Spread Of Signals Research Articles

Development of Neuronal Guidance Fibers for Stimulating Electrodes: Basic Construction and Delivery of a Growth Factor.

State-of-the-art treatment for sensorineural hearing loss is based on electrical stimulation of residual spiral ganglion neurons (SGNs) with cochlear implants (CIs). Due to the anatomical gap between the electrode contacts of the CI and the residual afferent fibers of the SGNs, spatial spreading of the stimulation signal hampers focused neuronal stimulation. Also, the efficiency of a CI is limited because SGNs degenerate over time due to loss of trophic support. A promising option to close the anatomical gap is to install fibers as artificial nerve guidance structures on the surface of the implant and install on these fibers drug delivery systems releasing neuroprotective agents. Here, we describe the first steps in this direction. In the present study, suture yarns made of biodegradable polymers (polyglycolide/poly-ε-caprolactone) serve as the basic fiber material. In addition to the unmodified fiber, also fibers modified with amine groups were employed. Cell culture investigations with NIH 3T3 fibroblasts attested good cytocompatibility to both types of fibers. The fibers were then coated with the extracellular matrix component heparan sulfate (HS) as a biomimetic of the extracellular matrix. HS is known to bind, stabilize, modulate, and sustainably release growth factors. Here, we loaded the HS-carrying fibers with the brain-derived neurotrophic factor (BDNF) which is known to act neuroprotectively. Release of this neurotrophic factor from the fibers was followed over a period of 110 days. Cell culture investigations with spiral ganglion cells, using the supernatants from the release studies, showed that the BDNF delivered from the fibers drastically increased the survival rate of SGNs in vitro. Thus, biodegradable polymer fibers with attached HS and loaded with BDNF are suitable for the protection and support of SGNs. Moreover, they present a promising base material for the further development towards a future neuronal guiding scaffold.

Does the yield curve signal recessions? New evidence from an international panel data analysis

In this paper, we reexamine the predictive power of the yield spread across countries and over time. Using a dynamic panel/dichotomous model framework and a unique dataset covering 13 OECD countries over the period 1975–2019, we empirically show that the yield spread signals recessions. This result is robust to different econometric specifications, controlling for recession risk factors and time sampling. Using a new cluster analysis methodology, we present empirical evidence of a partial homogeneity of the predictive power of the yield spread. Our results provide a valuable framework for monitoring economic cycles.

Корреляционный прием частотно-манипулированных сигналов в режиме с псевдослучайной перестройкой рабочей частоты

Proposals are presented on the use of signals generated on the basis of the three-element Barker sequence for the mode of frequency-hopping spread spectrum (FHSS). The conditions for the application of the frequency hopping mode are considered. An algorithm for synthesizing signals with a simultaneous change in their frequency and phase structure has been developed. An analysis of the properties of the developed signals was carried out. The positive and negative aspects of the implementation of the developed approach are shown. Proposals for their practical application are formulated. The frequency-hopping spread spectrum is actively used in many telecommunication standards and technologies in order to increase the noise immunity of transmissions in a multipath channel. As a result, due to the short stay of the signal at the carrier frequency, the probability of long-term operation in a channel with deep fading is reduced. Since the structure of the signal and frequency-hopping spread spectrum parameters are determined by known protocols and standards, this makes it possible to evaluate its capabilities in practical applications. In order to reduce the negative consequences caused by the considered collisions, it is proposed to generate signals for the slow frequency-hopping spread spectrum based on the three-element Barker sequence. Features of the implementation of this approach are considered in this article.

Two Stage Multi Sensor Detection Scheme for Large Scale WSN Using Spatial Proximity

Intuition suggests that in a large-size sensor network, event signal spreads over a sub-region known as event region. The sub-set of sensors inside the event region is located close to each other in the form of a cluster. On the contrary, the reports from the rest of the sensors that are far away from the event will be less credible and prone to faulty detection. In this work, such fact is exploited to improve the detection performance of the detection schemes at the fusion center by proposing a two-stage detection mechanism. In other words, the proposed two-stage detection scheme exploits the spatial proximity of the event region sensors. Numerical results are provided to assess the detection performance of the proposed scheme that shows that the proposed detection scheme has a superior performance over the traditional detection schemes.

Innate and adaptive resistance to RNAi: a major challenge and hurdle to the development of double stranded RNA-based pesticides.

RNA interference (RNAi) is a post-transcriptional gene silencing process where short interfering RNAs degrade targeted mRNA. Exploration of gene function through reverse genetics is the major achievement of RNAi discovery. Besides, RNAi can be used as a potential strategy for the control of insect pests. This has led totheidea of developing RNAi-based pesticides. Differential RNAi efficiency in the different insect orders is the biggest biological obstacle in developing RNAi-based pesticides. dsRNA stability, the sensitivity of core RNAi machinery, uptake of dsRNA and amplification and spreading of the RNAi signal are the key factors responsible for RNAi efficiency in insects. This review discusses the physiological and adaptive factors responsible for reduced RNAi in insects that pose a major challenge in developing dsRNA- based pesticides.

Optogenetic control of receptors reveals distinct roles for actin- and Cdc42-dependent negative signals in chemotactic signal processing

During chemotaxis, neutrophils use cell surface G Protein Coupled Receptors to detect chemoattractant gradients. The downstream signaling system is wired with multiple feedback loops that amplify weak inputs and promote spatial separation of cell front and rear activities. Positive feedback could promote rapid signal spreading, yet information from the receptors is transmitted with high spatial fidelity, enabling detection of small differences in chemoattractant concentration across the cell. How the signal transduction network achieves signal amplification while preserving spatial information remains unclear. The GTPase Cdc42 is a cell-front polarity coordinator that is predictive of cell turning, suggesting an important role in spatial processing. Here we directly measure information flow from receptors to Cdc42 by pairing zebrafish parapinopsina, an optogenetic G Protein Coupled Receptor with reversible ON/OFF control, with a spectrally compatible red/far red Cdc42 Fluorescence Resonance Energy Transfer biosensor. Using this toolkit, we show that positive and negative signals downstream of G proteins shape a rapid, dose-dependent Cdc42 response. Furthermore, F-actin and Cdc42 itself provide two distinct negative signals that limit the duration and spatial spread of Cdc42 activation, maintaining output signals local to the originating receptors.

Grant-Free Access via Bilinear Inference for Cell-Free MIMO With Low-Coherence Pilots

We propose a novel joint activity, channel and data estimation (JACDE) scheme for multiple-input multiple-output (MIMO) systems. The contribution aims to allow significant overhead reduction of MIMO systems by enabling grant-free access, while maintaining moderate throughput per user. To that end, we extend the conventional MIMO transmission framework so as to incorporate activity detection capability without resorting to spreading informative data symbols, in contrast with related work which typically relies on signal spreading. Our method leverages a Bayesian message passing scheme based on Gaussian approximation, which jointly performs active user detection (AUD), channel estimation (CE), and multi-user detection (MUD), incorporating also a well-structured low-coherence pilot design based on frame theory, which mitigates pilot contamination, and finally complemented with a detector empowered by bilinear message passing. The efficacy of the resulting JACDE-based grant-free access scheme in the cell-free MIMO system setup compliant with fifth generation (5G) new radio (NR) orthogonal frequency-division multiplexing (OFDM) signaling is demonstrated by simulation results. The results are shown to outperform the current state-of-the-art and approach the performance of an idealized (genie-aided) scheme in which user activity and channel coefficients are perfectly known.

Self-Healing Coatings for Corrosion Protection: The Importance of the Transport of Active Agents from the Coating Towards the Defect

In so called smart or intelligent self-healing coatings active agents that are safely stored inside the coating are released upon onset of corrosion. This release is triggered by a suitable trigger signal that should be a safe indicator for the onset of corrosion and its continuation. Different from the current standard where release from pigments occurs via leaching, the safe storage should ensure that there is no uncontrolled release of the active agents when they are not needed for inhibiting corrosion and restoring protection. While there are many studies on different concepts for storage and active release triggered by corrosion, achieving an efficient transport of the released agents to the defective site(s) is a likewise crucial but so far widely neglected issue. Recently it was proposed that the signal spreading from the defect into the coating can be significantly enhanced by the use of layers of conducting polymer, such as polypyrrole, applied as an intermediate layer between the metal substrate and the organic coating. In that case the decrease in potential is the signal that is spread. Here, we will show that by such polypyrrole layers also the transport of active agents can be significantly enhanced. To enable a fundamental in-depth study of the mobility of active agents from the coating towards the defective site, a dedicated experimental model set-up was designed especially for the study of ions transport. The main question to be addressed was whether the main transport will be along the metal│PPy interface or rather through the matrix of the reduced polypyrrole. Zinc was chosen as metallic substrate, owing to its importance in galvanized steel products. The corrosion potential at the defective site was used as a measure for the amount of corrosion inhibitor released into the defect and hence as a measure to reflect the ionic transport and self-healing efficiency of the coating by different corrosion inhibitors. The progress of polypyrrole reduction, in turn, was monitored by use of Scanning Kelvin Probe (SKP) for recording the change of potential as a function of distance from the defect and of time. The concentration of corrosion inhibitor at the defective site was also quantified using ICP-MS (OES) analysis of the solution in the defect at different times. In order to ensure for reliable quantification of the transport that released corrosion inhibitor moving towards the defect is not reacting with corroding metal at the interface special PVB│PPy│Au-Glass model samples were utilized. The results indicate that Ce4+ is more effective than Ce3+ for reaching and passivating the defect. In addition, organic corrosion inhibitors (8-HQ, β-CD and L-Car) were found to be highly efficient in inhibiting the defective site. This is proposed to be due through a synergistic mechanism, which is based on an interaction of the passivating effect of these corrosion inhibitors and the passivating effect of polypyrrole. The synergistic mechanism shows astonishing passivation effects, resulting in anodic potential shifts of the corrosion potential of more than 600 mV. Concerning the main path for ionic transport, it was found that this occurs mainly through the matrix of the (partially) reduced polypyrrole. Hence, the transport of positive ions should be favored compared to the one of negative ions.

Automatic Modulation Recognition Through Wireless Sensor Networks in Aeronautical Wireless Channel

The Doppler effect causes frequency offset and spectrum spread of communication signals, which increases the difficulty of feature extraction when identifying the modulation mode in aeronautical wireless channels. To improve the signal modulation recognition capability of the single monitoring node in Wireless Sensor Networks (WSN), a method based on the bidirectional convolution gated recurrent deep neural network (Bi-CGDNN) with an attention mechanism is proposed in this paper. We design the framework with different types of network layers, realizing frequency offset suppression and feature mapping. In addition, quadrature sampling signals and instantaneous feature statistics are collected to generate the dataset. Thus, the waveform features and phase-frequency information of the signals can be used for combinatorial analysis. In particular, the attention mechanism is introduced to optimize the framework for better feature perception and higher recognition rates. Experimental results show that our method achieves great recognition effects at different maximum Doppler frequencies. The recognition rate reaches 98.1% at the signal-to-noise ratio (SNRs) of 8dB with the Doppler frequency of 200Hz.

Evaluation of intracellular processes in quinolinic acid-induced brain damage by imaging reactive oxygen species generation and mitochondrial complex I activity

PurposeOur study aimed to elucidate the intracellular processes associated with quinolinic acid (QA)-induced brain injury by acquiring semiquantitative fluorescent images of reactive oxygen species (ROS) generation and positron emission tomography (PET) images of mitochondrial complex I (MC-I) activity.MethodsEx vivo fluorescent imaging with dihydroethidium (DHE) and PET scans with 18F-BCPP-EF were conducted at 3 h and 24 h after QA injection into the rat striatum. Immunohistochemical studies were performed 24 h after QA injection into the rat brain using monoclonal antibodies against neuronal nuclei (NeuN) and CD11b.ResultsA strong DHE-derived fluorescent signal was detected in a focal area within the QA-injected striatum 3 h after QA injection, and increased fluorescent signal spread throughout the striatum and parts of the cerebral cortex after 24 h. By contrast, 18F-BCPP-EF uptake in the QA-injected rat brain was unchanged after 3 h and markedly decreased after 24 h, not only in the striatum but also in the cerebral hemisphere. The fluorescent signal in the striatum 24 h after QA injection colocalised with microglial marker expression.ConclusionsWe successfully obtained functional images of focal ROS generation during the early period of excitotoxic injury, and microglial ROS generation and mitochondrial dysfunction were observed during the progression of the inflammatory response. Both ex vivo DHE imaging and in vivo 18F-BCPP-EF-PET were sufficiently sensitive to detect the respective processes of QA-induced brain damage. Our study contributes to the functional imaging of multiple events during the pathological process.

Second-order phase correction of NMR spectra acquired using linear frequency-sweeps

NMR spectra acquired with experiments using frequency-sweeps such as the wide-band uniform-rate smooth truncation (WURST) spin-echo and Carr-Purcell-Meiboom-Gill (CPMG) sequences cannot be absorptively phased by using only conventional zeroth- and first-order phase correction. Implementation of phase correction up to the second-order is described for obtaining absorptive spectra, which have more desirable line shapes and noise properties than magnitude spectra. The relationship of the second-order phase to the parameters of frequency sweeps is derived. The second-order phasing in the frequency-domain is equivalent to a point spread in the time-domain signal. The application of second-order phase correction is demonstrated with a wideline 35Cl CPMG spikelet spectrum.

MRI features of signet ring rectal cancer.

Signet Ring Rectal Cancer (SRRC) of rectum is rare high-grade subtype with poor prognosis and characteristic histopathology. We evaluated its imaging appearance and correlated its outcomes. We conducted a retrospective review of the rectal MRIs of 97 patients with rectal SRRC, evaluating tumor morphology, T2 signal, length, location, pattern of tumor growth, nodal status and location, EMVI (extramural vascular invasion), site of metastases, and response to chemotherapy. The tumor signal on T2W images was categorized into intermediate, T2 hyperintense, and fluid/mucin bright. Imaging findings were correlated with risk of metastatic/ recurrent disease, disease-free survival, and overall survival. The median age of patients of SRRC in our study was 35years and more frequently found in male patients. The common imaging features of SRRC were T2-hyperintense signal (63%), infiltrative growth pattern (76%), positive MR CRM (Circumferential Resection Margin on MRI) (84%), presence of EMVI (51%), and advanced T and N stage (97% and 84%, respectively). Peritoneum and nodes were the most common sites of metastases. Raised serum CEA (Carcino-embryonic Antigen) levels, positive MR CRM status, extramesorectal adenopathy, and advanced N stage had statistically significant predictive value for recurrence or metastases. Elevated serum CEA levels (p = 0.019) and intermediate T2 signal (p = 0.012) demonstrated significant independent association with poor overall survival, while advanced N stage (p = 0.033) demonstrated significant independent association with worse disease-free survival in multivariate analysis. SRRC affected young patients and demonstrated T2-hyperintense signal and subepithelial spread in an infiltrative pattern. Elevated CEA levels and T2-intermediate signal intensity are independent predictors for worse overall survival and advanced nodal stage is independent prognostic factor of poor disease-free survival. MRI rectum can pinpoint the pathology given the distinct MRI morphology and age of presentation.

Contribution of Mitochondria to Insulin Secretion by Various Secretagogues

Significance:Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+ homeostasis, all affecting insulin secretion.Recent Advances:Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca2+ influx was found to enhance GSIS, reflecting cytosolic Ca2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase.Critical Issues:It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis.Future Directions:Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 36, 920–952.

Partial discharge detection method for lower porcelain shell of oil paper insulation bushing based on spatial UHF signals

The partial discharge in lower porcelain shell of oil paper insulation bushing is one of the important reasons for transformer failures. Based on the analysis of the oil paper insulation bushing structure characteristics, the finite difference time domain simulation model of the partial discharge in lower porcelain shell is established. And the path of UHF signal of partial discharge is obtained that the signal spreads through the insulation between capacitor screens and oil passage to the outer space. Then the lower porcelain shell partial discharge detection method based on the space UHF signal is proposed and verified.

Development of a neonate X-ray phantom for 2D imaging applications using single-tone inkjet printing.

Inkjet printers can be used to fabricate anthropomorphic phantoms by the use of iodine-doped ink. However, challenges persist in implementing this technique. The calibration from grayscale to ink density is complex and time-consuming. The purpose of this work is to develop a printing methodology that requires a simpler calibration and is less dependent on printer characteristics to produce the desired range of x-ray attenuation values. Conventional grayscale printing was substituted by single-tone printing; that is, the superposition of pure black layers of iodinated ink. Printing was performed with a consumer-grade inkjet printer using ink made of potassium-iodide (KI) dissolved in water at 1g/ml. A calibration for the attenuation of ink was measured using a commercial x-ray system at 70kVp. A neonate radiograph obtained at 70kVp served as an anatomical model. The attenuation map of the neonate radiograph was processed into a series of single-tone images. Single-tone images were printed, stacked, and imaged at 70kVp. The phantom was evaluated by comparing attenuation values between the printed phantom and the original radiograph; attenuation maps were compared using the structural similarity index measure (SSIM), while attenuation histograms were compared using the Kullback-Leibler (KL) divergence. A region of interest (ROI)-based analysis was also performed, where the attenuation distribution within given ROIs was compared between phantom and patient. The phantom sharpness was evaluated in terms of modulation transfer function (MTF) estimates and signal spread profiles of high spatial resolution features in the image. The printed phantom required 36 pages. The printing queue was automated and it took about 2h to print the phantom. The radiograph of the printed phantom demonstrated a close resemblance to the original neonate radiograph. The SSIM of the phantom with respect to that of the patient was 0.53. Both patient and phantom attenuation histograms followed similar distributions, and the KL divergence between such histograms was 0.20. The ROI-based analysis showed that the largest deviations from patient attenuation values were observed at the higher and lower ends of the attenuation range. The limiting resolution of the proposed methodology was about 1mm. A methodology to generate a neonate phantom for 2D imaging applications, using single-tone printing, was developed. This method only requires a single-value calibration and required less than 2h to print a complete phantom.

Noise-like discrete signals for asynchronous code division radio systems

This article discusses noise-like discrete signals (pseudo-random sequences) for asynchronous code division systems for radio channels. Asynchrony implies the use of sequences that are statistically uncorrelated for an arbitrary cyclically shifted copy of the signals, i.e. their cross-correlation coefficient for arbitrarily chosen starting points is close to zero. The fundamental theoretical limit for this characteristic is the well-known Welch boundary. In this paper, we compare the correlation properties of various sets (Gold codes, Kasami sequences, etc.) with this fundamental limit. The parameters of different codes are estimated, the corresponding bound is shown and compared with the real correlation characteristics of the codes. For the approximation, the Laurent series expansion and the Puiseau series were used. The asymptotic properties were also estimated. The paper also considers new ensembles of noise-like discrete signals for asynchronous systems. These codes are statistically uncorrelated, asymptotically the square of their cross-correlation for arbitrary starting points tends to the theoretical Welch bound. Moreover, the cardinality (power of the set) of new signal ensembles is much higher than that of Gold codes and Kasami sets. Consequently, the practical use of such noise-like discrete signals will increase the capacity of asynchronous code division systems for radio channels and reduce the cost of communication services. In addition, new sets of spreading signals will be useful for the implementation of the so-called. soft capacity, i.e. when, if necessary, the base station can increase the subscriber capacity with a slight decrease in the quality of service.

Analysis of Beam Forming Antenna using Soft-Computing Techniques

Antenna Beam forming is a technology or a technique that is finding increasing use in systems of cellular telecommunication, especially 5G, as well as many other wireless systems. Beam forming refers to the formation of a beam of energy from a set of phased arrays. With the use of phased arrays, it is possible to control the direction and shape of the beam from multiple antennas, based on the spacing between antennas and the phase of signal from each antenna element in the array. Beam forming focuses a wireless signal towards a specific receiving device, rather than having the signal spread in all directions from the broadcast antenna. By focusing signal in specific direction, the beam forming technique allows delivery of higher signal quality to the receiver, which would result in faster information transfer with fewer errors and without the need to boost the broadcast power. Beam forming technique is also used to reduce the interference of signals. Beam forming is majorly involved with computing resources which requires high time and power resources. Parameters that would be analyzed during this project are Half Power Beam width (HPBW), First Null Beam width (FNBW), Gain, Voltage Standing Wave Ratio, Front to Back Power Ratio, Side Lobe Levels.

Short-lived detection of an introduced vertebrate eDNA signal in a nearshore rocky reef environment.

Environmental DNA (eDNA) is increasingly used to measure biodiversity of marine ecosystems, yet key aspects of the temporal dynamics of eDNA remain unknown. Of particular interest is in situ persistence of eDNA signals in dynamic marine environments, as eDNA degradation rates have predominantly been quantified through mesocosm studies. To determine in situ eDNA residence times, we introduced an eDNA signal from a non-native fish into a protected bay of a Southern California rocky reef ecosystem, and then measured changes in both introduced and background eDNA signals across a fixed transect over 96 hours. Foreign eDNA signal was no longer detected only 7.5 hours after introduction, a time substantially shorter than the multi-day persistence times in laboratory studies. Moreover, the foreign eDNA signal spread along the entire 38 m transect within 1.5 hours after introduction, indicating that transport and diffusion play a role in eDNA detectability even in protected low energy marine environments. Similarly, native vertebrate eDNA signals varied greatly over the 96 hours of observation as well as within two additional nearby fixed transects sampled over 120 hours. While community structure did significantly change across time of day and tidal direction, neither accounted for the majority of observed variation. Combined, results show that both foreign and native eDNA signatures can exhibit substantial temporal heterogeneity, even on hourly time scales. Further work exploring eDNA decay from lagrangian perspective and quantifying effects of sample and technical replication are needed to better understand temporal variation of eDNA signatures in nearshore marine environments.

Differential compartmentalization of BMP4/NOGGIN requires NOGGIN trans-epithelial transport.

Using self-organizing human models of gastrulation, we previously showed that (1) BMP4 initiates the cascade of events leading to gastrulation, (2) BMP4 signal reception is restricted to the basolateral domain, and (3) in a human-specific manner, BMP4 directly induces the expression of NOGGIN. Here, we report the surprising discovery that in human epiblasts, NOGGIN and BMP4 were secreted into opposite extracellular spaces. Interestingly, apically presented NOGGIN could inhibit basally delivered BMP4. Apically imposed microfluidic flow demonstrated that NOGGIN traveled in the apical extracellular space. Our co-localization analysis detailed the endocytotic route that trafficked NOGGIN from the apical space to the basolateral intercellular space where BMP4 receptors were located. This apical-basal transcytosis was indispensable for NOGGIN inhibition. Taken together, the segregation of activator/inhibitor into distinct extracellular spaces challenges classical views of morphogen movement. We propose that the transport of morphogen inhibitors regulates the spatial availability of morphogens during embryogenesis.

Voluntary Bank Debt Renegotiation and Bondholders' Wealth

I utilize bondholder wealth and corporate investment e ffects to test theories of why voluntary bank debt renegotiation happens without any default. Bondholders react positively to renegotiations that relax loan covenants, consistent with Gârleanu and Zwiebel (2009) that lenders transfer control rights back to the firm upon receiving favorable credit information. Positive bondholder reaction also rejects the alternative hypothesis that relaxing covenants signals weakened bank monitoring. Bondholders do not have a negative reaction to the renegotiated loan spread increase. Firms also invest more conservatively after such renegotiations. These results fail to support Gorton and Kahn (2000) that increased loan spread signals that asset substitution cannot be avoided. Lastly, I find that debt overhang is reduced following loan renegotiations that relax covenants.