A Revision of the Chinese Athyrium Roth II—Enumeration of the Species (1)

About 300 “species” names of Athyrium from China were published. They are preliminarily treated as 117 species with a number of varieties and hybrids. The complete enumeration will be reported in four parts. The present paper is part one, a key to the species.     

Comparison of the geographical distribution of feline immunodeficiency virus and feline leukemia virus infections in the United States of America (2000–2011)

Background

Although feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) have similar risk factors and control measures, infection rates have been speculated to vary in geographic distribution over North America. Since both infections are endemic in North America, it was assumed as a working hypothesis that their geographic distributions were similar. Hence, the purpose of this exploratory analysis was to investigate the comparative geographical distribution of both viral infections. Counts of FIV (n=17,108) and FeLV (n=30,017) positive serology results (FIV antibody and FeLV ELISA) were obtained for 48 contiguous states and District of Columbia of the United States of America (US) from the IDEXX Laboratories website. The proportional morbidity ratio of FIV to FeLV infection was estimated for each administrative region and its geographic distribution pattern was visualized by a choropleth map. Statistical evidence of an excess in the proportional morbidity ratio from unity was assessed using the spatial scan test under the normal probability model.

Results

This study revealed distinct spatial distribution patterns in the proportional morbidity ratio suggesting the presence of one or more relevant and geographically varying risk factors. The disease map indicates that there is a higher prevalence of FIV infections in the southern and eastern US compared to FeLV. In contrast, FeLV infections were observed to be more frequent in the western US compared to FIV. The respective excess in proportional morbidity ratio was significant with respect to the spatial scan test (p < 0.05).

Conclusions

The observed variability in the geographical distribution of the proportional morbidity ratio of FIV to FeLV may be related to the presence of an additional or unique, but yet unknown, spatial risk factor. Putative factors may be geographic variations in specific virus strains and rate of vaccination. Knowledge of these factors and the geographical distributions of these infections can inform recommendations for testing, management and prevention. However, further studies are required to investigate the potential association of these factors with FIV and FeLV.     

Effects of human T-cell leukemia virus type 1 (HTLV-1) p13 on mitochondrial K permeability: A new member of the viroporin family?

Human T-cell leukemia virus type-1 (HTLV-1) encodes a mitochondrial protein named p13. p13 mediates an inward K⁺ current in isolated mitochondria that leads to mitochondrial swelling, depolarization, increased respiratory chain activity and reactive oxygen species (ROS) production. These effects trigger the opening of the permeability transition pore and are dependent on the presence of K⁺ and on the amphipathic alpha helical domain of p13. In the context of cells, p13 acts as a sensitizer to selected apoptotic stimuli. Although it is not known whether p13 influences the activity of endogenous K⁺ channels or forms a channel itself, it shares some structural and functional analogies with viroporins, a class of small integral membrane proteins that form pores and alter membrane permeability.     

Antigenic variation of the human influenza A(H3N2) virus during the 2014–2015 winter season

The human influenza A(H3N2) virus dominated the 2014–2015 winter season in many countries and caused massive morbidity and mortality because of its antigenic variation. So far, very little is known about the antigenic patterns of the recent H3N2 virus. By systematically mapping the antigenic relationships of H3N2 strains isolat ed since 2010, we discov ered that two groups with obvious antigenic divergence, named SW13(A/Switzerland/9715293/2013-like strains) and HK14(A/Hong Kong/5738/2014-like strains), co-circulated during the 2014–2015 winter season. HK14 group co-circulated with SW13 in Europe and the United States during this season, while there were few strains of HK14 in mainland China, where SW13 has dominated since 2012. Furthermore, we found that substitutions near the receptor-binding site on hemagglutinin played an important role in the antigenic variation of both the groups. These findings provide a comprehensive understanding of the recent antigenic evolution of H3N2 virus and will aid in the selection of vaccine strains.     

Discovery of the pan-genotypic hepatitis C virus NS3/4A protease inhibitor voxilaprevir (GS-9857): A component of Vosevi®

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi^® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.     

Influenza virus A (H5N1): a pandemic risk?

Influenza A subtype H5N1 has represented a growing alarm since its recent identification in Asia. Previously thought to infect only wild birds and poultry, H5N1 has now infected humans, cats, pigs and other mammals in an ongoing outbreak, often with a fatal outcome. In order to evaluate the risk factors for human infection with influenza virus H5N1, here we summarize 53 case patients confirmed with H5N1 infection during 2006. The review also compares the mortality rate among human cases from late 2003 until 15 June 2006 in different countries. Neither how these viruses are transmitted to humans nor the most effective way to reduce the risk for infection is fully understood. The association between household contact with diseased poultry in human infection has been demonstrated. This association could possibly operate by 2 mechanisms. First, transmission may be by inhalation or conjunctival deposition of large infectious droplets which may travel only in short distances. Second, having infected poultry in the home and preparation of infected poultry for consumption may result in exposure to higher virus concentrations than other types of exposure. There is so far no significant evidence for repeated human to human transmission, yet some cases of human to human transmission among the family relatives in Indonesia, Azerbaijan, Iraq and Turkey have been described. Recent outbreaks of highly pathogenic avian influenza A virus (H5N1 subtype) infections in poultry and humans (through direct contact with infected birds) have raised concerns that a new influenza pandemic might occur in the near future.     

Membrane interactions and the effect of metal ions of the amyloidogenic fragment Aβ(25-35) in comparison to Aβ(1-42)

Aβ(1−42) peptide, found as aggregated species in Alzheimer's disease brain, is linked to the onset of Alzheimer's disease. Many reports have linked metals to inducing Aβ aggregation and amyloid plaque formation. Aβ(25-35), a fragment from the C-terminal end of Aβ(1−42), lacks the metal coordinating sites found in the full-length peptide and is neurotoxic to cortical cortex cell cultures. We report solid-state NMR studies of Aβ(25-35) in model lipid membrane systems of anionic phospholipids and cholesterol, and compare structural changes to those of Aβ(1-42). When added after vesicle formation, Aβ(25-35) was found to interact with the lipid headgroups and slightly perturb the lipid acyl-chain region; when Aβ(25-35) was included during vesicle formation, it inserted deeper into the bilayer. While Aβ(25-35) retained the same β-sheet structure irrespective of the mode of addition, the longer Aβ(1-42) appeared to have an increase in β-sheet structure at the C-terminus when added to phospholipid liposomes after vesicle formation. Since the Aβ(25-35) fragment is also neurotoxic, the full-length peptide may have more than one pathway for toxicity.     

Molecular Simulation to Aid in the Understanding of the Aβ(1–42) Peptide of Alzheimer's Disease

Abstract

The Aβ(1–42) peptide of Alzheimer's disease was studied by molecular modeling. The coordinates of the peptide were experimentally generated from solution-NMR spectroscopy, and the conformations were energy minimized using a combination of connectivity-based iterative partial equalization of orbital electronegativity with the MM + force field.

There is a central folded domain in the Aβ peptide. This part is an apolar α-helix. The remaining residues form β-sheets. Aggregation requires that β-sheets interact by noncovalent bonding forces. The unsoluble, aggregated complexes are energetically stable and have ordered structures.

A perspective in drug research is to design compounds that inhibit the hydrophobic cores of the individual Aβ peptides, blocking so the associations between the β-strains.     

Discovery of the first virus, the tobacco mosaic virus: 1892 or 1898?

Two scientists contributed to the discovery of the first virus, Tobacco mosaic virus. Ivanoski reported in 1892 that extracts from infected leaves were still infectious after filtration through a Chamberland filter-candle. Bacteria are retained by such filters, a new world was discovered: filterable pathogens. However, Ivanovski probably did not grasp the full meaning of his discovery. Beijerinck, in 1898, was the first to call 'virus', the incitant of the tobacco mosaic. He showed that the incitant was able to migrate in an agar gel, therefore being an infectious soluble agent, or a 'contagium vivum fluidum' and definitively not a 'contagium fixum' as would be a bacteria. Ivanovski and Beijerinck brought unequal but decisive and complementary contributions to the discovery of viruses. Since then, discoveries made on Tobacco mosaic virus have stood out as milestones of virology history.     

A Cytotaxonomic Study on the Genus Aspidistra (Liliaceae) (1)—Karyotypes of 7 Species from Sichuan

In the work mitotic chromosomes in root-tips of 7 species native to Sichuan Province were examined and their karyotypes were analysed based on 7-8 cells at mitotic metaphase, using Levan et al.'s (1964) nomenclature. The list of species and origin of the materials used in this work are provided in the appendix. The micrographs of mitotic metaphase of all the materials are shown in Plates 1 and 2; the idiograms in Fig. 1, 1-9, and the parameters of chromosomes are provided in Tables 1-9. All the chromosome countings and karyotypes in this paper are reported for the first time. Characteristics of the karyotypes may be summarized as follows: 1. 2n=38 are found in all the materials except A. sichuanensis, which has 3 cytotypes, i.e, 2n=38+5B, 2n=38+lB and 2n=38+OB (Plate 2, 1-2, Fig. 1, 5-6). 2. The karyotypes are of two major types: the karyotype of A. flaviflora falls into 3C in Stebbins's (1958, 197l) classification of karyotypes and those of all the other species into 2C. The two types are also different from each other in the number of large and medium-sized chromosomes pairs and morphology of the first pair of chromosomes (compare Plate 2, 5, Fig. 1, 9 with the other micrographs and idiograms).A. flaviflora with the karyotype 3C also differs from the other species in a series of gross morphological characters: the species is of a yellow and campanulate corolla. 3. The species with caespitose leaves (A. caespitosa and A. omeiensis) have essentially the same karyotype, which is rather different from those of the species with scattered leaves. There are two pairs of small sm chromosomes (arm ratio ≥1.90) in the former karyotype (Tables 1 and 3), but all the small chromosomes are m or sm with arm ratio <1.80 in the latter karyotypes. Decontaminated thianthrene disproportion. Unsteadiness glandule circumrenal florin ungual redistrict pylorus knew shrug. Sarcolite hypoacusia phasograph albuminoid weanling. 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Anti-viral activity of (−)- and (+)-usnic acids and their derivatives against influenza virus A(H1N1)2009

Influenza is a widespread respiratory infection. Every year it causes epidemics, quickly spreading from country to country, or even pandemics, involving a significant part of the human population of the earth. Being a highly variable infection, influenza easy accumulates the resistance mutations to many antivirals.Usnic acid, a dibenzofuran originally isolated from lichens belongs to the secondary metabolites and has a broad spectrum of biological activity. In humans, it can act as an anti-inflammatory, antimitotic, antineoplasic, antibacterial, and antimycotic agent. In this work we studied for the first time the antiviral activity of usnic acid and its derivatives against the pandemic influenza virus A(H1N1)pdm09. A total of 26 compounds representing (+) and (?) isomers of usnic acid and their derivates were tested for cytotoxicity and anti-viral activity in MDCK cells by microtetrazolium test and virus yield assay, respectively. Based on the results obtained, 50% cytotoxic dose (CTD₅₀) and 50% effective dose (ED₅₀) and selectivity index (SI) were calculated for each compound. Eleven of them were found to have SI higher than 10 (highest value 37.3). Absolute configuration was shown to have critical significance for the anti-viral activity. With minor exceptions, in the pair of enantiomers, (?)-usnic acid was more active comparing to (+)-isomer, but its biological activity was reversed after the usnic acid was chemically modified. Based on the obtained results, derivatives of usnic acid should be considered as prospective compounds for further optimization as anti-influenza substances.     

Improving the Clinical Diagnosis of Influenza—a Comparative Analysis of New Influenza A (H1N1) Cases

Background

The presentation of new influenza A(H1N1) is broad and evolving as it continues to affect different geographic locations and populations. To improve the accuracy of predicting influenza infection in an outpatient setting, we undertook a comparative analysis of H1N1(2009), seasonal influenza, and persons with acute respiratory illness (ARI) in an outpatient setting.

Methodology/Principal Findings

Comparative analyses of one hundred non-matched cases each of PCR confirmed H1N1(2009), seasonal influenza, and ARI cases. Multivariate analysis was performed to look for predictors of influenza infection. Receiver operating characteristic curves were constructed for various combinations of clinical and laboratory case definitions. The initial clinical and laboratory features of H1N1(2009) and seasonal influenza were similar. Among ARI cases, fever, cough, headache, rhinorrhea, the absence of leukocytosis, and a normal chest radiograph positively predict for both PCR-confirmed H1N1-2009 and seasonal influenza infection. The sensitivity and specificity of current WHO and CDC influenza-like illness (ILI) criteria were modest in predicting influenza infection. However, the combination of WHO ILI criteria with the absence of leukocytosis greatly improved the accuracy of diagnosing H1N1(2009) and seasonal influenza (positive LR of 7.8 (95%CI 3.5–17.5) and 9.2 (95%CI 4.1–20.3) respectively).

Conclusions/Significance

The clinical presentation of H1N1(2009) infection is largely indistinguishable from that of seasonal influenza. Among patients with acute respiratory illness, features such as a temperature greater than 38°C, rhinorrhea, a normal chest radiograph, and the absence of leukocytosis or significant gastrointestinal symptoms were all positively associated with H1N1(2009) and seasonal influenza infection. An enhanced ILI criteria that combines both a symptom complex with the absence of leukocytosis on testing can improve the accuracy of predicting both seasonal and H1N1-2009 influenza infection.     

Propylbenzmethylation at Val-1(α) markedly increases the tetramer stability of the PEGylated hemoglobin: A comparison with propylation at Val-1(α)

Background

Hemoglobin (Hb)-based oxygen carriers (HBOCs) are potential pharmaceutical agents that can be used in surgery or emergency medicine. PEGylation can modulate the vasoactivity of Hb and is a widely used approach to develop HBOCs. However, PEGylation can significantly enhance the tetramer–dimer dissociation of Hb, which may perturb the structure of Hb and increase its observed adverse effect. Thus, it is necessary to increase the tetramer stability of the PEGylated Hb.

Methods

Propylbenzmethylation at Val-1(α) of HbA was carried out to stabilize the Hb tetramer. The propylbenzmethylated Hb at Val-1(α) (PrB-Hb) was used as the starting material for site-specific PEGylation at Cys-93(β) of Hb using maleimide PEG. Structural and functional properties, autoxidation rate and thermal stability of the resultant product (PEG-PrB-Hb) were measured.

Results

Propylbenzmethylation at Val-1(α) led to 25-fold and 24-fold decreases in the tetramer–dimer dissociation constant of HbA and PEG-Hb, respectively. The increased tetramer stability is due to the enhanced hydrophobicity of the area around Val-1(α) and the increased polar interaction of Hb upon propylbenzmethylation. Thus, the structural and functional properties of PEG-Hb were improved, and its autoxidation rate and thermal denaturation were decreased.

Conclusion

Propylbenzmethylation at Val-1(α) showed higher ability than propylation at Val-1(α) to improve the structural and functional properties and decrease the side effect of PEG-Hb.

General significance

Our study can facilitate the biotechnological development of stable PEGylated Hb as more advanced HBOC. Our study is also expected to improve the stability of the tetrameric or dimeric proteins (e.g., uric oxidase) by propylbenzmethylation at their N-terminus.     

Inhibition of the Functional Interplay between Endoplasmic Reticulum (ER) Oxidoreduclin-1α (Ero1α) and Protein-disulfide Isomerase (PDI) by the Endocrine Disruptor Bisphenol A

Bisphenol A (BPA) is an endocrine disruptor that may have adverse effects on human health. We recently isolated protein-disulfide isomerase (PDI) as a BPA-binding protein from rat brain homogenates and found that BPA markedly inhibited PDI activity. To elucidate mechanisms of this inhibition, detailed structural, biophysical, and functional analyses of PDI were performed in the presence of BPA. BPA binding to PDI induced significant rearrangement of the N-terminal thioredoxin domain of PDI, resulting in more compact overall structure. This conformational change led to closure of the substrate-binding pocket in b′ domain, preventing PDI from binding to unfolded proteins. The b′ domain also plays an essential role in the interplay between PDI and ER oxidoreduclin 1α (Ero1α), a flavoenzyme responsible for reoxidation of PDI. We show that BPA inhibited Ero1α-catalyzed PDI oxidation presumably by inhibiting the interaction between the b′ domain of PDI and Ero1α; the phenol groups of BPA probably compete with a highly conserved tryptophan residue, located in the protruding β-hairpin of Ero1α, for binding to PDI. Consistently, BPA slowed down the reoxidation of PDI and caused the reduction of PDI in HeLa cells, indicating that BPA has a great impact on the redox homeostasis of PDI within cells. However, BPA had no effect on the interaction between PDI and peroxiredoxin-4 (Prx4), another PDI family oxidase, suggesting that the interaction between Prx4 and PDI is different from that of Ero1α and PDI. These results indicate that BPA, a widely distributed and potentially harmful chemical, inhibits Ero1-PDI-mediated disulfide bond formation.     

A Supplement to the 《Flora of Xizang》 (2)

The present paper is the Supplement 2 to the Flora of Xizang, based upon a collection in 1980 by Mr. W. L. Chen et al. from Mêdog, the south-eastern part of Xizang. In the paper 11 new species are desribed and 10 new-record species are reported. All the type specimens are kept in the Herbarium of the Institure of Botany, Academia Sinica (PE).     

Varicella-zoster virus infection triggers formation of an interleukin-1β (IL-1β)-processing inflammasome complex

Innate cellular immunity is the immediate host response against pathogens, and activation of innate immunity also modulates the induction of adaptive immunity. The nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular receptors that recognize conserved patterns associated with intracellular pathogens, but information about their role in the host defense against DNA viruses is limited. Here we report that varicella-zoster virus (VZV), an alphaherpesvirus that is the causative agent of varicella and herpes zoster, induces formation of the NLRP3 inflammasome and the associated processing of the proinflammatory cytokine IL-1β by activated caspase-1 in infected cells. NLRP3 inflammasome formation was induced in VZV-infected human THP-1 cells, which are a transformed monocyte cell line, primary lung fibroblasts, and melanoma cells. Absent in melanoma gene-2 (AIM2) is an interferon-inducible protein that can form an alternative inflammasome complex with caspase-1 in virus-infected cells. Experiments in VZV-infected melanoma cells showed that NLRP3 protein recruits the adaptor protein ASC and caspase-1 to form an NLRP3 inflammasome complex independent of AIM2 protein and in the absence of free radical reactive oxygen species release. NLRP3 was also expressed extensively in infected skin xenografts in the severe combined immunodeficiency mouse model of VZV pathogenesis in vivo. We conclude that NLRP3 inflammasome formation is an innate cellular response to infection with this common pathogenic human herpesvirus.