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Aim: This article is based on our previous research, which was presented as a poster at the ECTRIMS Congress 2018 and published as a conference abstract (https://www.professionalabstracts.com/ectrims2018/iplanner/#/presentation/1698). Cognitive-motor interference (CMI) has been observed in both healthy controls (HC) and persons with multiple sclerosis (pwMS), but limited and contradictory data is making it difficult to assess the impact of motor and cognitive functioning levels on CMI. The aim of this study was to investigate CMI in pwMS and HC by means of a dual task postural paradigm, to compare them between groups and to analyse the influence of motor and cognitive functioning levels assessed with complementary instruments on observed CMI. Methods: The dual task posturography paradigm serves to quantify the impact of a cognitive (i.e., performing serial subtractions), a motor challenge (closing eyes), or both challenges combined (triple task) on body sway during standing in an upright position feet closed. The data analysed were acquired in one interventional and four observational studies and selected based on predefined criteria and by systematic quality control. A total of 113 pwMS and 42 HC were selected for analysis. Results: Comparable changes in motor and cognitive performance due to cognitive or combined cognitive-motor challenges were observed in both HC and pwMS. Combining both tasks did not result in further changes in motor performance but resulted in a decrease in cognitive performance. This reduction in cognitive performance with an additional motor challenge correlated with lower levels of cognitive and motor functioning in pwMS. Unexpectedly, an increase in body sway due to a cognitive or combined cognitive-motor challenges was primarily observed in pwMS and HC with better cognitive and motor functioning. Conclusions: The results suggest that dual-task effects are not disease-specific but rather reflect individually different adaptation strategies depending on the specific motor and cognitive functioning levels.

Adenine nucleotides, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), as well as the nucleoside 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 (K2P) channels. The inflammation of the central nervous system (CNS) impairs the 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 the sensory function and how this is impacted by inflammation. Here, we show that signaling via neuronal A1R is important for the 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 the 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 (DDI) 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.

Background: Walking disability is one of the most frequent and burdening symptoms of progressive multiple sclerosis (MS). Most of the exercise intervention studies that showed an improvement in mobility performance were conducted in low to moderately disabled relapsing–remitting MS patients with interventions using the legs. However, MS patients with substantial walking disability hardly can perform these tasks. Earlier work has indicated that aerobic arm training might also improve walking performance and could therefore be a therapeutic option in already moderately disabled progressive MS patients.Methods: Patients with progressive MS and EDSS 4–6.5 were randomized using a computer-generated algorithm list to either a waitlist control group (CG) or an intervention group (IG). The IG performed a 12-week home-based, individualized arm ergometry exercise training program. Maximum walking distance as measured by the 6-min walking test (6MWT) was the primary endpoint. Secondary endpoints included aerobic fitness, other mobility tests, cognitive functioning, as well as fatigue and depression.Results: Of n = 86 screened patients, 53 with moderate disability (mean EDSS 5.5, SD 0.9) were included and data of 39 patients were analyzed. Patients in the IG showed strong adherence to the program with a mean of 67 (SD 26.4) training sessions. Maximum work load (Pmax) increased in the training group while other fitness indicators did not. Walking distance in the 6MWT improved in both training and waitlist group but not significantly more in trained patients. Similarly, other mobility measures showed no differential group effect. Cognitive functioning remained unchanged. No serious events attributable to the intervention occurred.Conclusion: Although maximum work load improved, 3 months of high-frequency arm ergometry training of low to moderate intensity could not show improved walking ability or cognitive functioning in progressive MS compared to a waitlist CG.The study was registered at www.clinicaltrials.gov (NCT03147105) and funded by the local MS self-help organization.

Background: Progressive multifocal leukoencephalopathy (PML) caused by JCV is a rare but frequently fatal disease of the central nervous system, usually affecting immunocompromised individuals. Our study aims to expand the data on patient characteristics, diagnosis, clinical course, possible PML-directed treatment, and outcome of patients with PML at a German tertiary-care hospital.Methods:In this single-center observational cohort study, 37 consecutive patients with a confirmed diagnosis of PML seen at the University Medical Center Hamburg-Eppendorf from 2013 until 2019 were retrospectively analyzed by chart review with a special focus on demographics, risk factors, and clinical aspects as well as PML-directed treatment and survival.Results:We identified 37 patients with definite, probable, and possible PML diagnosis. 36 patients (97%) had underlying immunosuppressive disorders such as HIV/AIDS (n = 17; 46%), previous treatment with monoclonal antibodies (n = 6; 16%), hematological or oncological malignancies (n = 6; 16%), sarcoidosis (n = 5; 14%), solid organ transplantation (n = 1; 3%), and diagnosis of mixed connective tissue disease (n = 1; 3%). In only one patient no evident immunocompromised condition was detected (n = 1; 3%). Treatment attempts to improve the outcome of PML were reported in 13 patients (n = 13; 35%). Twenty seven percent of patients were lost to follow-up (n = 10). Twenty four-month survival rate after diagnosis of PML was 56% (n = 15).Conclusion: This interdisciplinary retrospective study describes epidemiology, risk factors, clinical course, and treatment trials in patients with PML at a German tertiary-care hospital. Acquired immunosuppression due to HIV-1 constituted the leading cause of PML in this monocenter cohort.

BackgroundImpairment of visual function is one of the major symptoms of people with multiple sclerosis (pwMS). A multitude of disease effects including inflammation and neurodegeneration lead to structural impairment in the visual system. However, the gold standard of disability quantification, the expanded disability status scale (EDSS), relies on visual assessment charts. A more comprehensive assessment of visual function is the full contrast sensitivity function (CSF), but most tools are time consuming and not feasible in clinical routine. The quantitative CSF (qCSF) test is a computerized test to assess the full CSF. We have already shown a better correlation with visual quality of life (QoL) than for classical high and low contrast charts in multiple sclerosis (MS).ObjectiveTo study the precision, test duration, and repeatability of the qCSF in pwMS. In order to evaluate the discrimination ability, we compared the data of pwMS to healthy controls.MethodsWe recruited two independent cohorts of MS patients. Within the precision cohort (n = 54), we analyzed the benefit of running 50 instead of 25 qCSF trials. The repeatability cohort (n = 44) was assessed by high contrast vision charts and qCSF assessments twice and we computed repeatability metrics. For the discrimination ability we used the data from all pwMS without any previous optic neuritis and compared the area under the log CSF (AULCSF) to an age-matched healthy control data set.ResultsWe identified 25 trials of the qCSF algorithm as a sufficient amount for a precise estimate of the CSF. The median test duration for one eye was 185 s (range 129–373 s). The AULCSF had better test–retest repeatability (Mean Average Precision, MAP) than visual acuity measured by standard high contrast visual acuity charts or CSF acuity measured with the qCSF (0.18 vs. 0.11 and 0.17, respectively). Even better repeatability (MAP = 0.19) was demonstrated by a CSF-derived feature that was inspired by low-contrast acuity charts, i.e., the highest spatial frequency at 25% contrast. When compared to healthy controls, the MS patients showed reduced CSF (average AULCSF 1.21 vs. 1.42, p < 0.01).ConclusionHigh precision, usability, repeatability, and discrimination support the qCSF as a tool to assess contrast vision in pwMS.

While transcripts of neuronal mitochondrial genes are strongly suppressed in central nervous system inflammation, it is unknown whether this results in mitochondrial dysfunction and whether an increase of mitochondrial function can rescue neurodegeneration. Here, we show that predominantly genes of the electron transport chain are suppressed in inflamed mouse neurons, resulting in impaired mitochondrial complex IV activity. This was associated with post-translational inactivation of the transcriptional co-regulator proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In mice, neuronal overexpression of Ppargc1a, which encodes for PGC-1α, led to increased numbers of mitochondria, complex IV activity, and maximum respiratory capacity. Moreover, Ppargc1a-overexpressing neurons showed a higher mitochondrial membrane potential that related to an improved calcium buffering capacity. Accordingly, neuronal deletion of Ppargc1a aggravated neurodegeneration during experimental autoimmune encephalomyelitis, while neuronal overexpression of Ppargc1a ameliorated it. Our study provides systemic insights into mitochondrial dysfunction in neurons during inflammation and commends elevation of mitochondrial activity as a promising neuroprotective strategy.

Blood-brain barrier (BBB) dysfunction is critically involved in determining the extent of several central nervous systems (CNS) pathologies and here in particular neuroinflammatory conditions. Inhibiting BBB breakdown could reduce the level of vasogenic edema and the number of immune cells invading the CNS, thereby counteracting neuronal injury. Transient receptor potential (TRP) channels have an important role as environmental sensors and constitute attractive therapeutic targets that are involved in calcium homeostasis during pathologies of the CNS. Transient receptor potential vanilloid 4 (TRPV4) is a calcium permeable, non-selective cation channel highly expressed in endothelial cells. As it is involved in the regulation of the blood brain barrier permeability and consequently cerebral edema formation, we anticipated a regulatory role of TRPV4 in CNS inflammation and subsequent neuronal damage. Here, we detected an increase in transendothelial resistance in mouse brain microvascular endothelial cells (MbMECs) after treatment with a selective TRPV4 inhibitor. However, this effect was abolished after the addition of IFNγ and TNFα indicating that inflammatory conditions override TRPV4-mediated permeability. Accordingly, we did not observe a protection of Trpv4-deficient mice when compared to wildtype controls in a preclinical model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and no differences in infarct sizes following transient middle cerebral artery occlusion (tMCAO), the experimental stroke model, which leads to an acute postischemic inflammatory response. Furthermore, Evans Blue injections did not show differences in alterations of the blood brain barrier (BBB) permeability between genotypes in both animal models. Together, TRPV4 does not regulate brain microvascular endothelial permeability under inflammation.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a second messenger that evokes calcium release from intracellular organelles by the engagement of calcium release channels, including members of the Transient Receptor Potential (TRP) family, such as TRPML1, the (structurally) related Two Pore Channel type 1 (TPC1) and TPC2 channels as well as Ryanodine Receptors type 1 (RYR1; Guse, 2012). NAADP evokes calcium release from acidic calcium stores of many cell types (Guse, 2012), and NAADP-sensitive Ca2+ stores have been described in hippocampal neurons of the rat (Bak et al., 1999; McGuinness et al., 2007). Glutamate triggers Ca2+-mediated neuronal excitotoxicity in inflammation-induced neurodegenerative pathologies such as Multiple Sclerosis (MS; Friese et al., 2014), and when applied extracellularly to neurons glutamate can elevate NAADP levels in these cells. Accordingly, glutamate-evoked Ca2+ signals from intracellular organelles were inhibited by preventing organelle acidification (Pandey et al., 2009). Analysis of reported RNA sequencing experiments of cultured hippocampal neurons revealed the abundance of Mcoln1 (encoding TRPML1), Tpcn1, and Tpcn2 (encoding TPC1 and TPC2, respectively) as potential NAADP target channels in these cells. Transcripts encoding Ryr1 were not found in contrast to Ryr2 and Ryr3. To study the contribution of NAADP signaling to glutamate-evoked calcium transients in murine hippocampal neurons we used the NAADP antagonists Ned-19 (Naylor et al., 2009) and BZ194 (Dammermann et al., 2009). Our results show that both NAADP antagonists significantly reduce glutamate-evoked calcium transients. In addition to extracellular glutamate application, we studied synchronized calcium oscillations in the cells of the neuronal cultures evoked by addition of the GABAA receptor antagonist bicuculline. Pretreatment with Ned-19 (50 μM) or BZ194 (100 μM) led to an increase in the frequency of bicuculline-induced calcium oscillations at the cost of calcium transient amplitudes. Interestingly, Ned-19 triggered a rise in intracellular calcium concentrations 25 min after bicuculline stimulation, leading to the question whether NAADP acts as a neuroprotective messenger in hippocampal neurons. Taken together, our results are in agreement with the concept that NAADP signaling significantly contributes to glutamate evoked Ca2+ rise in hippocampal neurons and to the amplitude and frequency of synchronized Ca2+ oscillations triggered by spontaneous glutamate release events.

The prolonged drought of recent years combined with the steadily increasing bark beetle infestation (Ips typographus) is causing enormous damage in Germany’s spruce forests. This preliminary study investigates whether early spruce infestation by the bark beetle (green attack) can be detected using indices based on airborne spatial high-resolution (0.3 m) hyperspectral data and field spectrometer measurements. In particular, a new hyperspectral index based on airborne data has been defined and compared with other common indices for bark beetle detection. It shows a very high overall accuracy (OAA = 98.84%) when validated with field data. Field measurements and a long-term validation in a second study area serve the validation of the robustness and transferability of the index to other areas. In comparison with commonly used indices, the defined index has the ability to detect a larger proportion of infested spruces in the green attack phase (60% against 20% for commonly used indices). This index confirms the high potential of the red-edge domain to distinguish infested spruces at an early stage. Overall, our index has great potential for forest preservation strategies aimed at the detection of infested spruces in order to mitigate the outbreaks.

The status, changes, and disturbances in geomorphological regimes can be regarded as controlling and regulating factors for biodiversity. Therefore, monitoring geomorphology at local, regional, and global scales is not only necessary to conserve geodiversity, but also to preserve biodiversity, as well as to improve biodiversity conservation and ecosystem management. Numerous remote sensing (RS) approaches and platforms have been used in the past to enable a cost-effective, increasingly freely available, comprehensive, repetitive, standardized, and objective monitoring of geomorphological characteristics and their traits. This contribution provides a state-of-the-art review for the RS-based monitoring of these characteristics and traits, by presenting examples of aeolian, fluvial, and coastal landforms. Different examples for monitoring geomorphology as a crucial discipline of geodiversity using RS are provided, discussing the implementation of RS technologies such as LiDAR, RADAR, as well as multi-spectral and hyperspectral sensor technologies. Furthermore, data products and RS technologies that could be used in the future for monitoring geomorphology are introduced. The use of spectral traits (ST) and spectral trait variation (STV) approaches with RS enable the status, changes, and disturbances of geomorphic diversity to be monitored. We focus on the requirements for future geomorphology monitoring specifically aimed at overcoming some key limitations of ecological modeling, namely: the implementation and linking of in-situ, close-range, air- and spaceborne RS technologies, geomorphic traits, and data science approaches as crucial components for a better understanding of the geomorphic impacts on complex ecosystems. This paper aims to impart multidimensional geomorphic information obtained by RS for improved utilization in biodiversity monitoring.

Primary progressive multiple sclerosis (PPMS) shows a highly variable disease progression with poor prognosis and a characteristic accumulation of disabilities in patients. These hallmarks of PPMS make it difficult to diagnose and currently impossible to efficiently treat. This study aimed to identify plasma metabolite profiles that allow diagnosis of PPMS and its differentiation from the relapsing-remitting subtype (RRMS), primary neurodegenerative disease (Parkinson’s disease, PD), and healthy controls (HCs) and that significantly change during the disease course and could serve as surrogate markers of multiple sclerosis (MS)-associated neurodegeneration over time. We applied untargeted high-resolution metabolomics to plasma samples to identify PPMS-specific signatures, validated our findings in independent sex- and age-matched PPMS and HC cohorts and built discriminatory models by partial least square discriminant analysis (PLS-DA). This signature was compared to sex- and age-matched RRMS patients, to patients with PD and HC. Finally, we investigated these metabolites in a longitudinal cohort of PPMS patients over a 24-month period. PLS-DA yielded predictive models for classification along with a set of 20 PPMS-specific informative metabolite markers. These metabolites suggest disease-specific alterations in glycerophospholipid and linoleic acid pathways. Notably, the glycerophospholipid LysoPC(20:0) significantly decreased during the observation period. These findings show potential for diagnosis and disease course monitoring, and might serve as biomarkers to assess treatment efficacy in future clinical trials for neuroprotective MS therapies.

In the face of rapid global change it is imperative to preserve geodiversity for the overall conservation of biodiversity. Geodiversity is important for understanding complex biogeochemical and physical processes and is directly and indirectly linked to biodiversity on all scales of ecosystem organization. Despite the great importance of geodiversity, there is a lack of suitable monitoring methods. Compared to conventional in-situ techniques, remote sensing (RS) techniques provide a pathway towards cost-effective, increasingly more available, comprehensive, and repeatable, as well as standardized monitoring of continuous geodiversity on the local to global scale. This paper gives an overview of the state-of-the-art approaches for monitoring soil characteristics and soil moisture with unmanned aerial vehicles (UAV) and air- and spaceborne remote sensing techniques. Initially, the definitions for geodiversity along with its five essential characteristics are provided, with an explanation for the latter. Then, the approaches of spectral traits (ST) and spectral trait variations (STV) to record geodiversity using RS are defined. LiDAR (light detection and ranging), thermal and microwave sensors, multispectral, and hyperspectral RS technologies to monitor soil characteristics and soil moisture are also presented. Furthermore, the paper discusses current and future satellite-borne sensors and missions as well as existing data products. Due to the prospects and limitations of the characteristics of different RS sensors, only specific geotraits and geodiversity characteristics can be recorded. The paper provides an overview of those geotraits.

The present study aimed to evaluate and analyse the variation of morphological parameters in garlic according to genotype and crop year, to obtain valuable insights for identifying genotypes with superior performance under specific environmental or cultivation conditions. Fifteen autumn garlic genotypes selected from the Oltenia region, Romania, and the registered 'Benone' variety, cultivated in the Craiova area, were evaluated over two consecutive years (2022 and 2023). The study's results revealed significant differences among genotypes for all analysed traits (bulb weight, bulb size, number of cloves), highlighting the influence of both genotype and year on these characteristics. Notably, genotype M15 exhibited the highest bulb weight (49 g). Local genotypes outperformed the registered variety, underscoring the superiority of the selected genotypes and their value for breeding or cultivation purposes. These findings provide important insights for selecting garlic genotypes based on specific environmental conditions and cultivation requirements. The information obtained may contribute to improving garlic production and quality in the Oltenia region, as well as promoting genetic diversity and crop sustainability.

Abstract Background Accurate detection of pheromones is crucial for chemical communication and reproduction in insects. In holometabolous flies and moths, the sensory neuron membrane protein 1 (SNMP1) is essential for detecting long-chain aliphatic pheromones by olfactory neurons. However, its function in hemimetabolous insects and its role for detecting pheromones of a different chemical nature remain elusive. Therefore, we investigated the relevance of SNMP1 for pheromone detection in a hemimetabolous insect pest of considerable economic importance, the desert locust Schistocerca gregaria, which moreover employs the aromatic pheromone phenylacetonitrile (PAN) to govern reproductive behaviors. Results Employing CRISPR/Cas-mediated gene editing, a mutant locust line lacking functional SNMP1 was established. In electroantennography experiments and single sensillum recordings, we found significantly decreased electrical responses to PAN in SNMP1-deficient (SNMP1−/−) locusts. Moreover, calcium imaging in the antennal lobe of the brain revealed a substantially reduced activation of projection neurons in SNMP1−/− individuals upon exposure to PAN, indicating that the diminished antennal responsiveness to PAN in mutants affects pheromone-evoked neuronal activity in the brain. Furthermore, in behavioral experiments, PAN-induced effects on pairing and mate choice were altered in SNMP1−/− locusts. Conclusions Our findings emphasize the importance of SNMP1 for chemical communication in a hemimetabolous insect pest. Moreover, they show that SNMP1 plays a crucial role in pheromone detection that goes beyond long-chain aliphatic substances and includes aromatic compounds controlling reproductive behaviors.

Abstract Mesenchymal stem/stromal cells (MSCs) are not only capable of self-renewal, trans-differentiation, homing to damaged tissue sites and immunomodulation by secretion of trophic factors but are also easy to isolate and expand. Because of these characteristics, they are used in numerous clinical trials for cell therapy including immune and neurological disorders, diabetes, bone and cartilage diseases and myocardial infarction. However, not all trials have successful outcomes, due to unfavourable microenvironmental factors and the heterogenous nature of MSCs. Therefore, genetic manipulation of MSCs can increase their prospect. Currently, most studies focus on single transfection with one gene. Even though the introduction of more than one gene increases the complexity, it also increases the effectivity as different mechanism are triggered, leading to a synergistic effect. In this review we focus on the methodology and efficiency of co-transfection, as well as the opportunities and pitfalls of these genetically engineered cells for therapy. Graphical abstract

Abstract Background Interprofessionalism is considered a key component in modern health profession education. Nevertheless, there remains ongoing debate about when and where to introduce interprofessional trainings in the curriculum. We identified anatomy, a subject commonly shared among health professionals, as a practical choice for initiating early intergroup-contact between first-year medical and midwifery students. Our study examined the effects of a four-hour block course in anatomy on interprofessional socialization and valuing, as well as long-term effects on intergroup contact. Methods Based on different concepts and theories of learning, we implemented 12 interprofessional learning stations. Several measures were taken to foster group cohesion: (1) self-directed working in interprofessional tandems on authentic obstetric tasks, (2) competing with other tandems, (3) creating positive interdependencies during task completion, and (4) allowing room for networking. In a pre-post design with a three-month follow-up, we assessed the outcomes of this ultra-brief training with qualitative essays and quantitative scales. Results After training, both groups improved in interprofessionalism scores with strong effect sizes, mean difference in ISVS-21 = 0.303 [95% CI: 0.120, 0.487], P

Predicting seafood consumption behavior is essential for fishing companies to adjust their production plans and marketing strategies. To achieve accurate predictions, this paper introduces a model for forecasting seafood consumption behavior based on an interpretable machine learning algorithm. Additionally, the Shapley Additive exPlanation (SHAP) model and the Accumulated Local Effects (ALE) plot were integrated to provide a detailed analysis of the factors influencing Shanghai residents’ intentions to purchase salmon. In this study, we constructed nine regression prediction models, including ANN, Decision Tree, GBDT, Random Forest, AdaBoost, XGBoost, LightGBM, CatBoost, and NGBoost, to predict the consumers’ intentions to purchase salmon and to compare their predictive performance. In addition, Bayesian optimization algorithm is used to optimize the hyperparameters of the optimal regression prediction model to improve the model prediction accuracy. Finally, the SHAP model was used to analyze the key factors and interactions affecting the consumers’ willingness to purchase salmon, and the Accumulated Local Effects plot was used to show the specific prediction patterns of different influences on salmon consumption. The results of the study show that salmon farming safety and ease of cooking have significant nonlinear effects on salmon consumption; the BO-CatBoost nonlinear regression prediction model demonstrates superior performance compared to the benchmark model, with the test set exhibiting RMSE, MSE, MAE, R2 and TIC values of 0.155, 0.024, 0.097, 0.902, and 0.313, respectively. This study can provide technical support for suppliers in the salmon value chain and help their decision-making to adjust their corporate production plan and marketing activities

We present the parsec-scale radio spectra of a representative sample of 13 Palomar–Green radio-quiet quasars, based on our new Very Long Baseline Array (VLBA) observations at 8.4 and 23.6 GHz and our earlier VLBA studies at 1.5 and 5.0 GHz. The radio core emission generally exhibits a flat spectrum at 1.5–5.0 GHz, which indicates a compact optically thick synchrotron source on a scale smaller than the broad-line region (BLR) radius R _BLR ∼ 0.01–0.1 pc. The 8.4–23.6 GHz spectral slope remains flat in four objects indicating the inner radius of the radio source R _in 0.3. The 8.4–23.6 GHz radio emission in the high- L / L _Edd objects may be weak due to more extended emission from a radiation-pressure-driven wind. Future submillimeter observations can further constrain the inward radial extent of the radio emission down to the coronal scale.