Neural phoneme discrimination in variable speech in newborns - Associations with dyslexia risk and later language skills.

A crucial skill in infant language acquisition is learning of the native language phonemes. This requires the ability to group complex sounds into distinct auditory categories based on their shared features. Problems in phonetic learning have been suggested to underlie language learning difficulties in dyslexia, a developmental reading-skill deficit. We investigated auditory abilities important for language acquisition in newborns with or without a familial risk for dyslexia with electrophysiological mismatch responses (MMRs). We presented vowel changes in a sequence of acoustically varying vowels, requiring grouping of the stimuli to two phoneme categories. The vowel changes elicited an MMR which was significantly diminished in infants whose parents had the most severe dyslexia in our sample. Phoneme-MMR amplitude and its hemispheric lateralization were associated with language test outcomes assessed at 28 months, an age at which it becomes possible to behaviourally test children and several standardized tests are available. In addition, statistically significant MMRs to violations of a complex sound-order rule were only found in infants without dyslexia risk, but these results are very preliminary due to small sample size. The results demonstrate the relevance of the newborn infants' readiness for phonetic learning for their emerging language skills. Phoneme extraction difficulties in infants at familial risk may contribute to the phonological deficits observed in dyslexia.

Phylogenetics of Australasian gall flies (Diptera: Fergusoninidae): Evolutionary patterns of host-shifting and gall morphology.

This study investigated host-specificity and phylogenetic relationships in Australian galling flies, Fergusonina Malloch (Diptera: Fergusoninidae), in order to assess diversity and explore the evolutionary history of host plant affiliation and gall morphology. A DNA barcoding approach using COI data from 203 Fergusonina specimens from 5gall types on 56 host plant species indicated 85 presumptive fly species. These exhibited a high degree of host specificity; of the 40 species with multiple representatives, each fed only on a single host genus, 29 (72.5%) were strictly monophagous, and 11 (27.5%) were reared from multiple closely related hosts. COI variation within species was not correlated with either sample size or geographic distance. However variation was greater within oligophagous species, consistent with expectations of the initial stages of host-associated divergence during speciation. Phylogenetic analysis using both nuclear and mitochondrial genes revealed host genus-restricted clades but also clear evidence of multiple colonizations of both host plant genus and host species. With the exception of unilocular peagalls, evolution of gall type was somewhat constrained, but to a lesser degree than host plant association. Unilocular peagalls arose more often than any other gall type, were primarily located at the tips of the phylogeny, and did not form clades comprising more than a few species. For ecological reasons, species of this gall type are predicted to harbor substantially less genetic variation than others, possibly reducing evolutionary flexibility resulting in reduced diversification in unilocular gallers.

Genetic differentiation associated with host plants and geography among six widespread species of South American Blepharoneura fruit flies (Tephritidae).

Tropical herbivorous insects are astonishingly diverse, and many are highly host-specific. Much evidence suggests that herbivorous insect diversity is a function of host plant diversity; yet, the diversity of some lineages exceeds the diversity of plants. Although most species of herbivorous fruit flies in the Neotropical genus Blepharoneura are strongly host-specific (they deposit their eggs in a single host plant species and flower sex), some species are collected from multiple hosts or flowers and these may represent examples of lineages that are diversifying via changes in host use. Here, we investigate patterns of diversification within six geographically widespread Blepharoneura species that have been collected and reared from at least two host plant species or host plant parts. We use microsatellites to (1) test for evidence of local genetic differentiation associated with different sympatric hosts (different plant species or flower sexes) and (2) examine geographic patterns of genetic differentiation across multiple South American collection sites. In four of the six fly species, we find evidence of local genetic differences between flies collected from different hosts. All six species show evidence of geographic structure, with consistent differences between flies collected in the Guiana Shield and flies collected in Amazonia. Continent-wide analyses reveal - in all but one instance - that genetically differentiated flies collected in sympatry from different host species or different sex flowers are not one another's closest relatives, indicating that genetic differences often arise in allopatry before, or at least coincident with, the evolution of novel host use.

Efficacy and safety of non-hormonal remedies for vaginal dryness: open, prospective, randomized trial.

OBJECTIVES: To prove non-inferiority of the first non-hormonal vaginal cream in Germany, Vagisan(®) Moisturising Cream (CREAM), compared to a non-hormonal vaginal gel (GEL) for vulvovaginal atrophy (VVA) symptom relief. METHOD: This was a 12-week multicenter, open-label, prospective, randomized, two-period, cross-over phase-III trial. The primary endpoint was the cumulative VVA subjective symptom score of the respective treatment period. Secondary endpoints were assessment of single VVA subjective and objective symptoms, VVA objective symptom score, vaginal pH, safety parameters, overall assessment of efficacy, tolerability and evaluation of product properties. In total, 117 women were randomly allocated to either one of the two treatments, each administered for 4 weeks; 92 women were included in the per-protocol analysis (primary analysis). The main outcome measure was cumulative VVA subjective symptom score. RESULTS: Regarding VVA symptom relief, results confirmed non-inferiority of CREAM compared to GEL and even indicated superiority of CREAM. Frequency and intensity of subjective symptoms and objective findings were clearly reduced, with CREAM showing better results compared to GEL. Mean VVA objective symptom score significantly decreased; improvement was significantly greater with CREAM. Vaginal pH decreased only following CREAM treatment. Tolerability was superior for CREAM: burning and itching, mostly rated as mild, occurred markedly less often with CREAM than with GEL. Overall satisfaction with treatment efficacy, tolerability and most product properties were rated significantly superior for CREAM. CONCLUSIONS: Subjective and objective VVA symptoms were reliably and safely reduced by both non-hormonal topical products. However, efficacy and tolerability of CREAM were shown to be superior to GEL.

Stress urinary incontinent women, the influence of age and hormonal status on estrogen receptor alpha and beta gene expression and protein immunoexpression in paraurethral tissues.

The underlying cause of stress urinary incontinence (SUI) is an anatomical abnormality associated with paraurethral connective tissue dysfunction. The question as to whether estrogens affect the quality of that tissue remains unexplained. Samples of paraurethral connective tissue from 81 women were examined (the SUI's n = 49; the control's n = 32). In both groups, the patients were subdivided into pre- and postmenopausals. Primary study outcome was comparison of the estrogen receptor alpha (ERα) and the estrogen receptor beta (ERß) gene and protein in paraurethral tissue between SUI and control group. Secondary study outcome was comparison of these receptors according to hormonal status of the patients and their age. In both examined groups, we found both ER proteins. The ERα gene expression was detected in-19/32 (SUI) samples and in 24/31 (control), and ERß gene expression 31/32 and 30/31 samples, respectively. The SUI's had significantly lower ERa gene expression premenopausally than the control's. The analysis found considerably lower ERß and reduced ERα gene expression in postmenopausals, approaches the significance level. There was also significant decrease in both receptors' genes expression in post-53 women, compared to younger patients. Spearman's correlation test revealed a statistically significant decrease in ERß gene with age. Both estrogen receptors are found in women's paraurethral tissue, so this tissue is an estrogen target. No correlation between ERß gene expression and immunoexpression and SUI was found. The ERα gene seems to play a key role in SUI in the premenopausal period, but ERß gene expression in the paraurethral connective tissue decreases with age.

The development of the perceptual organization of sound by frequency separation in 5-11-year-old children.

The analysis of the auditory scene begins from the moment we hear sounds, making it possible for the infant to distinguish the mother's voice from other sounds in the environment. The purpose of the study was to determine, in two experiments, whether the frequency separation threshold, at which the perception of a mixture of sounds turns from being perceived as one stream to two streams, differs between two groups of school-aged children (ages 5-8 and 9-11 years) and adults. The results show a developmental course for the perception of auditory streams that is not simply dependent upon frequency discrimination. This suggests that maturation of the stream segregation process follows a longer developmental course than maturation of simple feature discrimination. The data indicate that the ability to hear distinct sound streams in the environment takes time to develop and becomes sharpened with experience and maturity.

Mobilization of bone marrow-derived progenitors.

Bone marrow (BM) is a source of various stem and progenitor cells in the adult, and it is able to regenerate a variety of tissues following transplantation. In the 1970s the first BM stem cells identified were hematopoietic stem cells (HSCs). HSCs have the potential to differentiate into all myeloid (including erythroid) and lymphoid cell lineages in vitro and reconstitute the entire hematopoietic and immune systems following transplantation in vivo. More recently, nonhematopoietic stem and progenitor cells have been identified that can differentiate into other cell types such as endothelial progenitor cells (EPCs), contributing to the neovascularization of tumors as well as ischemic tissues, and mesenchymal stem cells (MSCs), which are able to differentiate into many cells of ectodermal, endodermal, and mesodermal origins in vitro as well as in vivo. Following adequate stimulation, stem and progenitor cells can be forced out of the BM to circulate into the peripheral blood, a phenomenon called "mobilization." This chapter reviews the molecular mechanisms behind mobilization and how these have led to the various strategies employed to mobilize BM-derived stem and progenitor cells in experimental and clinical settings. Mobilization of HSCs will be reviewed first, as it has been best-explored--being used extensively in clinics to transplant large numbers of HSCs to rescue cancer patients requiring hematopoietic reconstitution--and provides a paradigm that can be generalized to the mobilization of other types of BM-derived stem and progenitor cells in order to repair other tissues.

"Primitive intelligence" in the auditory cortex.

The everyday auditory environment consists of multiple simultaneously active sources with overlapping temporal and spectral acoustic properties. Despite the seemingly chaotic composite signal impinging on our ears, the resulting perception is of an orderly "auditory scene" that is organized according to sources and auditory events, allowing us to select messages easily, recognize familiar sound patterns, and distinguish deviant or novel ones. Recent data suggest that these perceptual achievements are mainly based on processes of a cognitive nature ("sensory intelligence") in the auditory cortex. Even higher cognitive processes than previously thought, such as those that organize the auditory input, extract the common invariant patterns shared by a number of acoustically varying sounds, or anticipate the auditory events of the immediate future, occur at the level of sensory cortex (even when attention is not directed towards the sensory input).

The role of predictive models in the formation of auditory streams.

Sounds provide us with useful information about our environment which complements that provided by other senses, but also poses specific processing problems. How does the auditory system distentangle sounds from different sound sources? And what is it that allows intermittent sound events from the same source to be associated with each other? Here we review findings from a wide range of studies using the auditory streaming paradigm in order to formulate a unified account of the processes underlying auditory perceptual organization. We present new computational modelling results which replicate responses in primary auditory cortex [Fishman, Y.I., Arezzo, J.C., Steinschneider, M., 2004. Auditory stream segregation in monkey auditory cortex: effects of frequency separation, presentation rate, and tone duration. J. Acoust. Soc. Am. 116, 1656-1670; Fishman, Y. I., Reser, D. H., Arezzo, J.C., Steinschneider, M., 2001. Neural correlates of auditory stream segregation in primary auditory cortex of the awake monkey. Hear. Res. 151, 167-187] to tone sequences. We also present the results of a perceptual experiment which confirm the bi-stable nature of auditory streaming, and the proposal that the gradual build-up of streaming may be an artefact of averaging across many subjects [Pressnitzer, D., Hupé, J. M., 2006. Temporal dynamics of auditory and visual bi-stability reveal common principles of perceptual organization. Curr. Biol. 16(13), 1351-1357.]. Finally we argue that in order to account for all of the experimental findings, computational models of auditory stream segregation require four basic processing elements; segregation, predictive modelling, competition and adaptation, and that it is the formation of effective predictive models which allows the system to keep track of different sound sources in a complex auditory environment.

[Strategies against the stigmatisation of mentally ill subjects and their practical realisation in the example of Irrsinnig Menschlich e. V]. / Strategien gegen die Stigmatisierung psychisch kranker Menschen und ihre praktische Umsetzung am Beispiel des Irrsinnig Menschlich e. V.

In our society people with mental illness are still stigmatised and exposed to various forms of discrimination. Individual and structural discrimination and discrimination due to self-stigmatisation can be distinguished. The association "Irrsinnig Menschlich" ("Madly human") in Leipzig will serve as a model to present approaches to reduce these different kinds of discrimination of mentally ill people. The school project "Crazy? So what!" and the film festival "Ausnahmezustand" ("state of emergency"), carried out all over Germany in 2006, will be described in more detail. The first evaluation of both projects showed a reduction of stigmatisation to be possible. Students participating in the project tended to decrease their social distance to the mentally ill. These developments were not present with the control groups. Although the majority of the audience at the film festival either knew somebody who is mentally ill or were themselves suffering from a mental illness, the results showed that watching these documentaries can result in a reduction of social distance towards mentally ill people. Only long-term efforts can make anti-stigma campaigns successful and effective. Irrsinnig Menschlich has established the framework for this.

Biased relevance filtering in the auditory system: A test of confidence-weighted first-impressions.

Although first-impressions are known to impact decision-making and to have prolonged effects on reasoning, it is less well known that the same type of rapidly formed assumptions can explain biases in automatic relevance filtering outside of deliberate behavior. This paper features two studies in which participants have been asked to ignore sequences of sound while focusing attention on a silent movie. The sequences consisted of blocks, each with a high-probability repetition interrupted by rare acoustic deviations (i.e., a sound of different pitch or duration). The probabilities of the two different sounds alternated across the concatenated blocks within the sequence (i.e., short-to-long and long-to-short). The sound probabilities are rapidly and automatically learned for each block and a perceptual inference is formed predicting the most likely characteristics of the upcoming sound. Deviations elicit a prediction-error signal known as mismatch negativity (MMN). Computational models of MMN generally assume that its elicitation is governed by transition statistics that define what sound attributes are most likely to follow the current sound. MMN amplitude reflects prediction confidence, which is derived from the stability of the current transition statistics. However, our prior research showed that MMN amplitude is modulated by a strong first-impression bias that outweighs transition statistics. Here we test the hypothesis that this bias can be attributed to assumptions about predictable vs. unpredictable nature of each tone within the first encountered context, which is weighted by the stability of that context. The results of Study 1 show that this bias is initially prevented if there is no 1:1 mapping between sound attributes and probability, but it returns once the auditory system determines which properties provide the highest predictive value. The results of Study 2 show that confidence in the first-impression bias drops if assumptions about the temporal stability of the transition-statistics are violated. Both studies provide compelling evidence that the auditory system extrapolates patterns on multiple timescales to adjust its response to prediction-errors, while profoundly distorting the effects of transition-statistics by the assumptions formed on the basis of first-impressions.

Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance.

The second generation Hoechst-Bayer non-nucleoside inhibitor, HBY 097 (S-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroqui noxalin-2(1H)-thione), is an extremely potent inhibitor of HIV-1 reverse transcriptase (RT) and of HIV-1 infection in cell culture. HBY 097 selects for unusual drug-resistance mutations in HIV-1 RT (e.g. Gly190Glu) when compared with other non-nucleoside RT inhibitors (NNRTIs), such as nevirapine, alpha-APA and TIBO. We have determined the structure of HBY 097 complexed with wild-type HIV-1 RT at 3.1 A resolution. The HIV-1 RT/HBY 097 structure reveals an overall inhibitor geometry and binding mode differing significantly from RT/NNRTI structures reported earlier, in that HBY 097 does not adopt the usual butterfly-like shape. We have determined the structure of the Tyr188Leu HIV-1 RT drug-resistant mutant in complex with HBY 097 at 3.3 A resolution. HBY 097 binds to the mutant RT in a manner similar to that seen in the wild-type RT/HBY 097 complex, although there are some repositioning and conformational alterations of the inhibitor. Conformational changes of the structural elements forming the inhibitor-binding pocket, including the orientation of some side-chains, are observed. Reduction in the size of the 188 side-chain and repositioning of the Phe227 side-chain increases the volume of the binding cavity in the Tyr188Leu HIV-1 RT/HBY 097 complex. Loss of important protein-inhibitor interactions may account for the reduced potency of HBY 097 against the Tyr188Leu HIV-1 RT mutant. The loss of binding energy may be partially offset by additional contacts resulting from conformational changes of the inhibitor and nearby amino acid residues. This would suggest that inhibitor flexibility can help to minimize drug resistance.

HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α.

Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic.

Hypoxia inducible factor (HIF)-2α accelerates disease progression in mouse models of leukemia and lymphoma but is not a poor prognosis factor in human AML.

Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.

Polyclonal antibodies to mannan from yeast also recognize the carbohydrate structure of gp120 of the AIDS virus: an approach to raise neutralizing antibodies to HIV-1 infection in vitro.

This study initiates a new method of developing an antigen which might be useful in the prevention of HIV-1 infection. Using a mannan preparation from Saccharomyces cerevisiae neutralizing antiserum was raised in rabbits which prevents HIV-1 infection in vitro up to a titre of 1:128. The corresponding antibody preparation neutralized the in vitro infectivity down to a concentration of 5 micrograms/ml. Analytical studies suggest that the antibodies are directed against the mannose residues of the HIV-1 glycoprotein (gp) 120 and its precursor gp 160.

Inhibition of HIV and virus replication by polysulphated polyxylan: HOE/BAY 946, a new antiviral compound.

Xylanpoly-(hydrogen sulphate) disodium salt with a molecular weight of about 6000 daltons (HOE/BAY 946) completely inhibited syncytium formation induced by the infection of T lymphocytes with HIV as well as viral replication at concentrations above 25 micrograms/ml. This dose was found to be inhibitory for several strains of HIV-1 and HIV-2. Low molecular weight fractions of the compound were less active against HIV, and high molecular derivatives were as active as HOE/BAY 946. A direct influence of the drug on the infectivity of the virus could not be demonstrated. The drug inhibited the reverse transcriptase of HIV. Treatment of permanently HIV-infected U937 cells resulted in a drastic reduction of virus particles released into the supernatant and points to an additional mode of action. A therapeutic effect of HOE/BAY 946 against retroviruses in vivo could be demonstrated in Friend leukaemia virus-infected mice. A clinical pilot study with the compound was started recently in Germany with AIDS patients who did not tolerate or refused to take zidovudine and with asymptomatic virus carriers.

The D-mannose-specific lectin from Gerardia savaglia blocks binding of human immunodeficiency virus type I to H9 cells and human lymphocytes in vitro.

The new D-mannose-specific lectin from Gerardia savaglia is shown to prevent infection of H9 cells with human immunodeficiency virus type 1 (HIV-1; strain HTLV-IIIB). At a concentration of 0.2 microM, complete protection was achieved. Even at a 50-fold higher concentration, this lectin is not toxic for the cells. Moreover, the lectin inhibits syncytium formation in the HTLV-IIIB/H9-Jurkat cell system to 100% at 0.2 microM. This effect was abolished by coaddition of D-mannose at a stoichiometric ratio of lectin to sugar of 1:500. The lectin-caused inhibition of syncytia formation was observed also in the HIV-1/human lymphocyte system. Perhaps more importantly, it is shown that the lectin reacts with the oligosaccharide side chains of the HIV-1 gp120 env molecule, which very likely can be classified to the high-mannose oligosaccharides. These data provide the basis for a rational screening for compounds interfering with gp120-CD4 interactions.

A rapid streptavidin-capture ELISA specific for the detection of antibodies to feline foamy virus.

We report a simple procedure for the rapid development of an ELISA with the potential for wide application to any defined protein antigen. The procedure involves the expression of protein encoded by a PCR product, using a commercially available T-vector that adds a biotin tag, and a single step purification by affinity for streptavidin for direct use in ELISA. In our experiments, a recombinant protein from the nucleocapsid domain of the feline foamy virus gag gene was expressed as a fusion protein with a biotin tag and then applied directly to streptavidin-coated ELISA wells. An extract from a clone with the insert in antisense orientation was used as a control. Non-specific reactions with antigen extracts from both sense and antisense clones were observed in 6 of the 376 (1.6%) sera tested. Antibody to feline foamy virus, which forms a stable persistent infection in cats, was detected in 107 of 201 (53%) Australian cats, but none of 175 sera from veterinarians. There was a 100% correlation between FeFV antibody detected by ELISA, immunoblot, serum neutralisation and virus isolation, confirming that this test is sensitive and specific.

The concept of auditory stimulus representation in cognitive neuroscience.

The sequence of neurophysiological processes elicited in the auditory system by a sound is analyzed in search of the stage at which the processes carrying sensory information cross the borderline beyond which they directly underlie sound perception. Neurophysiological data suggest that this transition occurs when the sensory input is mapped onto the physiological basis of sensory memory in the auditory cortex. At this point, the sensory information carried by the stimulus-elicited process corresponds, for the first time, to that contained by the actual sound percept. Before this stage, the sensory stimulus code is fragmentary, lacks the time dimension, cannot enter conscious perception, and is not accessible to top-down processes (voluntary mental operations). On these grounds, 2 distinct stages of auditory sensory processing, prerepresentational and representational, can be distinguished.

Secondary metabolites by chemical screening. 17. Nigericinol derivatives: synthesis, biological activities, and modeling studies.

The synthesis and the biological activity of C-1-reduced nigericin derivatives (nigericinols) are described and discussed. The dichloronigericinol 7 impressively demonstrated that the C-1 carboxylic acid moiety was not required for a distinct activity against bacteria and viruses. Based on the correlation between K+/H+ antiport activities and antibacterial activities it was deduced that the mode of action of the described nigericinols are related to their ionophoric properties. Molecular modeling studies showed that the efficiency of the nigericinols as ionophores correlates, qualitatively, with the probability of forming a cyclic structure, with the exception of 7.