Modeling suggests that virion production cycles within individual cells is key to understanding acute hepatitis B virus infection kinetics.

Hepatitis B virus (HBV) infection kinetics in immunodeficient mice reconstituted with humanized livers from inoculation to steady state is highly dynamic despite the absence of an adaptive immune response. To recapitulate the multiphasic viral kinetic patterns, we developed an agent-based model that includes intracellular virion production cycles reflecting the cyclic nature of each individual virus lifecycle. The model fits the data well predicting an increase in production cycles initially starting with a long production cycle of 1 virion per 20 hours that gradually reaches 1 virion per hour after approximately 3-4 days before virion production increases dramatically to reach to a steady state rate of 4 virions per hour per cell. Together, modeling suggests that it is the cyclic nature of the virus lifecycle combined with an initial slow but increasing rate of HBV production from each cell that plays a role in generating the observed multiphasic HBV kinetic patterns in humanized mice.

Trichoderols B-G, Six New Lipids from the Marine Algicolous Fungus Trichoderma sp. Z43.

Six new lipids, trichoderols B-G (1-6), along with a known one, triharzianin B (7), were isolated from the culture of Trichoderma sp. Z43 obtained from the surface of the marine brown alga Dictyopteris divaricata. Their structures and relative configurations were identified by interpretation of 1D/2D NMR and MS data. Compounds 1-7 were assayed for inhibiting the growth of three phytopathogenic fungi (Fusarium graminearum, Gaeumannomyces graminis, and Glomerella cingulata), four marine phytoplankton species (Amphidinium carterae, Heterocapsa circularisquama, Heterosigma akashiwo, and Prorocentrum donghaiense), and one marine zooplankton (Artemia salina). Compounds 1, 4, and 7 exhibited weak antifungal activities against three phytopathogenic fungi tested with MIC ≥ 64 µg/mL. All compounds displayed moderate antimicroalgal activity with IC50 ≥ 15 µg/mL and low toxicity to the brine shrimp Artemia salina.

A New Harziane Diterpene, Harziaketal A, and a New Sterol, Trichosterol A, from the Marine-Alga-Epiphytic Trichoderma sp. Z43.

One new diterpene, harziaketal A (1), and one new highly degraded sterol, trichosterol A (2), along with three known compounds, including one diterpene, harzianone (3), and two steroids, (22E,24R)-5α,6α-epoxy-ergosta-8(14),22-dien-3ß,7α-diol (4) and isoergokonin B (5), were isolated from the culture of the marine-alga-epiphytic fungus Trichoderma sp. Z43 by silica gel column chromatography (CC), Sephadex LH-20 CC, and preparative thin-layer chromatography (TLC). Their structures and relative configurations were assigned by nuclear magnetic resonance (NMR) and high resolution electrospray ionisation mass spectrometry (HR-ESI-MS) data, and the absolute configuration of 1 was established by X-ray diffraction. Compound 1 features a hemiketal unit situated at the four-membered ring of harziane-type diterpenes for the first time, while 2 represents the rare occurrence of sterols with rings A and B being degraded. Compounds 1 and 2 displayed weak inhibition against the tested phytoplankton (Amphidinium carterae, Heterocapsa circularisquama, Heterosigma akashiwo, and Prorocentrum donghaiense) with half maximal inhibitory concentration (IC50 ) ranging from 14 to 53 µg/mL.

Lipids and Terpenoids from the Deep-Sea Fungus Trichoderma lixii R22 and Their Antagonism against Two Wheat Pathogens.

Five new lipids, tricholixins A-E (1-5), and two known terpenoids, brasilane A (6) and harzianone A (7), were discovered from a deep-sea strain (R22) of the fungus Trichoderma lixii isolated from the cold seep sediments of the South China Sea. Their structures and relative configurations were identified by meticulous analysis of MS and IR as well as NMR data. The absolute configuration of 5 was ascertained by dimolybdenum-induced ECD data in particular. Compounds 1 and 2 represent the only two new butenolides from marine-derived Trichoderma, and they further add to the structural diversity of these molecules. Although 6 has been reported from a basidiomycete previously, it is the first brasilane aminoglycoside of Trichoderma origin. During the assay against wheat-pathogenic fungi, both 1 and 2 inhibited Fusarium graminearum with an MIC value of 25.0 µg/mL, and 6 suppressed Gaeumannomyces graminis with an MIC value of 12.5 µg/mL. Moreover, the three isolates also showed low toxicity to the brine shrimp Artemia salina.

The involvement of extracellular ATP in regulating the stunted growth of Arabidopsis plants by repeated wounding.

BACKGROUND: Extracellular ATP (exATP) has been shown to act as a signal molecule for regulating growth, development, and responses of plants to the external environment. RESULTS: In this study, we investigated the possible involvement of exATP in regulating the stunted growth caused by repeated wounding. The present work showed that the repeated wounding caused the decreases in leaf area, fresh weight, dry weight, and root length of Arabidopsis seedlings, while the exATP level was enhanced by the repeated wounding. Repeated application of exogenous ATP had similar effects on the plant growth, as the repeated wounding. Through the comparison of p2k1-3 mutant (in which T-DNA disrupted the gene coding P2K1, as exATP receptor) and wide type (WT) plants, it was found that the mutation in P2K1 decreased the sensitivity of plant growth to the repeated wounding and exogenous ATP application. Further works showed that the ibuprofen (IBU, an inhibitor of jasmonate biosynthesis) partially rescued the wound-induced growth degradation. In comparison, the P2K1 mutation partly rescued the wound-induced growth degradation, whereas this mutation failed to do so in the wounded seedlings treated with IBU, indicating that the role of exATP in regulating the growth degradation by repeated wounding could be linked to the JA signaling pathway. CONCLUSIONS: In conclusion, these results indicate that exATP could be a regulator for the stunted growth of plants by repeated wounding.

Extracellular ATP is involved in regulating Arabidopsis seed germination.

MAIN CONCLUSION: Extracellular ATP level induced a transient increase during germination of Arabidopsis seeds, and extracellular ATP could negatively regulate the seed germination by its receptor, DORN1. Extracellular ATP (exATP) acts as a signal molecule for regulating growth, development, and responses of plants to external environments. In this study, we investigated the possible involvement of exATP in regulating the seed germination of Arabidopsis thaliana. Treatments of Arabidopsis seeds with exogenous ATP delayed seed germination, suggesting that exATP could be a repressor for seed germination. During the germination of Arabidopsis seeds, the exATP level of the seeds presented a transient increase. When exogenous application of the glucose-hexokinase system effectively decreased the exATP level of the Arabidopsis seeds during germination, the percentage of germination was significantly enhanced, while the products of ATP hydrolysis had no effects on the germination. Further studies showed that the seeds of dorn 1-3 mutant plants (mutation in exATP receptor) showed a higher germination percentage, compared to the seeds of wide type (WT) plants. In addition, the dorn 1-3 mutant seeds were less sensitive to the delay-effect of exogenous ATP on seed germination than the WT seeds. The dorn 1-3 mutant seeds presented a higher GA (gibberellin) content, lower ABA (abscisic acid) content, and lower ratio of ABA/GA contents before the imbibition, compared to the WT seeds. The regulation of seed germination by exATP was dependent on the external temperature. These data suggest that exATP is involved in regulating Arabidopsis seed germination.

Sphinganine is associated with 24-h MAP in the non-sleepy with OSA.

INTRODUCTION: Excessive daytime sleepiness is a debilitating symptom of obstructive sleep apnea (OSA) linked to cardiovascular disease, and metabolomic mechanisms underlying this relationship remain unknown. We examine whether metabolites from inflammatory and oxidative stress-related pathways that were identified in our prior work could be involved in connecting the two phenomena. METHODS: This study included 57 sleepy (Epworth Sleepiness Scale (ESS) ≥ 10) and 37 non-sleepy (ESS < 10) participants newly diagnosed and untreated for OSA that completed an overnight in-lab or at home sleep study who were recruited from the Emory Mechanisms of Sleepiness Symptoms Study (EMOSS). Differences in fasting blood samples of metabolites were explored in participants with sleepiness versus those without and multiple linear regression models were utilized to examine the association between metabolites and mean arterial pressure (MAP). RESULTS: The 24-h MAP was higher in sleepy 92.8 mmHg (8.4) as compared to non-sleepy 88.8 mmHg (8.1) individuals (P = 0.03). Although targeted metabolites were not significantly associated with MAP, when we stratified by sleepiness group, we found that sphinganine is significantly associated with MAP (Estimate = 8.7, SE = 3.7, P = 0.045) in non-sleepy patients when controlling for age, BMI, smoking status, and apnea-hypopnea index (AHI). CONCLUSION: This is the first study to evaluate the relationship of inflammation and oxidative stress related metabolites in sleepy versus non-sleepy participants with newly diagnosed OSA and their association with 24-h MAP. Our study suggests that Sphinganine is associated with 24 hour MAP in the non-sleepy participants with OSA.

Identification of nonmonotonic concentration-responses in Tox21 high-throughput screening estrogen receptor assays.

Environmental endocrine-disrupting chemicals (EDCs) interfere with the metabolism and actions of endogenous hormones. It has been well documented in numerous in vivo and in vitro studies that EDCs can exhibit nonmonotonic dose response (NMDR) behaviors. Not conforming to the conventional linear or linear-no-threshold response paradigm, these NMDR relationships pose practical challenges to the risk assessment of EDCs. In the meantime, the endocrine signaling pathways and biological mechanisms underpinning NMDR remain incompletely understood. The US Tox21 program has conducted in vitro cell-based high-throughput screening assays for estrogen receptors (ER), androgen receptors, and other nuclear receptors, and screened the 10 K-compound library for potential endocrine activities. Using 15 concentrations across several orders of magnitude of concentration range and run in both agonist and antagonist modes, these Tox21 assay datasets contain valuable quantitative information that can be explored to evaluate the nonlinear effects of EDCs and may infer potential mechanisms. In this study we analyzed the concentration-response curves (CRCs) in all 8 Tox21 ERα and ERß assays by developing clustering and classification algorithms customized to the datasets to identify various shapes of CRCs. After excluding NMDR curves likely caused by cytotoxicity, luciferase inhibition, or autofluorescence, hundreds of compounds were identified to exhibit Bell or U-shaped CRCs. Bell-shaped CRCs are about 7 times more frequent than U-shaped ones in the Tox21 ER assays. Many compounds exhibit NMDR in at least one assay, and some EDCs well-known for their NMDRs in the literature were also identified, suggesting their nonmonotonic effects may originate at cellular levels involving transcriptional ER signaling. The developed computational methods for NMDR identification in ER assays can be adapted and applied to other high-throughput bioassays.

Hybrid computational modeling demonstrates the utility of simulating complex cellular networks in type 1 diabetes.

Persistent destruction of pancreatic ß-cells in type 1 diabetes (T1D) results from multifaceted pancreatic cellular interactions in various phase progressions. Owing to the inherent heterogeneity of coupled nonlinear systems, computational modeling based on T1D etiology help achieve a systematic understanding of biological processes and T1D health outcomes. The main challenge is to design such a reliable framework to analyze the highly orchestrated biology of T1D based on the knowledge of cellular networks and biological parameters. We constructed a novel hybrid in-silico computational model to unravel T1D onset, progression, and prevention in a non-obese-diabetic mouse model. The computational approach that integrates mathematical modeling, agent-based modeling, and advanced statistical methods allows for modeling key biological parameters and time-dependent spatial networks of cell behaviors. By integrating interactions between multiple cell types, model results captured the individual-specific dynamics of T1D progression and were validated against experimental data for the number of infiltrating CD8+T-cells. Our simulation results uncovered the correlation between five auto-destructive mechanisms identifying a combination of potential therapeutic strategies: the average lifespan of cytotoxic CD8+T-cells in islets; the initial number of apoptotic ß-cells; recruitment rate of dendritic-cells (DCs); binding sites on DCs for naïve CD8+T-cells; and time required for DCs movement. Results from therapy-directed simulations further suggest the efficacy of proposed therapeutic strategies depends upon the type and time of administering therapy interventions and the administered amount of therapeutic dose. Our findings show modeling immunogenicity that underlies autoimmune T1D and identifying autoantigens that serve as potential biomarkers are two pressing parameters to predict disease onset and progression.

Hepatitis B and Hepatitis D Viruses: A Comprehensive Update with an Immunological Focus.

Hepatitis B virus (HBV) and hepatitis delta virus (HDV) are highly prevalent viruses estimated to infect approximately 300 million people and 12-72 million people worldwide, respectively. HDV requires the HBV envelope to establish a successful infection. Concurrent infection with HBV and HDV can result in more severe disease outcomes than infection with HBV alone. These viruses can cause significant hepatic disease, including cirrhosis, fulminant hepatitis, and hepatocellular carcinoma, and represent a significant cause of global mortality. Therefore, a thorough understanding of these viruses and the immune response they generate is essential to enhance disease management. This review includes an overview of the HBV and HDV viruses, including life cycle, structure, natural course of infection, and histopathology. A discussion of the interplay between HDV RNA and HBV DNA during chronic infection is also included. It then discusses characteristics of the immune response with a focus on reactions to the antigenic hepatitis B surface antigen, including small, middle, and large surface antigens. This paper also reviews characteristics of the immune response to the hepatitis D antigen (including small and large antigens), the only protein expressed by hepatitis D. Lastly, we conclude with a discussion of recent therapeutic advances pertaining to these viruses.

Gender Differences in Mental Health of Bereaved Parents in an Only-Child Society: Evidence From China.

This study examined gender differences in mental health of bereaved parents related to the gender of deceased only child in China, an only-child society with traditional culture of son preference, using data drawn from the China Family Planning Survey on Vulnerable Households in 2017. The findings indicated that parents with deceased only child suffered from more negative mental health symptoms than nonbereaved parents. For only-child-death families, there were no statistically significant gender differences in mental health of parents, and the gender of the deceased only child was basically unrelated to maternal/paternal mental health. Due to the implementation of one-child policy in China, both sons and daughters are highly prized and equally relied on by aging parents owing to the irreplaceability of the only child, which might moderate the effects of traditional culture of son preference on bereaved parental mental health.

Post-processing of computed tomography perfusion in patients with acute cerebral ischemia: variability of inter-reader, inter-region of interest, inter-input model, and inter-software.

OBJECTIVE: To determine the reproducibility of quantitative computed tomography perfusion (CTP) parameters generated using different post-processing methods and identify the relative impact of subjective factors on the robustness of CTP parameters in acute ischemic stroke (AIS). MATERIALS AND METHODS: A total of 80 CTP datasets from patients with AIS or transient ischemic attack (TIA) were retrospectively post-processed by two observers using different regions of interest (ROI) types, input models, and software. The CTP parameters were derived for 10 parenchymal ROIs. The intra-class correlation coefficients (ICCs) were used to assess the reproducibility of the CTP parameters for various post-processing methods. The Spearman correlation test was used to detect potential relationships between software and input models. RESULTS: The ICCs with 95% confidence intervals (CIs) were 0.94 (0.93-0.96), 0.94 (0.92-0.96), 0.82 (0.79-0.86), and 0.87 (0.85-0.90) for inter-reader agreement by using elliptic ROI, irregular ROI, single-input model, and dual-input model, respectively. The ICCs with 95% CI were 0.98 (0.98-0.98), 0.46 (0.43-0.50), and 0.25 (0.20-0.30) for inter-ROI type, inter-input model, and inter-software agreement, respectively. CONCLUSIONS: Although the CTP parameters were stable when measured using different readers with different ROI types, they varied for different input models and software. The standardization of CTP post-processing is essential to reduce variability of CTP values. KEY POINTS: • The CTP parameters derived by different readers with different ROI types have agreements that range from good to excellent. • The CTP parameters derived from different input models and software programs have poor agreement but significant correlations.

Phenylhydrazone and Quinazoline Derivatives from the Cold-Seep-Derived Fungus Penicillium oxalicum.

Three new phenylhydrazones, penoxahydrazones A-C (compounds 1-3), and two new quinazolines, penoxazolones A (compound 4) and B (compound 5), with unique linkages were isolated from the fungus Penicillium oxalicum obtained from the deep sea cold seep. Their structures and relative configurations were assigned by analysis of 1D/2D NMR and mass spectroscopic data, and the absolute configurations of 1, 4, and 5 were established on the basis of X-ray crystallography or ECD calculations. Compound 1 represents the first natural phenylhydrazone-bearing steroid, while compounds 2 and 3 are rarely occurring phenylhydrazone tautomers. Compounds 4 and 5 are enantiomers that feature quinazoline and cinnamic acid units. Some isolates exhibited inhibition of several marine phytoplankton species and marine-derived bacteria.

[Regulation of extracellular ATP onchlorophyll content and fluorescence characteristics of Angelica sinensis seedlings under drought and low temperature stress].

As an important signal molecule, extracellular ATP(eATP) can regulate many physiological and biochemical responses to plant stress. In this study, the regulation of extracellular ATP(eATP) on chlorophyll content and chlorophyll fluorescence parameters of Angelica sinensis seedlings were studied under drought and low temperature stress. The results showed that all the chlorophyll content, the actual photochemical efficiency [Y(Ⅱ)], the electron transfer rate(ETR), the photochemical quenching coefficient(qP and qL) of A. sinensis leaves were significantly decreased under drought and low temperature stress, respectively. At the same time, non-photochemical quenching(NPQ and qN) were also all significantly increased, respectively. The application of eATP alleviated the decrease of chlorophyll content, Y(Ⅱ), ETR, qP and qL of A. sinensis leaves under drought and low temperature stress, and eliminated the increase of qN and NPQ. The results indicated that eATP could effectively increase the open ratio of PSⅡ reaction centers, and improve the electron transfer rate and light energy conversion efficiency of PSⅡ of A. sinensis leaves under drought and low temperature stress. It is beneficial to enhance the chlorophyll synthesis and the adaptability of PSⅡ about A. sinensis seedlings to drought and low temperature stress.

Trichorenins A-C, Algicidal Tetracyclic Metabolites from the Marine-Alga-Epiphytic Fungus Trichoderma virens Y13-3.

Three novel polyketide-like metabolites, trichorenins A-C (1-3), with a unique tetracyclic carbon skeleton were obtained from the culture of Trichoderma virens Y13-3, an epiphyte of the marine red alga Gracilaria vermiculophylla. Their structures and relative configurations were established by analysis of 1D/2D NMR and MS data, and their absolute configurations were unequivocally assigned by X-ray diffraction and ECD spectra aided by quantum chemical calculations. Compounds 1-3 exhibited potent inhibition against two marine phytoplankton species, Chattonella marina and Karlodinium veneficum.

Trichocarotins A-H and trichocadinin A, nine sesquiterpenes from the marine-alga-epiphytic fungus Trichoderma virens.

In addition to CAF-603, 14-hydroxy CAF-603 (trichocarane B), 7-ß-hydroxy CAF-603, and trichocarane A, eight new carotane sesquiterpenes, trichocarotins A-H, and one new cadinane sesquiterpene, trichocadinin A, were isolated from the culture of Trichoderma virens Y13-3, obtained from the surface of a marine red alga. Their structures and relative configurations were unambiguously assigned by interpretation of 1D/2D NMR and MS data, and their absolute configurations were established by X-ray diffraction or ECD spectra aided by quantum chemical calculations. These compounds represent two rarely occurring sesquiterpene types from filamentous fungi, and six of them feature potent inhibition against some marine plankton species.

Exploring the Detection of Metal Ions by Tailoring the Coordination Mode of V-Shaped Thienylpyridyl Ligand in Three MOFs.

By employing a rational design approach, we synthesized three luminescent metal-organic frameworks (MOFs) 1-3 affording different coordination modes of V-shaped thienylpyridyl ligand. Their application in detecting metal ions was explored, and the mechanism was inferred. And the result exhibits that MOF 3 is a dual-responsive luminescent probe for Fe3+ and Al3+ ions.

Sesteralterin and Tricycloalterfurenes A-D: Terpenes with Rarely Occurring Frameworks from the Marine-Alga-Epiphytic Fungus Alternaria alternata k21-1.

A new sesterterpene, sesteralterin (1), four new meroterpenes, tricycloalterfurenes A-D (2-5), and a known meroterpene, TCA-F (6), were obtained from the culture extract of an Alternaria alternata strain (k21-1) isolated from the surface of the marine red alga Lomentaria hakodatensis. The structures and relative/absolute configurations of these compounds were identified by spectroscopic analyses, mainly including 1D/2D NMR, ECD, and mass spectra and quantum chemical calculations. Compound 1 represents the first nitidasane sesterterpene naturally produced by fungi, and 2-5 feature a tetrahydrofuran unit rarely occurring in tricycloalternarenes. Compounds 1-6 were assayed for inhibition of the growth of four marine plankton and one marine alga-pathogenic bacterium.

[Research on the Anti-Pulmonary Fibrosis Effect of the Bletilla striata Polysaccharide in Rat Silicosis Model].

Objective: To investigate the anti-pulmonary fibrosis effect and the possible molecular mechanism of the Bletilla striata polysaccharide. Methods: Polysaccharide was prepared by water reflux extraction plus ethanol precipitation method, and following deproteinization process by Sevage method. Rat silicosis model was established by invasive intratracheal instillation method. The effect and molecular mechanism of the polysaccharide was evaluated by lung indexes, lung pathological change, serum levels of SOD,MDA,NF-κB,IL-1ß,PDGF,TGF-ß1,TNF-α,HYP were detected, and the contents of CD3~+,CD4~+,CD8~+T lymph cells and CD4~+/ CD8~+ratio were detected by flow cytometry. Results: Both low( 100 mg / kg) and high( 400 mg / kg) dosage polysaccharide treatment could remarkably elevate the serum SOD level and reduce the MDA,NO level, and effectively reverse the CD4~+/ CD8~+ratio comparing with the model group( P < 0. 01). Except the TNF-α level was significantly lower in the high dosage treatment group, there was no other effect in inflammatory cytokines and HYP content in serum. HE pathological section confirmed that the Bletilla striata polysaccharide treatment group can not effectively prevent lung fibrosis. Conclusion: The Bletilla striata polysaccharide has remarkable regulation effect on antioxidation system and immune system, but can not effectively prevent lung fibrosis, more effort should be made to study the active antipulmonary fibrosis components of Bletilla striata.