Macrophage recruitment and epithelial repair following hair cell injury in the mouse utricle

The sensory organs of the inner ear possess resident populations of macrophages, but the function of those cells is poorly understood. In many tissues, macrophages participate in the removal of cellular debris after injury and can also promote tissue repair. The present study examined injury-evoked macrophage activity in the mouse utricle. Experiments used transgenic mice in which the gene for the human diphtheria toxin receptor (huDTR) was inserted under regulation of the Pou4f3 promoter. Hair cells in such mice can be selectively lesioned by systemic treatment with diphtheria toxin (DT). In order to visualize macrophages, Pou4f3-huDTR mice were crossed with a second transgenic line, in which one or both copies of the gene for the fractalkine receptor CX3CR1 were replaced with a gene for GFP. Such mice expressed GFP in all macrophages, and mice that were CX3CR1GFP/GFP lacked the necessary receptor for fractalkine signaling. Treatment with DT resulted in the death of ~70% of utricular hair cells within seven days, which was accompanied by increased numbers of macrophages within the utricular sensory epithelium. Many of these macrophages appeared to be actively engulfing hair cell debris, indicating that macrophages participate in the process of ‘corpse removal’ in the mammalian vestibular organs. However, we observed no apparent differences in injury-evoked macrophage numbers in the utricles of CX3CR1+/GFP mice vs. CX3CR1GFP/GFP mice, suggesting that fractalkine signaling is not necessary for macrophage recruitment in these sensory organs. Finally, we found that repair of sensory epithelia at short times after DT-induced hair cell lesions was mediated by relatively thin cables of F-actin. After 56 days recovery, however, all cell-cell junctions were characterized by very thick actin cables

Selective deletion of cochlear hair cells causes rapid age-dependent changes in spiral ganglion and cochlear nucleus neurons

During nervous system development, critical periods are usually defined as early periods during which manipulations dramatically change neuronal structure or function, whereas the same manipulations in mature animals have little or no effect on the same property. Neurons in the ventral cochlear nucleus (CN) are dependent on excitatory afferent input for survival during a critical period of development. Cochlear removal in young mammals and birds results in rapid death of target neurons in the CN. Cochlear removal in older animals results in little or no neuron death. However, the extent to which hair-cell-specific afferent activity prevents neuronal death in the neonatal brain is unknown. We further explore this phenomenon using a new mouse model that allows temporal control of cochlear hair cell deletion. Hair cells express the human diphtheria toxin (DT) receptor behind the Pou4f3 promoter. Injections of DT resulted in nearly complete loss of organ of Corti hair cells within 1 week of injection regardless of the age of injection. Injection of DT did not influence surrounding supporting cells directly in the sensory epithelium or spiral ganglion neurons (SGNs). Loss of hair cells in neonates resulted in rapid and profound neuronal loss in the ventral CN, but not when hair cells were eliminated at a more mature age. In addition, normal survival of SGNs was dependent on hair cell integrity early in development and less so in mature animals. This defines a previously undocumented critical period for SGN survival

Fractalkine signaling regulates macrophage recruitment into the cochlea and promotes the survival of spiral ganglion neurons after selective hair cell lesion

Macrophages are recruited into the cochlea in response to injury caused by acoustic trauma or ototoxicity, but the nature of the interaction between macrophages and the sensory structures of the inner ear remains unclear. The present study examined the role of fractalkine signaling in regulating the injury-evoked behavior of macrophages following the selective ablation of cochlear hair cells. We used a novel transgenic mouse model in which the human diphtheria toxin receptor (huDTR) is selectively expressed under the control of Pou4f3, a hair cell-specific transcription factor. Administration of diphtheria toxin (DT) to these mice resulted in nearly complete ablation of cochlear hair cells, with no evident pathology among supporting cells, spiral ganglion neurons, or cells of the cochlear lateral wall. Hair cell death led to an increase in macrophages associated with the sensory epithelium of the cochlea. Their numbers peaked at 14 days after DT and then declined at later survival times. Increased macrophages were also observed within the spiral ganglion, but their numbers remained elevated for (at least) 56 d after DT. To investigate the role of fractalkine signaling in macrophage recruitment, we crossed huDTR mice to a mouse line that lacks expression of the fractalkine receptor (CX(3)CR1). Disruption of fractalkine signaling reduced macrophage recruitment into both the sensory epithelium and spiral ganglion and also resulted in diminished survival of spiral ganglion neurons after hair cell death. Our results suggest a fractalkine-mediated interaction between macrophages and the neurons of the cochlea. SIGNIFICANCE STATEMENT It is known that damage to the inner ear leads to recruitment of inflammatory cells (macrophages), but the chemical signals that initiate this recruitment and the functions of macrophages in the damaged ear are unclear. Here we show that fractalkine signaling regulates macrophage recruitment into the cochlea and also promotes the survival of cochlear afferents after selective hair cell lesion. Because these afferent neurons carry sound information from the cochlea to the auditory brainstem, their survival is a key determinant of the success of cochlear prosthetics. Our data suggest that fractalkine signaling in the cochlea is neuroprotective, and reveal a previously uncharacterized interaction between cells of the cochlea and the innate immune system

Correlations of Online Search Engine Trends with Coronavirus Disease (COVID-19) Incidence: Infodemiology Study

Background: The coronavirus disease (COVID-19) is the latest pandemic of the digital age. With the internet harvesting large amounts of data from the general population in real time, public databases such as Google Trends (GT) and the Baidu Index (BI) can be an expedient tool to assist public health efforts. Objective: The aim of this study is to apply digital epidemiology to the current COVID-19 pandemic to determine the utility of providing adjunctive epidemiologic information on outbreaks of this disease and evaluate this methodology in the case of future pandemics. Methods: An epidemiologic time series analysis of online search trends relating to the COVID-19 pandemic was performed from January 9, 2020, to April 6, 2020. BI was used to obtain online search data for China, while GT was used for worldwide data, the countries of Italy and Spain, and the US states of New York and Washington. These data were compared to real-world confirmed cases and deaths of COVID-19. Chronologic patterns were assessed in relation to disease patterns, significant events, and media reports. Results: Worldwide search terms for shortness of breath, anosmia, dysgeusia and ageusia, headache, chest pain, and sneezing had strong correlations (r>0.60, P<.001) to both new daily confirmed cases and deaths from COVID-19. GT COVID-19 (search term) and GT coronavirus (virus) searches predated real-world confirmed cases by 12 days (r=0.85, SD 0.10 and r=0.76, SD 0.09, respectively, P<.001). Searches for symptoms of diarrhea, fever, shortness of breath, cough, nasal obstruction, and rhinorrhea all had a negative lag greater than 1 week compared to new daily cases, while searches for anosmia and dysgeusia peaked worldwide and in China with positive lags of 5 days and 6 weeks, respectively, corresponding with widespread media coverage of these symptoms in COVID-19. Conclusions: This study demonstrates the utility of digital epidemiology in providing helpful surveillance data of disease outbreaks like COVID-19. Although certain online search trends for this disease were influenced by media coverage, many search terms reflected clinical manifestations of the disease and showed strong correlations with real-world cases and deaths

Analytical model of brittle destruction based on hypothesis of scale similarity

The size distribution of dust particles in nuclear fusion devices is close to the power function. A function of this kind can be the result of brittle destruction. From the similarity assumption it follows that the size distribution obeys the power law with the exponent between -4 and -1. The model of destruction has much in common with the fractal theory. The power exponent can be expressed in terms of the fractal dimension. Reasonable assumptions on the shape of fragments concretize the power exponent, and vice versa possible destruction laws can be inferred on the basis of measured size distributions.Comment: 10 pages, 3 figure

Semiclassical theory of electron drag in strong magnetic fields

We present a semiclassical theory for electron drag between two parallel two-dimensional electron systems in a strong magnetic field, which provides a transparent picture of the most salient qualitative features of anomalous drag phenomena observed in recent experiments, especially the striking sign reversal of drag at mismatched densities. The sign of the drag is determined by the curvature of the effective dispersion relation obeyed by the drift motion of the electrons in a smooth disorder potential. Localization plays a role in explaining activated low temperature behavior, but is not crucial for anomalous drag per se.Comment: 10 page

Coulomb Drag in the Extreme Quantum Limit

Coulomb drag resulting from interlayer electron-electron scattering in double layer 2D electron systems at high magnetic field has been measured. Within the lowest Landau level the observed drag resistance exceeds its zero magnetic value by factors of typically 1000. At half-filling of the lowest Landau level in each layer (nu = 1/2) the data suggest that our bilayer systems are much more strongly correlated than recent theoretical models based on perturbatively coupled composite fermion metals.Comment: 4 pages, 4 figure

Cadaveric Simulation of Endoscopic Endonasal Procedures: Analysis of Droplet Splatter Patterns During the COVID-19 Pandemic

Objective The primary mode of viral transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is thought to occur through the spread of respiratory droplets. The objective of this study was to investigate droplet and splatter patterns resulting from common endoscopic endonasal procedures. Study Design Cadaver simulation series. Setting Dedicated surgical laboratory. Subjects and Methods After instilling cadaver head specimens (n = 2) with fluorescein solution, endoscopic endonasal procedures were systematically performed to evaluate the quantity, size, and distance of droplets and splatter following each experimental condition. Results There were no observable fluorescein droplets or splatter noted in the measured surgical field in any direction after nasal endoscopy, septoplasty with microdebrider-assisted turbinoplasty, cold-steel functional endoscopic sinus surgery (FESS), and all experimental conditions using an ultrasonic aspirator. Limited droplet spread was noted with microdebrider FESS (2 droplets, <1 mm in size, within 10 cm), drilling of the sphenoid rostrum with a diamond burr (8, <1 mm, 12 cm), and drilling of the frontal beak with a cutting burr (5, <1 mm, 9 cm); however, the use of concurrent suction while drilling resulted in no droplets or splatter. The control condition of external activation of the drill resulted in gross contamination (11, 2 cm, 13 cm). Conclusion Our results indicate that there is very little droplet generation from routine rhinologic procedures. The droplet generation from drilling was mitigated with the use of concurrent suction. Extreme caution should be used to avoid activating powered instrumentation outside of the nasal cavity, which was found to cause droplet contamination

Observation of the screening signature in the lateral photovoltage of electrons in the Quantum Hall regime

The lateral photovoltage generated in the plane of a two-dimensional electron system (2DES) by a focused light spot, exhibits a fine-structure in the quantum oscillations in a magnetic field near the Quantum Hall conductivity minima. A double peak structure occurs near the minima of the longitudinal conductivity oscillations. This is the characteristic signature of the interplay between screening and Landau quantization.Comment: 4 pages, 4 figures, to be published in Phys. Rev.