Noise-Induced Inner Hair Cell Ribbon Loss Disturbs Central Arc Mobilization: A Novel Molecular Paradigm for Understanding Tinnitus

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.     

Bone marrow-derived mesenchymal stromal cells from patients with end-stage renal disease are suitable for autologous therapy

Background aimsMesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive and reparative properties in vitro and in vivo. Although autologous bone marrow (BM)-derived MSCs are already clinically tested in transplant recipients, it is unclear whether these BM cells are affected by renal disease. We assessed whether renal failure affected the function and therapeutic potential of BM-MSCs.MethodsMSCs from 10 adults with end-stage renal disease (ESRD) and 10 age-matched healthy controls were expanded from BM aspirates and tested for phenotype and functionality in vitro.ResultsMSCs from ESRD patients were >90% positive for CD73, CD90 and CD105 and negative for CD34 and CD45 and showed a similar morphology and differentiation capacity as MSCs from healthy controls. Of importance for their clinical utility, growth characteristics were similar in both groups, and sufficient numbers of MSCs were obtained within 4 weeks. Messenger RNA expression levels of self-renewal genes and factors involved in repair and inflammation were also comparable between both groups. Likewise, microRNA expression profiling showed a broad overlap between ESRD and healthy donor MSCs. ESRD MSCs displayed the same immunosuppressive capacities as healthy control MSCs, demonstrated by a similar dose-dependent inhibition of peripheral blood mononuclear cell proliferation, similar inhibition of proinflammatory cytokines tumor necrosis factor-α and interferon-γ production and a concomitant increase in the production of interleukin-10.ConclusionsExpanded BM-MSCs procured from ESRD patients and healthy controls are both phenotypically and functionally similar. These findings are important for the potential autologous clinical application of BM-MSCs in transplant recipients.     

Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization

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Nectar robbery by a hermit hummingbird: association to floral phenotype and its influence on flowers and network structure

Interactions between flowers and their visitors span the spectrum from mutualism to antagonism. The literature is rich in studies focusing on mutualism, but nectar robbery has mostly been investigated using phytocentric approaches focused on only a few plant species. To fill this gap, we studied the interactions between a nectar-robbing hermit hummingbird, Phaethornis ruber, and the array of flowers it visits. First, based on a literature review of the interactions involving  P. ruber, we characterized the association of floral larceny to floral phenotype. We then experimentally examined the effects of nectar robbing on nectar standing crop and number of visits of the pollinators to the flowers of Canna paniculata. Finally, we asked whether the incorporation of illegitimate interactions into the analysis affects plant–hummingbird network structure. We identified 97 plant species visited by P. ruber and found that P. ruber engaged in floral larceny in almost 30 % of these species. Nectar robbery was especially common in flowers with longer corolla. In terms of the effect on C. paniculata, the depletion of nectar due to robbery by P. ruber was associated with decreased visitation rates of legitimate pollinators. At the community level, the inclusion of the illegitimate visits of P. ruber resulted in modifications of how modules within the network were organized, notably giving rise to a new module consisting of P. ruber and mostly robbed flowers. However, although illegitimate visits constituted approximately 9 % of all interactions in the network, changes in nestedness, modularity, and network-level specialization were minor. Our results indicate that although a flower robber may have a strong effect on the pollination of a particular plant species, the inclusion of its illegitimate interactions has limited capacity to change overall network structure.     

Turning Defense into Offense: Defensin Mimetics as Novel Antibiotics Targeting Lipid II

We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections.     

A presumed case of functional convergence between the flowers of Schizolobium parahyba (Fabaceae) and species of Malpighiaceae

Flowers of Malpighiaceae have a flag petal with a sturdy base that Centridini bees clasp with their mandibles to free their legs and thus be able to harvest oil. We found that the yellow, nectariferous flowers of Schizolobium parahyba (Fabaceae) have a forward-flexed upper petal with a sturdy claw and an adnate filament. Two Centris species were among the most frequent bee visitors to S. parahyba flowers. These bees clasped the adnate filament and the claw of the upper petal with their mandibles and extended their mouthparts into the corolla to take nectar. During the visit they leaned on, or loosely grabbed, the stamens. Blooming in the same area and period were two yellow-flowered Stigmaphyllon species (Malpighiaceae) whose pollen was also found on loads carried by the Centris bees. The flexion and the sturdiness of the upper petal claw of Schizolobium parahyba flowers may be viewed as a trait that suits the mandible clasp of Centris bees. Although this clasp is not needed when the bees visit S. parahyba flowers, it is vital when the bees exploit flowers of the Malpighiaceae. We suggest that the sturdy claw and the adnate filament of S. parahyba may be viewed as an instance of presumed functional convergence with the upper petal of Malpighiaceae.     

Psychometric Properties of the Participation Scale among Former Buruli Ulcer Patients in Ghana and Benin

Background

Buruli ulcer is a stigmatising disease treated with antibiotics and wound care, and sometimes surgical intervention is necessary. Permanent limitations in daily activities are a common long term consequence. It is unknown to what extent patients perceive problems in participation in social activities. The psychometric properties of the Participation Scale used in other disabling diseases, such as leprosy, was assessed for use in former Buruli ulcer patients.

Methods

Former Buruli ulcer patients in Ghana and Benin, their relatives, and healthy community controls were interviewed using the Participation Scale, Buruli Ulcer Functional Limitation Score, and the Explanatory Model Interview Catalogue to measure stigma. The Participation Scale was tested for the following psychometric properties: discrimination, floor and ceiling effects, internal consistency, inter-item correlation, item-total correlation and construct validity.

Results

In total 386 participants (143 former Buruli ulcer patients with their relatives (137) and 106 community controls) were included in the study. The Participation Scale displayed good discrimination between former Buruli ulcer patients and healthy community controls. No floor and ceiling effects were found. Internal consistency (Cronbach''s alpha) was 0.88. In Ghana, mean inter-item correlation of 0.29 and item-total correlations ranging from 0.10 to 0.69 were found while in Benin, a mean inter-item correlation of 0.28 was reported with item-total correlations ranging from −0.08 to 0.79. With respect to construct validity, 4 out of 6 hypotheses were not rejected, though correlations between various constructs differed between countries.

Conclusion

The results indicate the Participation Scale has acceptable psychometric properties and can be used for Buruli ulcer patients in Ghana and Benin. Future studies can use this Participation Scale to evaluate the long term restrictions in participation in daily social activities of former BU patients.     

Gait Initiation in Children with Rett Syndrome

Rett syndrome is an X-linked neurodevelopmental condition mainly characterized by loss of spoken language and a regression of purposeful hand use, with the development of distinctive hand stereotypies, and gait abnormalities. Gait initiation is the transition from quiet stance to steady-state condition of walking. The associated motor program seems to be centrally mediated and includes preparatory adjustments prior to any apparent voluntary movement of the lower limbs. Anticipatory postural adjustments contribute to postural stability and to create the propulsive forces necessary to reach steady-state gait at a predefined velocity and may be indicative of the effectiveness of the feedforward control of gait. In this study, we examined anticipatory postural adjustments associated with gait initiation in eleven girls with Rett syndrome and ten healthy subjects. Muscle activity (tibialis anterior and soleus muscles), ground reaction forces and body kinematic were recorded. Children with Rett syndrome showed a distinctive impairment in temporal organization of all phases of the anticipatory postural adjustments. The lack of appropriate temporal scaling resulted in a diminished impulse to move forward, documented by an impairment in several parameters describing the efficiency of gait start: length and velocity of the first step, magnitude and orientation of centre of pressure-centre of mass vector at the instant of (swing-)toe off. These findings were related to an abnormal muscular activation pattern mainly characterized by a disruption of the synergistic activity of antagonistic pairs of postural muscles. This study showed that girls with Rett syndrome lack accurate tuning of feedforward control of gait.