greater than that in C. dactylon (P < 0.05). Additionally, C. dactylon had the highest electrolyte osmotic rate, and E. comosum was the lowest. Meanwhile, the semilethal low temperature was the lowest (-13.6°C) in E. comosum as compared to C. dactlylon (-6.86°C) and P. paniceum (-9.37°C). Both the contents of Chlorophyll a and Chlorophyll b were highest in P. paniceum, lowest in C. dactylon, and those in E. comosum were medium. These suggested that E. comosum may have the strongest cold resistance capacity, and that in C. dactylon was the weakest. The results showed that E. comosum was the best option to the rock slope protection due to their strongest anti-cold ability among these three grasses.

The essence of grass growth is a complex system that is driven by light energy. The accumulation of 90% of the dry matter comes from the production of photosynthesis. In this study, we investigated the effect of decomposing leaf litter of Eucalyptus grandis on the growth and photosynthetic characteristics of Lolium perenne by pot experiment. Four treatments with different amounts of leaf litter were designed, including A1 (30 g/pot), A2 (60 g/pot), A3 (90 g/pot) and control (0 g/pot; CK), and the blank experiment groups with distilled fallen leaves were set as the above. The growth indices (including shoot biomass, root biomass and leaf area) were measured, and the photosynthetic characteristics were tested during 9:00-11:00 am on a sunny day. The test results showed that increasing amounts of E grandis leaf litter significantly inhibited the accumulation of shoot and root biomass, growth of leaf area, synthesis of photosynthetic pigments (chlorophyll a, chlorophyll b and cartenoids), photosynthetic rate and gas exchange parameters (Gs, Ci and Tr) of L. perenne seedlings (P A1 > A2 > A3 (P < 0.05). The blank experimental showed that soil chemical and physical properties have not been changed by leaf litter decomposition. This demonstrated that the allelochemicals from E. grandis leaf litter decomposition can negatively affect the photosynthetic capacity and decrease the accumulation of biomass, and eventually inhibit the growth of L. perenne.