New sesquiterpenoids from the flowers of pentanema britannicum (L.) D.Gut.Larr.

Five new sesquiterpenoids, (4S, 5S, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (1), (4S, 5 R, 6S, 7S, 8 R)-5,6-dihydroxy-1-acetoxy-10(14)-en-britannilactone (2), 6-O-propionyl-britannilactone (3), 1ß-hydroxy-3α-acetoxyeudesma-11(13)-en-12,8ß-olide (4) and 1ß,5ß-dihydroxyeudesma-11(13)-en-12,8ß-olide (5), along with twelve known ones were isolated from the flowers of Pentanema britannicum (L.) D.Gut.Larr. Among them, compounds 1 and 2 were stereoisomers which belong to 1,10-seco-eudesmane sesquiterpenoid with rare double bond between C-10 and C-14. The structures of the isolated compounds were elucidated by various spectroscopic methods, including 1D and 2D NMR experiments.

The accumulation of modular serine protease mediated by a novel circRNA sponging miRNA increases Aedes aegypti immunity to fungus.

BACKGROUND: Mosquitoes transmit many infectious diseases that affect human health. The fungus Beauveria bassiana is a biological pesticide that is pathogenic to mosquitoes but harmless to the environment. RESULTS: We found a microRNA (miRNA) that can modulate the antifungal immunity of Aedes aegypti by inhibiting its cognate serine protease. Fungal infection can induce the expression of modular serine protease (ModSP), and ModSP knockdown mosquitoes were more sensitive to B. bassiana infection. The novel miRNA-novel-53 is linked to antifungal immune response and was greatly diminished in infected mosquitoes. The miRNA-novel-53 could bind to the coding sequences of ModSP and impede its expression. Double fluorescence in situ hybridization (FISH) showed that this inhibition occurred in the cytoplasm. The amount of miRNA-novel-53 increased after miRNA agomir injection. This resulted in a significant decrease in ModSP transcript and a significant increase in mortality after fungal infection. An opposite effect was produced after antagomir injection. The miRNA-novel-53 was also knocked out using CRISPR-Cas9, which increased mosquito resistance to the fungus B. bassiana. Moreover, mosquito novel-circ-930 can affect ModSP mRNA by interacting with miRNA-novel-53 during transfection with siRNA or overexpression plasmid. CONCLUSIONS: Novel-circ-930 affects the expression level of ModSP by a novel-circ-930/miRNA-novel-53/ModSP mechanism to modulate antifungal immunity, revealing new information on innate immunity in insects.

Peptidome analysis reveals critical roles for peptides in a rat model of intestinal ischemia/reperfusion injury.

Intestinal ischemia/reperfusion injury (IIRI) has the potential to be life threatening and is associated with significant morbidity and serious damage to distant sites in the body on account of disruption of the intestinal mucosal barrier. In the present study, we have explored this line of research by comparing and identifying peptides that originated from the intestinal segments of IIRI model rats by using liquid chromatography-mass spectrometry (LC-MS). We also analyzed the basic characteristics, cleavage patterns, and functional domains of differentially expressed peptides (DEPs) between the IIRI model rats and control (sham-operated) rats and identified bioactive peptides that are potentially associated with ischemia reperfusion injury. We also performed bioinformatics analyses in order to identify the biological roles of the DEPs based on their precursor proteins. Enrichment analysis demonstrated the role of several DEPs in impairment of the intestinal mucosal barrier caused by IIRI. Based on the results of comprehensive ingenuity pathway analysis, we identified the DEPs that were significantly correlated with IIRI. We identified a candidate precursor protein (Actg2) and seven of its peptides, and we found that Actg2-6 had a more significant difference in its expression, a longer half-life, and better lipophilicity, hydrophobicity, and stability than the other candidate Actg2 peptides examined. Furthermore, we observed that Actg2-6 might play critical roles in the protection of the intestinal mucosal barrier during IIRI. In summary, our study provides a better understanding of the peptidomics profile of IIRI, and the results indicate that Actg2-6 could be a useful target in the treatment of IIRI.

OTU7B Modulates the Mosquito Immune Response to Beauveria bassiana Infection via Deubiquitination of the Toll Adaptor TRAF4.

The Aedes aegypti mosquito transmits devastating flaviviruses, such as Zika, dengue, and yellow fever viruses. For more effective control of the vector, the pathogenicity of Beauveria bassiana, a fungus commonly used for biological control of pest insects, may be enhanced based on in-depth knowledge of molecular interactions between the pathogen and its host. Here, we identified a mechanism employed by B. bassiana, which efficiently blocks the Ae. aegypti antifungal immune response by a protease that contains an ovarian tumor (OTU) domain. RNA-sequencing analysis showed that the depletion of OTU7B significantly upregulates the mRNA level of immunity-related genes after a challenge of the fungus. CRISPR-Cas9 knockout of OTU7B conferred a higher resistance of mosquitoes to the fungus B. bassiana. OTU7B suppressed activation of the immune response by preventing nuclear translocation of the NF-κB transcription factor Rel1, a mosquito orthologue of Drosophila Dorsal. Further studies identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as an interacting protein of OTU7B. TRAF4-deficient mosquitoes were more sensitive to fungal infection, indicating TRAF4 to be the adaptor protein that activates the Toll pathway. TRAF4 is K63-link polyubiquitinated at K338 residue upon immune challenge. However, OTU7B inhibited the immune signaling by enzymatically removing the polyubiquitin chains of mosquito TRAF4. Thus, this study has uncovered a novel mechanism of fungal action against the host innate immunity, providing a platform for further improvement of fungal pathogen effectiveness. IMPORTANCE Insects use innate immunity to defend against microbial infection. The Toll pathway is a major immune signaling pathway that is associated with the antifungal immune response in mosquitoes. Our study identified a fungal-induced deubiquitinase, OTU7B, which, when knocked out, promotes the translocation of the NF-κB factor Rel1 into the nucleus and confers enhanced resistance to fungal infection. We further found the counterpart of OTU7B, TRAF4, which is a component of the Toll pathway and acts as an adaptor protein. OTU7B enzymatically removes K63-linked polyubiquitin chains from TRAF4. The immune response is suppressed, and mosquitoes become much more sensitive to the Beauveria bassiana infection. Our findings reveal a novel mechanism of fungal action against the host innate immunity.

Aedes aegypti CLIPB9 activates prophenoloxidase-3 in the presence of CLIPA14 after fungal infection.

Melanization is an integral part of the insect defense system and is often induced by pathogen invasion. Phenoloxidases (POs) are critical enzymes that catalyze melanin formation. PO3 is associated with the antifungal response of the mosquito, Aedes aegypti, but the molecular mechanism of the prophenoloxidase-3 (PPO3) activation is unclear. Here we report that PPO3 cleavage activation is mediated by a clip-domain serine protease, CLIPB9. We purified recombinant CLIPB9 and found that it cleaved PPO3 and increased PO activity in the hemolymph. We then identified CLIPA14 (a serine protease homolog) by co-immunoprecipitation using anti-CLIPB9 antibody. After being cleaved by CLIPB9, Ae. aegypti CLIPA14 acted as a cofactor for PPO3 activation. In addition, dsRNA co-silencing of CLIPB9 and CLIPA14 genes reduced melanization after infection with the entomopathogen, Beauveria bassiana, making the adult mosquitoes more sensitive to fungal infection. These results illustrate the roles of CLIPB9 and CLIPA14 in the PPO activation pathway and revealed the complexity of the upstream serine protease network controlling melanization.

Sesquiterpene lactone dimers from the fruit of Carpesium abrotanoides L.

Seven undescribed sesquiterpene lactone dimers (SLDs) (carpeabrodilactones A-G), one known SLD, and six known sesquiterpenes were isolated from the fruit of Carpesium abrotanoides L. Carpeabrodilactone A was a dimeric carabrane featuring a rare C-13-C-13' linkage. Carpeabrodilactones B and C are the first two SLDs to be described possessing a carabranolide unit and a guaianolide unit connected by an O-ether linkage. The structures of the SLDs were assigned based on HRESIMS, NMR analysis, 13C NMR calculation, ECD calculation, and modified Mosher's method. Four SLDs showed potent cytotoxicity against K562 and/or A549 cells, with IC50 values below 10 µM, but none inhibited protein tyrosine phosphatases at 40 µM, including PTP1B, SHP1, CD45, and TCPTP.

Second Language Proficiency Modulates the Dependency of Bilingual Language Control on Domain-General Cognitive Control.

The relationship between bilingual language control and domain-general cognitive control has been a hot topic in the research field of bilingualism. Previous studies mostly examined the correlation between performances of bilinguals in language control tasks and that in domain-general cognitive control tasks and came to the conclusions that they overlap, partially overlap, or are qualitatively different. These contradictory conclusions are possibly due to the neglect of the moderating effect of second language (L2) proficiency, that is, the relationship between bilingual language control and domain-general cognitive control might vary with the L2 proficiency of bilinguals. To examine this hypothesis, we recruited 36 unbalanced Chinese-English bilinguals to perform the Simon task (to assess domain-general cognitive control), Oxford Placement Test (to assess L2 proficiency), and picture naming tasks in single-and dual-language contexts (to evoke local and global language control). We find that Simon scores positively predicted switching costs in bilinguals with low L2 proficiency, but not in bilinguals with high L2 proficiency. Furthermore, Simon scores positively predicted mixing costs in bilinguals with high L2 proficiency, but not in bilinguals with low L2 proficiency. These results verify the moderating effect of L2 proficiency on the relationship between bilingual language control and domain-general cognitive control, that is, bilinguals with more proficient L2 rely on domain-general cognitive control less for local language control and more for global language control. This may imply a shift from local to global for the dependency of bilingual language control on domain-general cognitive control during the L2 development of bilinguals.

Massive cranium from Harbin in northeastern China establishes a new Middle Pleistocene human lineage.

It has recently become clear that several human lineages coexisted with Homo sapiens during the late Middle and Late Pleistocene. Here, we report an archaic human fossil that throws new light on debates concerning the diversification of the Homo genus and the origin of H. sapiens. The fossil was recovered in Harbin city in northeastern China, with a minimum uranium-series age of 146 ka. This cranium is one of the best preserved Middle Pleistocene human fossils. Its massive size, with a large cranial capacity (∼1,420 mL) falling in the range of modern humans, is combined with a mosaic of primitive and derived characters. It differs from all the other named Homo species by presenting a combination of features, such as long and low cranial vault, a wide and low face, large and almost square orbits, gently curved but massively developed supraorbital torus, flat and low cheekbones with a shallow canine fossa, and a shallow palate with thick alveolar bone supporting very large molars. The excellent preservation of the Harbin cranium advances our understanding of several less-complete late Middle Pleistocene fossils from China, which have been interpreted as local evolutionary intermediates between the earlier species Homo erectus and later H. sapiens. Phylogenetic analyses based on parsimony criteria and Bayesian tip-dating suggest that the Harbin cranium and some other Middle Pleistocene human fossils from China, such as those from Dali and Xiahe, form a third East Asian lineage, which is a part of the sister group of the H. sapiens lineage. Our analyses of such morphologically distinctive archaic human lineages from Asia, Europe, and Africa suggest that the diversification of the Homo genus may have had a much deeper timescale than previously presumed. Sympatric isolation of small populations combined with stochastic long-distance dispersals is the best fitting biogeographical model for interpreting the evolution of the Homo genus.

Geochemical provenancing and direct dating of the Harbin archaic human cranium.

As one of the most complete archaic human fossils, the Harbin cranium provides critical evidence for studying the diversification of the Homo genus and the origin of Homo sapiens. However, the unsystematic recovery of this cranium and a long and confused history since the discovery impede its accurate dating. Here, we carried out a series of geochemical analyses, including non-destructive X-ray fluorescence (XRF), rare earth elements (REE), and the Sr isotopes, to test the reported provenance of the Harbin cranium and get better stratigraphic constraints. The results show that the Harbin cranium has very similar XRF element distribution patterns, REE concentration patterns, and Sr isotopic compositions to those of the Middle Pleistocene-Holocene mammalian and human fossils recently recovered from the Harbin area. The sediments adhered in the nasal cavity of the Harbin cranium have a 87Sr/86Sr ratio of 0.711898, falling in the variation range measured in a core drilled near the Dongjiang Bridge, where the cranium was discovered during its reconstruction. The regional stratigraphic correlations indicate that the Harbin cranium was probably from the upper part of the Upper Huangshan Formation of the Harbin area, which has an optically stimulated luminescence dating constraint between 138 and 309 ka. U-series disequilibrium dating (n = 10) directly on the cranium suggests that the cranium is older than 146 ka. The multiple lines of evidence from our experiments consistently support the theory that the Harbin cranium is from the late Middle Pleistocene of the Harbin area. Our study also shows that geochemical approaches can provide reliable evidence for locating and dating unsystematically recovered human fossils, and potentially can be applied to other human fossils without clear provenance and stratigraphy records.

New protein tyrosine phosphatase inhibitors from fungus Aspergillus gorakhpurensis F07ZB1707.

Twelve new compounds, aspergorakhins A-L (1-12) coupled with one known xanthone leptosphaerin D (13), were isolated from the extract of soil-derived fungus Aspergillus gorakhpurensis F07ZB1707. Their structures were elucidated by spectroscopic data analysis including UV, IR, NMR, and HRESIMS. The absolute configurations of 5 and 8-11 were identified using ECD and OR calculations. All compounds were tested by enzyme inhibitory activity assay in vitro. Aspergorakhin A (1) showed selective activities against PTP1B and SHP1 over TCPTP with IC50 values 0.57, 1.19, and 22.97 µM, respectively. Compounds 1 and 2 exhibited modest cytotoxicity against tumor cell lines A549, HeLa, Bel-7402, and SMMC-7721 with IC50 values in the range of 6.75-83.4 µM.

Biological and Psychological Perspectives of Resilience: Is It Possible to Improve Stress Resistance?

The term "resilience" refers to the ability to adapt successfully to stress, trauma and adversity, enabling individuals to avoid stress-induced mental disorders such as depression, posttraumatic stress disorder (PTSD) and anxiety. Here, we review evidence from both animal models and humans that is increasingly revealing the neurophysiological and neuropsychological mechanisms that underlie stress susceptibility, as well as active mechanisms underlying the resilience phenotype. Ultimately, this growing understanding of the neurobiological mechanisms of resilience should result in the development of novel interventions that specifically target neural circuitry and brain areas that enhance resilience and lead to more effective treatments for stress-induced disorders. Stress resilience can be improved, but the outcomes and effects depend on the type of intervention and the species treated.

Association between different combination of measures for obesity and new-onset gallstone disease.

BACKGROUND: Body mass index(BMI) is a calculation index of general obesity. Waist circumference(WC) is a measure of body-fat distribution and always used to estimate abdominal obesity. An important trait of general obesity and abdominal obesity is their propensity to coexist. Using one single measure of obesity could not estimate persons at risk for GSD precisely. OBJECTIVES: This study aimed to compare the predictive values of various combination of measures for obesity(BMI, WC, waist to hip ratio) for new-onset GSD. METHODS: We prospectively studied the predictive values of various combination of measures for obesity for new-onset GSD in a cohort of 88,947 participants who were free of prior gallstone disease, demographic characteristics and biochemical parameters were recorded. RESULTS: 4,329 participants were identified to have GSD among 88,947 participants during 713 345 person-years of follow-up. Higher BMI, WC and waist to hip ratio (WHtR) were significantly associated with higher risks of GSD in both genders even after adjustment for potential confounders. In males, the hazard ratio for the highest versus lowest BMI, WC, WHtR were 1.63(1.47~1.79), 1.53(1.40~1.68), 1.44(1.31~1.58), respectively. In females, the hazard ratio for the highest versus lowest BMI, WC, WHtR were 2.11(1.79~2.49), 1.85(1.55~2.22), 1.84(1.55~2.19), respectively. In male group, the combination of BMI+WC improved the predictive ability of the model more clearly than other combinations after adding them to the multivariate model in turn, while for females the best predictive combination was BMI+WHtR. CONCLUSIONS: Elevated BMI, WC and WHtR were independent risk factors for new-onset GSD in both sex groups after additional adjustment was made for potential confounders. In males, the combination of BMI+WC seemed to be the most predictable model to evaluate the effect of obesity on new-onset GSD, while the best combination in females was BMI+WHtR.