The Early Subcortical Response at the Fundamental Frequency of Speech Is Temporally Separated from Later Cortical Contributions.

Most parts of speech are voiced, exhibiting a degree of periodicity with a fundamental frequency and many higher harmonics. Some neural populations respond to this temporal fine structure, in particular at the fundamental frequency. This frequency-following response to speech consists of both subcortical and cortical contributions and can be measured through EEG as well as through magnetoencephalography (MEG), although both differ in the aspects of neural activity that they capture: EEG is sensitive to both radial and tangential sources as well as to deep sources, whereas MEG is more restrained to the measurement of tangential and superficial neural activity. EEG responses to continuous speech have shown an early subcortical contribution, at a latency of around 9 msec, in agreement with MEG measurements in response to short speech tokens, whereas MEG responses to continuous speech have not yet revealed such an early component. Here, we analyze MEG responses to long segments of continuous speech. We find an early subcortical response at latencies of 4-11 msec, followed by later right-lateralized cortical activities at delays of 20-58 msec as well as potential subcortical activities. Our results show that the early subcortical component of the FFR to continuous speech can be measured from MEG in populations of participants and that its latency agrees with that measured with EEG. They furthermore show that the early subcortical component is temporally well separated from later cortical contributions, enabling an independent assessment of both components toward further aspects of speech processing.

Attentional Modulation of the Cortical Contribution to the Frequency-Following Response Evoked by Continuous Speech.

Selective attention to one of several competing speakers is required for comprehending a target speaker among other voices and for successful communication with them. It moreover has been found to involve the neural tracking of low-frequency speech rhythms in the auditory cortex. Effects of selective attention have also been found in subcortical neural activities, in particular regarding the frequency-following response related to the fundamental frequency of speech (speech-FFR). Recent investigations have, however, shown that the speech-FFR contains cortical contributions as well. It remains unclear whether these are also modulated by selective attention. Here we used magnetoencephalography to assess the attentional modulation of the cortical contributions to the speech-FFR. We presented both male and female participants with two competing speech signals and analyzed the cortical responses during attentional switching between the two speakers. Our findings revealed robust attentional modulation of the cortical contribution to the speech-FFR: the neural responses were higher when the speaker was attended than when they were ignored. We also found that, regardless of attention, a voice with a lower fundamental frequency elicited a larger cortical contribution to the speech-FFR than a voice with a higher fundamental frequency. Our results show that the attentional modulation of the speech-FFR does not only occur subcortically but extends to the auditory cortex as well.SIGNIFICANCE STATEMENT Understanding speech in noise requires attention to a target speaker. One of the speech features that a listener can use to identify a target voice among others and attend it is the fundamental frequency, together with its higher harmonics. The fundamental frequency arises from the opening and closing of the vocal folds and is tracked by high-frequency neural activity in the auditory brainstem and in the cortex. Previous investigations showed that the subcortical neural tracking is modulated by selective attention. Here we show that attention affects the cortical tracking of the fundamental frequency as well: it is stronger when a particular voice is attended than when it is ignored.

How to stay attached-Formation of the ricefish plug and changes of internal reproductive structures in the pelvic brooding ricefish, Oryzias eversi Herder et al. (2012) (Beloniformes: Adrianichthyidae).

Teleost fishes show an enormous diversity of parental care, ranging from no care to viviparity with maternal provisioning of embryos. External brooders carry their developing eggs attached to their bodies. This requires the formation of novel morphological structures to support attachment. The pelvic brooding ricefish Oryzias eversi evolved such a structure, called the "plug." The plug anchors attaching filaments from the fertilized eggs inside the female reproductive system, allowing the female to carry the embryos until hatching. Using histological sections and µ-computed tomography scanning, we show that the plug is formed by several types of interstitial cells, blood capillaries, and collagen fibrils that encapsulate the end of the attaching filaments in the anterior part of the gonoduct. Even 15 days after the loss of the protruding attaching filaments, the plug remains. In addition, the developed plug contains multinucleated giant cells that are derived from fusing macrophages. We thus hypothesize that the ricefish plug, which is vital for egg attachment in O. eversi, evolved due to an inflammatory reaction. We assume that it forms similar to a foreign body granuloma, as a reaction to irritation or injury of the gonoduct epithelium by the attaching filaments. Our study further corroborates that pelvic brooding entails a complex set of adaptations to prolonged egg-carrying in the female reproductive system. During brooding, for instance, ovulation in the ovary is suppressed and the anterior part of the gonoduct is characterized by an intricate, recessed folding.

Inflammation and convergent placenta gene co-option contributed to a novel reproductive tissue.

The evolution of pregnancy exposes parental tissues to new, potentially stressful conditions, which can trigger inflammation.1 Inflammation is costly2,3 and can induce embryo rejection, which constrains the evolution of pregnancy.1 In contrast, inflammation can also promote morphological innovation at the maternal-embryonic interface as exemplified by co-option of pro-inflammatory signaling for eutherian embryo implantation.1,4,5 Given its dual function, inflammation could be a key process explaining how innovations such as pregnancy and placentation evolved many times convergently. Pelvic brooding ricefishes evolved a novel "plug" tissue,6,7 which forms inside the female gonoduct after spawning, anchors egg-attaching filaments, and enables pelvic brooders to carry eggs externally until hatching.6,8 Compared to pregnancy, i.e., internal bearing of embryos, external bearing should alleviate constraints on inflammation in the reproductive tract. We thus hypothesized that an ancestral inflammation triggered by the retention of attaching filaments gave rise to pathways orchestrating plug formation. In line with our hypothesis, histological sections of the developing plug revealed signs of gonoduct injuries by egg-attaching filaments in the pelvic brooding ricefish Oryzias eversi. Tissue-specific transcriptomes showed that inflammatory signaling dominates the plug transcriptome and inflammation-induced genes controlling vital processes for plug development such as tissue growth and angiogenesis were overexpressed in the plug. Finally, mammalian placenta genes were enriched in the plug transcriptome, indicating convergent gene co-option for building, attaching, and sustaining a transient tissue in the female reproductive tract. This study highlights the role of gene co-option and suggests that recruiting inflammatory signaling into physiological processes provides a fast-track to evolutionary innovation.

Degradation of microvascular brain endothelial cell beta-catenin after co-culture with activated neutrophils from patients undergoing cardiac surgery with prolonged cardiopulmonary bypass.

The adhesion of highly activated neutrophils to cerebral microvascular endothelial cells (MVECs) may contribute to disruption and hyperpermeability of the blood-brain barrier (BBB) after cardiac surgery with prolonged cardiopulmonary bypass (CPB). A correlation between CPB duration and neutrophil-mediated BBB damage has not been investigated on the cellular level yet. Therefore, we studied the effects of neutrophils from cardiac surgery patients with CPB time <80 min (group I; n=8) and >80 min (group II; n=8) on the integrity of cultured porcine MVEC. Ex vivo, neutrophils of group II but not of group I significantly degraded the zonula adherens molecule beta-catenin whereas VE-cadherin and occludin were not modified. The transendothelial electric resistance as a measure for the integrity of the endothelial monolayers was reduced over time in both groups. In conclusion, prolonged CPB time entails neutrophil-mediated decrease in MVEC beta-catenin expression, and thus may be an important trigger for BBB disruption.

Cardiac surgery with extracorporeal circulation: neutrophil transendothelial migration is mediated by beta1 integrin (CD29) in the presence of TNF-alpha.

Cardiac surgery with extracorporeal circulation is associated with neutrophil activation, inflammation, and edema. Endothelial hyperpermeability elicited by the interaction of activated neutrophils and/or cytokines with endothelial cells may be critical in this regard. However, the immune and cellular mechanisms involved are not fully understood. Cocultures with human endothelial cells and neutrophils from cardiac surgery patients were used to evaluate the role of beta1 integrin activity and the proinflammatory cytokine tumor necrosis factor (TNF)-alpha in neutrophil transendothelial migration and in impairment of the integrity of endothelial cell-to-cell contacts. Blocking of CD29 (heavy chain of beta1 integrins) totally prevented neutrophil adhesion and transendothelial migration. Pretreatment of neutrophils with either a CD29-stimulating monoclonal antibody or the addition of TNF-alpha (0.1-10 U/ml) to the coculture failed to induce transendothelial migration. However, coculture of endothelial cells with CD29-stimulated neutrophils in the presence of 0.1-10 U/ml TNF-alpha strongly induced neutrophil transmigration. CD29/TNF-alpha-mediated transmigration was associated with intracellular redistribution of endothelial beta-catenin. We further showed that CD29/TNF-alpha-mediated effects involved PI3K and tyrosine kinase-dependent signaling via MAPK but were independent of nuclear transcription factor (NF)-kappaB activity. Inhibition of CD29/TNF-alpha might be a therapeutic option to limit endothelial dysfunction following cardiac surgery with extracorporeal circulation.

The Na+/H+ exchange inhibitor HOE642 prevents stress-induced epithelial barrier dysfunction.

Recently, evidence has been obtained that the Na+/H+ exchange (NHE) inhibitor HOE642 may stabilize endothelial and epithelial barrier function in vivo. However, the underlying mechanisms are not known. Therefore, we studied the influence of HOE642 on the barrier function of the epithelial cell line CaCo2. The phorbolester phorbol 12-myristate 13-acetate (PMA) was used to induce hyperpermeability of the epithelial layer which was indirectly determined by measuring the transepithelial electrical resistance (TER). Confocal laser scan microscopy (LSM) served to analyze the intracellular localization of adherens and tight junction molecules. In five independent experiments we found that HOE642 increased TER in non-treated CaCo2 cells (control: 350 +/- 28 Omega/cm2; HOE642: 444 +/- 53 Omega/cm2) and prevented PMA-induced barrier dysfunction (PMA: 33 +/- 12 Omega/cm2; PMA plus HOE642: 496 +/- 47 Omega/cm2). LSM showed that HOE642 prevented the PMA-induced disassociation of the zonula adherens molecule beta-catenin from the cell membrane and the decreased expression of the zonula occludens molecule ZO-1. From our data we conclude that HOE642 may prevent stress-induced epithelial dysfunction by stabilization of cell membrane-associated junction molecules.

In vivo inhibition of neutrophil activity by a FAS (CD95) stimulating module: arterial in-line application in a porcine cardiac surgery model.

OBJECTIVE: Cardiac surgery with cardiopulmonary bypass is associated with aberrant neutrophil activation and potentially severe pathogenic sequelae. This experimental study was done to evaluate a leukocyte inhibition module that rapidly inactivates neutrophils through CD95 stimulation. METHODS: German landrace pigs (4 groups, each n = 5) underwent cardiac surgery without cardiopulmonary bypass (group I), with cardiopulmonary bypass (group II), with cardiopulmonary bypass plus a leukocyte filter (group III), and with cardiopulmonary bypass plus a leukocyte inhibition module (group IV). The leukocyte filter or leukocyte inhibition module was introduced into the arterial line of the heart-lung machine. RESULTS: Leukocyte counts were decreased by up to 43% in group IV compared with values in group II (P =.023). In group IV, but not in groups I to III, no delay in spontaneous neutrophil apoptosis was observed after annexin V-propidium iodide staining. Late apoptotic (11.7%) or necrotic neutrophils (9.3%) were detected in 2 animals (group IV). Tumor necrosis factor alpha serum levels increased over time in groups I to III (>2-fold) but remained at baseline levels in group IV (P <.05). Interleukin 8-mediated chemotactic neutrophil transmigration activity increased over time in groups I to III but was totally abrogated in group IV at any time point. The perioperative increase of creatine kinase and creatine kinase MB levels was lower in groups III (1.5-fold and 1.3-fold, respectively) and IV (1.2-fold and 1.5-fold, respectively) compared with values in group II (both 1.9-fold). CONCLUSIONS: The leukocyte inhibition module downregulated cardiopulmonary bypass-related neutrophil activity and thus might be beneficial in cardiac surgery and other clinical settings with unappreciated neutrophil activation.

Relocalization of endothelial cell beta-catenin after coculture with activated neutrophils from patients undergoing cardiac surgery with cardiopulmonary bypass.

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with neutrophil activation, inflammation, and consecutive edema. The impairment of endothelial junction molecules, and thus, hyperpermeability elicited by the interaction of activated neutrophils with endothelial cells may be important in this regard. Cocultures with human endothelial cells and neutrophils from 10 cardiac surgery patients with CPB were used to evaluate the role of neutrophils in modifications of the endothelial zonula adherens molecules VE-cadherin and beta-catenin. Laser scan microscopic analyses showed that neutrophils, which were isolated after the beginning of CPB, significantly impaired intracellular redistribution of endothelial beta-catenin with regard to membrane association (p <.0002) and staining pattern (p <.0001). VE-cadherin localization was not found to be significantly modified. Western blots with total cell extracts showed that amounts of beta-catenin did not vary significantly after co-culture with activated neutrophils. Activated neutrophils during cardiac surgery with CPB may induce endothelial dysfunction by impairing beta-catenin localization and thus contribute to endothelial hyperpermeability.

Inhibition of neutrophil activity in cardiac surgery with cardiopulmonary bypass: a novel strategy with the leukocyte inhibition module.

Recently, we showed that the arterial in-line application of the leukocyte inhibition module (LIM) within the heart-lung machine limits overshooting leukocyte activity and cardiac tissue damage. Moreover, significantly better cardiac function was found in an experimental animal model when LIM was used. In the meantime, the first promising clinical data exist. LIM has to be regarded as an essential tool in extracorporeal circulation, in the future, to improve postoperative clinical outcome and to reduce costs. This review summarizes the biological background of LIM and the current experience obtained in experimental models and clinical studies.

Supernatants from human cytomegalovirus (HCMV)-infected retinal glial cells increase transepithelial electrical resistance in a cell culture model: evidence of HCMV immune escape in the eye?

The underlying mechanisms leading to persistence of human cytomegalovirus (HCMV) in the immune privileged retina are not fully understood. This in vitro study was done to evaluate the influence of HCMV-infected retinal glial cells on epithelial barrier functions. Glial cells derived from human eyes were cultured and infected with the clinical HCMV isolate Hi91. Supernatants of mock (GS(mock)) and Hi91 (GS(Hi91)) -infected glial cells were collected at 72 h post inoculation and used for incubation of CaCo-2 cells grown in transwell chambers. Transepithelial electrical resistance (TER) was analyzed as a measure of epithelial integrity. Virus-free GS(Hi91 )but not GS(mock) increased TER from 250 Omega/cm(2) to more than 1,000 Omega/cm(2)within 2 h. Increased TER values were measured up to 48 h (n = 3). No changes in TER were observed when conditioned supernatants from HCMV-infected human foreskin fibroblasts were used. No evidence of GS(Hi91)-induced modification of beta-catenin (zonula adherens) or occludin and ZO-1 (zonula occludens) was found. Our results suggest that HCMV-infected glial cells may support epithelial barrier functions by a yet unknown mechanism. Our findings may help to explain the ocular persistence of HCMV and the maintenance of ocular immune privilege early in infection.