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Several mosquito-borne arboviruses belonging to the genera Alphavirus, Flavivirus, and Bunyavirus have been reported to occur in mosquitoes and to infect humans and other vertebrates in western Europe. These zoonotic viruses circulate in nature either in an Aedes-mammal, Anopheles-mammal, or Culex-bird transmission cycle. Infected humans normally do not contribute to the virus circulation. West Nile virus (Flavivirus) caused an outbreak of fever, malaise, pain in eyes and muscles, and headache and encephalitis in southern France during 1962-1965, and an outbreak of encephalitis with a high case-fatality rate in Romania during 1996. West Nile virus has been isolated from birds, horses, and mosquitoes in Portugal, France, the former Czechoslovakia, and Romania. These data, together with reports of antibodies to West Nile virus in birds, domestic mammals, and humans in several other countries, show virus activity in southern and central Europe. Sindbis virus (Alphavirus) caused outbreaks of fever, rash, and arthralgia in northern Europe during 1981-1982, 1988, and 1995. Two California group viruses (Bunyavirus), Tahyna virus and Inkoo virus, have been identified in western Europe. Tahyna virus causes fever and respiratory symptoms and sometimes also central nervous system involvement. It occurs in most countries of central and southern Europe, and is most common in central Europe. Inkoo virus has not been associated with disease in humans in western Europe although Russian studies indicated that it can cause encephalitis. Inkoo virus occurs in northern Europe, especially in the far north. Batai virus of the Bunyamwera-group (Bunyavirus) occurs in southern, central, and northern Europe, most frequently in central Europe. The antibody prevalence in humans generally is very low, indicating that the potential of this virus as a human pathogen is probably low in Europe. The Lednice virus (Bunyavirus) has been reported only from the former Czechoslovakia and Romania, and apparently is not transmitted to humans. In addition to the six mosquito-borne viruses documented in western Europe, there is serological evidence of infection with a Semliki Forest complex virus (Alphavirus) in central and southern Europe. Although mosquito-borne viruses presently are not considered to be the cause of major health problems in western Europe, the morbidity caused by Sindbis virus, and the morbidity and mortality caused by West Nile virus, merit further studies on the ecology, epidemiology, and medical importance of these viruses. The California group of viruses and a virus of the Semliki Forest complex may be the cause of unrecognized health problems in western Europe. Specific sampling of potential vectors for virus isolation, detailed characterization of virus strains, and the use of fully characterized strains for serological diagnosis will help to elucidate the present and future potential of mosquito-borne viruses as human pathogens in Europe.
(1) a. The mating behavior (including copulation) is described for the first time in the following species: Pardosa modica, P. emertoni, P. saxatilis, P. lapidicina, Lycosa helluo, .L. gulosa, Dolomedes scriptus, Phidippus clarus, P. audax, Philodromus pernix, and Coriarachne versicolor. b. The courtship only is described for the first time in Phidippus purpuratus. c. In Lycosa rabida and Pardosa milvina new data concerning the copulation, and in Schizocosa crassipes new data concerning courtship, are added to what is already available from Montgomery's work. d. In Tibellns oblongus and Xysticus triguttatus new data are added to the accounts of Gerhardt, and of Emerton, respectively. (2) a. On the basis of a large number of observations and experiments with the males of 19 species from 4 families of vagabond spiders, it is pointed out that the senses involved in courtship may vary with the species. b. There is no evidence that a sense of smell is used in sex recognition by any spiders. At least this sense plays no part in initiating courtship activity in the male. c. There is no evidence that Attid males can "recognize" the females by any sense other than sight. At any rate, it appears that the visual stimulus is the only one that suffices to incite courtship in this family. d. In one Lycosid observed, Pardosa emertoni, the courtship behavior is elicited only when the male can both see and touch the female. e. In the Pisaurid, Dolomedes scriptus, the sole stimulus for courtship is the chemoperception by contact of an ether-soluble substance normally covering the cuticle of the female. f. In the Lycosid, Pardosa milvina, the chemoperception by contact of an ether-soluble substance normally covering the cuticle of the female, together with the simultaneous perception of tactile stimuli will elicit courtship. This probably holds for P. saxatilis, Lycosa rabida, Schizocosa crassipes, and perhaps for Pardosa modica. Moreover, the sight of a moving Lycosid of about their own size may, in some cases, be sufficient for these males to start courting. g. In the Lycosids, Pardosa banksi, and probably Lycosn gulosa and L. helluo, only the simultaneous perception of both tactile and tacto-chemical stimuli suffices. Visual stimuli play no part in eliciting courtship. h. The condition in the Thomisids is in all probability similar to that in the preceding group of Lycosids. (3) a. In the case of those species in which contact chemoperception occurs it is shown that perception is not limited to the tarsi. Such stimuli can be perceived on all the segments of the legs as well as on the abdomen. From the known distribution of the slit sense organs it is probable that they are the chemoreceptors involved in courtship.
Naturschutz in Germany
(1936)
RNA interference (RNAi) is triggered by recognition of double-stranded RNA (dsRNA), and elicits the silencing of gene(s) complementary to the dsRNA sequence. RNAi is thought to have emerged as a way of safeguarding the genome against mobile genetic elements and viral infection, thus maintaining genomic integrity. dsRNA is first processed into small interfering RNAs (siRNA) by the enzyme Dicer. siRNAs are ~21 to 25 -nt long, and contain a signature 5’ phosphate group and a two nucleotide long 3’ overhang (Bernstein et al., 2001). The siRNA is then loaded into the RNA-induced si-lencing complex (RISC), of which Argonaute is the primary catalytic component (Liu et al., 2004). Energetic asymmetry of the siRNA ends allows for its directional loading into RISC (Khvorova et al., 2003; Schwarz et al., 2003). Argonaute cleaves the passen-ger strand of the siRNA, leaving the guide strand of the siRNA bound to RISC (Gregory et al., 2005; Matranga et al., 2005; Rand et al., 2005). This single-stranded guide strand siRNA bound to Argonaute is able to recognize target mRNA in a sequence-specific manner, and cleaves the mRNA. Argonaute 2 in complex with single-stranded siRNA is sufficient for mRNA recognition and cleavage, thus forming a minimal RISC (Rivas et al., 2005). miRNAs, endogenously expressed small RNA genes which typically contain mismatches and non-Watson-Crick base pairing, are processed by this general pathway, although typically modulate gene expression by translational repression as opposed to cleavage of their target mRNA. The number of Argonaute genes is highly variable between species, ranging from one in S. pombe to twenty-seven in C. elegans. Earlier crystal structures of Argonaute apoen-zymes show the architecture of Argonaute to be a multidomain protein composed of N terminal, PAZ, MID, and PIWI domains (Song et al., 2004; Yuan et al., 2005). These multi-domain proteins are present in both prokaryotic and eukaryotic organisms. The role of Argonaute proteins in prokaryotes is still unknown, but based similarity to eu-karyotic Argonautes, they may also be involved in nucleic acid-directed regulatory pathways. These proteins have served as excellent models for learning about the struc-ture and function of this family of proteins. RNAi has found a widespread application for the simple yet effective knockdown of genes of interest. The catalytic cycle of RISC requires the binding of a number of different nucleotide structures to Argonaute, and we expect Argonaute to undergo a number of conforma-tional changes during the cycle of mRNA recognition by RISC (Filipowicz, 2005; Tom-ari and Zamore, 2005). Nevertheless, it remains unclear how the multi-domain ar-rangement of Argonaute recognizes and distinguishes between single-stranded and dou-ble-stranded oligonucleotides, which correspond to the Dicer-processed siRNA product, guide strand siRNA, and the guide strand / mRNA duplex. The Argonaute protein from Aquifex aeolicus was cloned, expressed, crystallized and solved by molecular replacement. Relative to earlier Argonaute structures, a 24° reorientation of the PAZ domain in this structure opens a basic cleft between the N-terminal and PAZ domains, exposing the guide strand binding pocket of PAZ. A 5.5-ns molecular dynamics simulation of Argonaute showed a strong tendency of the PAZ and N-terminal domains to be mobile. Binding of single-stranded DNA to Argonaute was monitored by total internal reflection fluorescence spectroscopy (TIRFS). The experi-ments showed biphasic kinetics indicative of large conformational changes, and re-vealed a hotspot of binding energy corresponding to the first 9 nucleotides, the so-called “seed region” most crucial for sequence-specific target recognition. As RNAi may have evolved as a way of safeguarding the genome viral infection, it is not surprising that viruses have evolved different strategies to suppress the host RNAi response in the form of viral suppressor protein. (Hock and Meister, 2008; Lecellier and Voinnet, 2004; Rashid et al., 2007; Song et al., 2004; Vastenhouw and Plasterk, 2004). These viral suppressors are widespread, having been identified in a number of different viral families. Not surprisingly, they generally share little sequence homology with one another, although they appear to exist as oligomers built upon a ~ 100-200 amino acid protomer. Tomato aspermy virus, a member of the Cucumoviruses, encodes for protein 2B (TAV 2B, 95 a.a., ~11.3 kDa) that acts as an RNAi suppressor. Intriguingly, a similar genomic arrangement is seen in RNAi suppressors in the Nodaviruses, a family of viruses that can infect both plants and animals, such as Flock house virus b2 (FHV b2). The 2B and b2 proteins are both derived from a frameshifted ORF within the RNA polymerase gene (Chao et al., 2005). In spite of this genomic similarity, the 2B and b2 proteins share little sequence identity, and it is not well understood how the Cucumovirus 2B proteins suppress RNAi. To address how TAV 2B suppresses RNAi, the oligonucleotide-binding properties of TAV 2B were studied. TAV 2B shows a preference for double-stranded RNA oligonucleotides corresponding to siRNAs and miRNAs, and also binds to single-stranded RNA oligonucleotides. A stretch of positively charged residues between amino acids 20-30 are critical for RNA binding. Binding to RNA oligomerizes and induces a conformational change in TAV 2B into a primarily helical structure. These studies sug-gest that suppression of RNAi by TAV 2B may occur by targeting different stages of the RNAi pathway. TAV 2B falls under the category of more general RNAi suppres-sors, with potentially multiple targets for suppression.
The reggie protein family consists of two homologous members, reggie-1 and reggie-2, also termed flotillin-2 and flotillin-1, respectively, that are ubiquitously expressed and evolutionarily well conserved, suggesting an important but so far ill-defined function. In various cell types, both reggies have been found to be constitutively associated with lipid rafts by means of acylation modifications and oligomerization. Lipid rafts are glycosphingolipid- and cholesterol-rich membrane microdomains which have been implicated in several cellular processes including membrane transport and signal transduction through growth factor receptors. However, the molecular details of these processes are still poorly understood. With the observation that reggies colocalize with activated glycosylphosphatidylinositolanchored proteins (GPI-APs) and Fyn kinase in rafts, a role for these proteins in signaling events has been suggested. In agreement with that, we have previously shown that reggie-1 becomes multiply tyrosine phosphorylated by Src kinases in response to epidermal growth factor (EGF) stimulation, pointing to a function for reggie-1 in growth factor signaling. Furthermore, overexpression of reggie-1 enhances spreading on fibronectin substrate in a tyrosine-dependent manner, thus revealing a role for reggie-1 in regulation of actin cytoskeleton through growth factor receptors. Due to the similarity shared by reggie proteins at amino acid level and to their ability to form hetero-oligomeric complexes, the first aim of this study was to analyze the putative tyrosine phosphorylation of reggie-2 in growth factor stimulated cells. Similarly to reggie-1, reggie-2 was found to be multiply tyrosine phosphorylated by Src kinase and to exist in a molecular complex with Src, with the degree of co-immunoprecipitation dependent on the activity of Src. Recent studies from us have also shown that administration of EGF results in the endocytosis of reggie-1 from the plasma membrane into endosomes, which is in line with a proposed role for reggies in membrane trafficking processes. In order to characterize in detail the endocytic mechanism that mediates the uptake of reggie-1, the dependency of reggie-1 endocytosis on clathrin and dynamin was investigated by means of overexpressing a variant form of Eps15 or a dominant negative form of dynamin-2. In either case the translocation of reggie-1 into endosomes in response to EGF was not affected, and this, together with the results that reggie-1 colocalized with cholera toxin (CTX) but not with transferrin receptor (TfnR) during EGF signaling, indicates that reggie-1 is taken up by means of a dynaminindependent, raft-mediated pathway. These findings are very well in line with recent data showing the pathway of entry into cells of reggie-2 as a raft-mediated endocytic pathway. The endocytosis of reggie-2 in response to EGF was also analyzed in this study. Similarly to reggie-1, in growth factor stimulated cells reggie-2 underwent a translocation from the plasma membrane to endosomes where the two reggies were found to colocalize with each other, suggesting that epidermal growth factor signaling might trigger the endocytosis of reggie oligomers. In addition, colocalization with both the late endosomal marker LAMP3/CD63 and epidermal growth factor receptor (EGFR) was detected, again indicating a function for reggies in signal transduction through growth factor receptors. EGFR has been reported to localize in rafts but, although this association is thought to be functional during EGF stimulation, how segregation of EGFR into rafts modulates its endocytosis and signaling is still under debate. Since reggie oligomers have recently been suggested to define a raft subtype, a further aim of this study was to investigate whether the depletion of reggies by means of small interfering RNA could interfere with the signaling and the trafficking through EGFR. Knockdown of reggie-2 resulted in an altered tyrosine phosphorylation of EGFR in response to EGF, while the degree of ubiquitination was not affected. Less efficient phosphorylation of tyrosine residues, especially of those which are docking sites for Grb2 and Shc, led in turn to an impaired activation of p38 and ERK1/2 MAPKs. Depletion of reggie-2 did not affect the early trafficking of activated EGFRs, with receptors being endocytosed and delivered to late endosomes as efficiently as in control cells. This would be in line with the normal degree of ubiquitination observed for EGFR, as ubiquitin moieties have been proposed to represent sorting tags that ensure receptor endocytosis into early endosomes and its proper intracellular trafficking. On the contrary, after prolonged EGF stimulation, depletion of reggie-2 resulted in a decreased downregulation of both receptor-bound ligand and EGFR, and in their accumulation in intracellular vesicles, thus pointing to a role for reggie-2 in the degradative pathway. Taken all together, these data ndicate that the association of EGFR with reggie-microdomains is likely to be important for proper receptor trafficking and signaling.
Distribution and variation in deer (Genus Odocoileus) of the Pacific Coastal Region of North America
(1936)
A generic drug product (World Health Organization (WHO) terminology: multisource product) is usually marketed and manufactured after the expiry date of the innovator’s patent. Generic drugs are less expensive than the innovator products because generic manufacturers do not have to amortize the investment costs of research, development, marketing, and promotion. Multisource products must contain the same active pharmaceutical ingredients (APIs) as the original formulation and have to be shown to be interchangeable with the original formulation. Multisource products have to be shown bioequivalent to the innovator counterpart with respect to pharmacokinetic and pharmacodynamic properties. Multisource products are therefore identical in dose, strength, route of administration, safety, efficacy, and intended use. Bioequivalence can be demonstrated by in vitro dissolution, pharmacokinetic, pharmacodynamic or clinical studies. Since 2000, the U.S. Food and Drug Administration (FDA) allows the approval of certain multisource products solely on the basis of in vitro studies, i.e. by waiving in vivo studies in humans (“Biowaiver”), based on the Biopharmaceutics Classification Scheme (BCS). The BCS characterizes APIs by their solubility and permeability in the gastrointestinal tract (GIT). The different BCS Classes I-IV (Class I: high solubility, high permeability; Class II: low solubility, high permeability; Class III: high solubility, low permeability and Class IV: low solubility, low permeability) result from all possible combinations of high and low solubility with high and low permeability. Since the adoption of the BCS by the FDA in 1995, the BCS criteria have been under continuous development. In 2006, the WHO has released the most recent bioequivalence guidance including relaxed criteria for bioequivalence studies based on modified BCS criteria. According to this guidance, APIs belonging to the BCS classes I – and under defined conditions - II and III – are eligible for a biowaiver-based approval. The principal objective of this work was to characterize the first-line anti tuberculosis APIs, isoniazid, pyrazinamide, ethambutol dihydrochloride and rifampicin, according to their physicochemical, biopharmaceutical, pharmacokinetic and pharmacological properties and to classify them according to the BCS. Ethambutol dihydrochloride and isoniazid were classified as borderline BCS class I/III APIs. Pyrazinamide was classified as a BCS class III and rifampicin as a BCS class II API. Based on the BCS classification and the additional criteria defined in the WHO bioequivalence guidance, the possibility of biowaiver-based approval for immediate release (immediate release) solid oral dosage forms containing the first-line antituberculosis drugs was evaluated. A biowaiver-based approval with defined constraints was recommended for immediate release solid oral dosage forms containing isoniazid (interaction with reducing sugars), pyrazinamide and ethambutol dihydrochloride (relative narrow therapeutic index). Rifampicin was classified as a BCS class II API, and it was concluded that rifampicin containing solid oral immediate release drug products as well as Scale-Up and Post-Approval Changes (SUPAC) changes should not be approved by a biowaiver on the following basis: (i) its solubility and dissolution are highly variable due to polymorphism and instability, (ii) concomitant intake of food and antacids reduces its absorption and bioavailability, (iii) no in vitro predictive dissolution test has been found which correlates to in vivo absorption and (iv) several publications reporting cases of non-bioequivalent and bioinequivalent rifampicin products have been located in the literature. Thus, it is recommended that bioequivalence of rifampicin containing solid oral immediate release drug products should be established by in vivo pharmacokinetic studies in humans. This risk-benefit benefit assessment of a biowaiver-based approval was presented as a poster at the American Association of Pharmaceutical Scientists (AAPS) 2005 and subsequently published as “Biowaiver Monographs” in the Journal of Pharmaceutical Sciences. Based on the assessment of the dissolution properties of the antituberculosis drugs for a biowaiver approval, quality control dissolution methodologies for the International Pharmacopoeia (Pharm. Int.) were developed, presented at the WHO expert meeting and adopted in the Pharm. Int. (http://www.who.int/medicines/publications/pharmprep/OMS_TRS_948.pdf). Additionally, preliminary biowaiver recommendations were also developed for four firstline antimalarial drugs listed on the WHO Essential Medicines List (EML): Quinine, as both the hydrochloride and sulphate, and proguanil hydrochloride were classified as borderline BCS class I/III APIs. Since quinine is a narrow therapeutic index drug and many cases of non-bioequivalence have been reported in the literature, a biowaiverbased approval was not recommended. For solid oral immediate release dosage forms containing proguanil a biowaiver-based approval was recommended under the condition that they dissolve very rapidly. Primaquine phosphate was classified as a BCS class I API. Therefore, a biowaiver-based approval was recommended for immediate release solid oral dosage forms containing primaquine phosphate. Mefloquine hydrochloride was classified as a basic, BCS class IV/II API, making it ineligible for the biowaiver. Additionally, reports of non-bioequivalence and a narrow therapeutic index were found in the scientific literature. Consequently, bioequivalence of solid oral immediate release dosage forms containing mefloquine hydrochloride should be established by in vivo pharmacokinetic studies. The results for quinine hydrochloride and sulphate, proguanil hydrochloride, primaquine diphosphate and mefloquine hydrochloride were presented as a poster at the Pharmaceutical Sciences World Congress (PSWC) 2007 and published as a WHO Collaborating Center Report in June 2006. The aim of this project was to collect, evaluate, generate and publish relevant information for a biowaiver-based approval of essential medicines in order to provide a summary to local regulatory authorities. This information complements the selected list of essential medicines by providing information about the biopharmaceutical properties and pharmaceutical quality of solid oral immediate release dosage forms containing these APIs. The aim of the biowaiver project, inspired by the WHO and brought in life by the International Pharmaceutical Federation (FIP), is to enable access to essential medicines in standardized quality at an affordable price. In this work, a significant contribution to this aim in the form of four biowaiver monographs for the antituberculosis drugs and several reports on the antimalarials has been achieved.
1. In investigating a spontaneous epidemic disease of rabbits, a micro-organism was isolated in pure cultures which reproduced the characteristic lesions of the natural disease.
2. The bacteriological characters of this bacillus are described and the impossibility of identifying it with previously recorded organisms justifies its being considered a new species. The name Bacterium monocytogenes is proposed.
3. Animal passage raised "virulence" when the doses were well chosen, and increased virulence accentuated the production of necrotic lesions. Overwhelming doses of culture resulted in lowering of "virulence" by animal passage.
4. Bacterium monocytogenes, in doses less than the M.L.D., produced in the circulating blood of rabbits an extreme monocytosis. The responses of the other white cells. were either transient or inconstant.
5. Repeated doses of the organism became progressively less effective as stimuli to large mononuclear production.
6. The cell content of the thoracic duct did not reflect the high degree of monocytosis in the circulating blood.
7. On intrapleural injection of peptone broth and B. coli, the cells of the resultant exudate were primarily polymorphonuclears, even though the circulating blood showed a high monocytosis. With intrapleural injection of B. monocytogenes, when the blood stream was rich in large mononuclears, a pleural exudate containing 30 per cent of these cells was obtained.
8. Phagocytosis experiments in vitro showed that the large mononuclears, while they phagocyted B. coli indifferently, took up B. monocytogenes with an avidity in all respects equal to that of the polymorphonuclear neutrophiles.
Aside from material collected and annotated during my trip to Ecuador in April and May 1973, mentioned in the frrst part of the present paper (1975), the author has been able to study Aphyllophorales and agarics collected by Dumont and others, deposited at The Botanical Garden in New York. The results are presented in the following pages. A few species from limitrophous regions are added. The first article in this series was published in Beiheft 51 zur Nova Hedwigia, pp. 239-246, 1975.