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"Schulz, Kristina"
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The independence of the media and its regulatory agencies : shedding new light on formal and actual independence against the national context
With contributions from leading researchers from different regions of Europe and the United States, the publication's scope is unique in its comprehensiveness in relation to a specific topic and its innovative approach. Contributions go beyond existing theory in exploring methodologies to operationalize and measure formal and actual levels of independence of media and its regulatory agencies.
Book
Simultaneous BOLD fMRI and fiber-optic calcium recording in rat neocortex
Simultaneous functional magnetic resonance imaging (fMRI) and fiber-optic–based calcium recordings in rats allow investigation of the relationship between blood oxygen level–dependent (BOLD) fMRI signals and the underlying neural activity. The study uncovers prolonged BOLD signal components involving glial activation.
Functional magnetic resonance imaging (fMRI) based on blood oxygen level–dependent (BOLD) contrast is widely used for probing brain activity, but its relationship to underlying neural activity remains elusive. Here, we combined fMRI with fiber-optic recordings of fluorescent calcium indicator signals to investigate this relationship in rat somatosensory cortex. Electrical forepaw stimulation (1–10 Hz) evoked fast calcium signals of neuronal origin that showed frequency-dependent adaptation. Additionally, slower calcium signals occurred in astrocyte networks, as verified by astrocyte-specific staining and two-photon microscopy. Without apparent glia activation, we could predict BOLD responses well from simultaneously recorded fiber-optic signals, assuming an impulse response function and taking into account neuronal adaptation. In cases with glia activation, we uncovered additional prolonged BOLD signal components. Our findings highlight the complexity of fMRI BOLD signals, involving both neuronal and glial activity. Combined fMRI and fiber-optic recordings should help to clarify cellular mechanisms underlying BOLD signals.
Journal Article
Purinergic Signaling in the Vertebrate Olfactory System
Adenosine 5'-triphosphate (ATP) is an ubiquitous co-transmitter in the vertebrate brain. ATP itself, as well as its breakdown products ADP and adenosine are involved in synaptic transmission and plasticity, neuron-glia communication and neural development. Although purinoceptors have been demonstrated in the vertebrate olfactory system by means of histological techniques for many years, detailed insights into physiological properties and functional significance of purinergic signaling in olfaction have been published only recently. We review the current literature on purinergic neuromodulation, neuron-glia interactions and neurogenesis in the vertebrate olfactory system.
Journal Article
Reorganization of cortical population activity imaged throughout long-term sensory deprivation
The authors explore how sensory maps are reshaped by experience
in vivo
, using chronic two-photon calcium imaging to follow whisker-evoked activity of individual layer 2/3 neurons in adult mouse barrel cortex over weeks. By first measuring activity with whiskers intact and then with continued trimming of all but one whisker, they describe how the redistribution of population activity underlies large-scale cortical remapping.
Sensory maps are reshaped by experience. It is unknown how map plasticity occurs
in vivo
in functionally diverse neuronal populations because activity of the same cells has not been tracked over long time periods. Here we used repeated two-photon imaging of a genetic calcium indicator to measure whisker-evoked responsiveness of the same layer 2/3 neurons in adult mouse barrel cortex over weeks, first with whiskers intact, then during continued trimming of all but one whisker. Across the baseline period, neurons displayed heterogeneous yet stable responsiveness. During sensory deprivation, responses to trimmed whisker stimulation globally decreased, whereas responses to spared whisker stimulation increased for the least active neurons and decreased for the most active neurons. These findings suggest that recruitment of inactive, 'silent' neurons is part of a convergent redistribution of population activity underlying sensory map plasticity. Sensory-driven responsiveness is a key property controlling experience-dependent activity changes in individual neurons.
Journal Article
Piezo activity levels need to be tightly regulated to maintain normal morphology and function in pericardial nephrocytes
Due to their position on glomerular capillaries, podocytes are continuously counteracting biomechanical filtration forces. Most therapeutic interventions known to generally slow or prevent the progression of chronic kidney disease appear to lower these biomechanical forces on podocytes, highlighting the critical need to better understand podocyte mechano-signalling pathways. Here we investigated whether the mechanotransducer Piezo is involved in a mechanosensation pathway in
Drosophila
nephrocytes, the podocyte homologue in the fly. Loss of function analysis in Piezo depleted nephrocytes reveal a severe morphological and functional phenotype. Further, pharmacological activation of endogenous Piezo with Yoda1 causes a significant increase of intracellular Ca
++
upon exposure to a mechanical stimulus in nephrocytes, as well as filtration disturbances. Elevated Piezo expression levels also result in a severe nephrocyte phenotype. Interestingly, expression of Piezo which lacks mechanosensitive channel activity, does not result in a severe nephrocyte phenotype, suggesting the observed changes in Piezo wildtype overexpressing cells are caused by the mechanosensitive channel activity. Moreover, blocking Piezo activity using the tarantula toxin GsMTx4 reverses the phenotypes observed in nephrocytes overexpressing Piezo. Taken together, here we provide evidence that Piezo activity levels need to be tightly regulated to maintain normal pericardial nephrocyte morphology and function.
Journal Article
Using Genetically Encoded Calcium Indicators to Study Astrocyte Physiology: A Field Guide
Ca
2+
imaging is the most frequently used technique to study glial cell physiology. While chemical Ca
2+
indicators served to visualize and measure changes in glial cell cytosolic Ca
2+
concentration for several decades, genetically encoded Ca
2+
indicators (GECIs) have become state of the art in recent years. Great improvements have been made since the development of the first GECI and a large number of GECIs with different physical properties exist, rendering it difficult to select the optimal Ca
2+
indicator. This review discusses some of the most frequently used GECIs and their suitability for glial cell research.
Journal Article
Invasive lobular carcinoma: clinicopathological features and subtypes
Objective
To analyze the characteristics of invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC) and to investigate the impact of histology on axillary lymph node (ALN) involvement in luminal A subtype tumors.
Methods
We retrospectively analyzed patients diagnosed with ILC or IDC from 2012 to 2016 who underwent surgery. Patients constituted 493 primary early breast cancer cases (82 ILC; 411 IDC).
Results
Compared with IDC, ILC tumors were significantly more likely to be grade 2, estrogen receptor- (ER) positive (+), have a lower proliferation rate (Ki67 <14%), and a higher pathological T stage (pT2–4). The luminal A subtype was significantly more common in ILC compared with IDC. In a multivariate regression model, grade 2, ER+, progesterone receptor-positive, pT2, and pT3 were significantly associated with ILC. Additionally, with the luminal A subtype, ALN involvement (pathological node stage (pN)1–3) was significantly more frequent with ILC versus IDC.
Conclusions
Our data suggest that grade 2, positive hormone receptor status, and higher pathological T stage are associated with ILC. With the luminal A subtype, ALN involvement was more frequent with ILC versus IDC.
Journal Article
Neuroinflammation causes mitral cell dysfunction and olfactory impairment in a multiple sclerosis model
Background
Olfactory dysfunction is an underestimated symptom in multiple sclerosis (MS). Here, we examined the pathogenic mechanisms underlying inflammation-induced dysfunction of the olfactory bulb using the animal model of MS, experimental autoimmune encephalomyelitis (EAE).
Results
Reduced olfactory function in EAE was associated with the degeneration of short-axon neurons, immature neurons, and both mitral and tufted cells, along with their synaptic interactions and axonal repertoire. To dissect the mechanisms underlying the susceptibility of mitral cells, the main projection neurons of the olfactory bulb, we profiled their responses to neuroinflammation by single-nucleus RNA sequencing followed by functional validation. Neuroinflammation resulted in the induction of potassium channel transcripts in mitral cells, which was reflected in increased halothane-induced outward currents of these cells, likely contributing to the impaired olfaction in EAE animals.
Conclusion
This study reveals the crucial role of mitral cells and their potassium channel activity in the olfactory bulb during EAE, thereby enhancing our understanding of neuroinflammation-induced neurodegeneration in MS.
Journal Article
Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab
Background:
Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown.
Methods:
Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into ‘TP’, ‘other-HER2-targeted therapy’ and ‘no-HER2-targeted therapy’ according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM).
Results:
A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%.
Conclusion:
First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.
Journal Article
Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation
Adenine nucleotides such as ATP, ADP, and adenosine are important modulators of neuronal function by engaging P1 and P2 purinergic receptors. In mitral cells, signaling of the G protein-coupled P1 receptor adenosine 1 receptor (A1R) affects the olfactory sensory pathway by regulating high voltage-activated calcium channels and two-pore domain potassium channels. Central nervous system (CNS) inflammation impairs olfactory function and gives rise to large amounts of extracellular ATP and adenosine, which act as pro-inflammatory and anti-inflammatory mediators, respectively. However, it is unclear whether neuronal A1R in the olfactory bulb modulates sensory function and how this is impacted by inflammation. Here we show that signaling via neuronal A1R is important for physiological olfactory function, while it cannot counteract inflammation-induced hyperexcitability and olfactory deficit. Using neuron-specific A1R-deficient mice in patch-clamp recordings, we found that adenosine modulates spontaneous dendro-dendritic signaling in mitral and granule cells via A1R. Furthermore, neuronal A1R deficiency resulted in olfactory dysfunction in two separate olfactory tests. In mice with experimental autoimmune encephalomyelitis (EAE) we detected immune cell infiltration and microglia activation in the olfactory bulb as well as hyperexcitability of mitral cells and olfactory dysfunction. However, neuron-specific A1R activity was unable to attenuate glutamate excitotoxicity in primary olfactory bulb neurons in vitro or EAE-induced olfactory dysfunction and disease severity in vivo. Together, we demonstrate that A1R modulates the dendro-dendritic inhibition at the site of mitral and granule cells and impacts the processing of the olfactory sensory information, while A1R activity was unable to counteract inflammation-induced hyperexcitability.
Journal Article