Spectral and temporal atomic coherence interaction in Eu3+ : NaYF4 and Eu3+ : BiPO4.

We investigate the spectral and temporal atomic coherence interaction based on out-of-phase fluorescence (FL) and spontaneous parametric four-wave mixing (SFWM) from the hexagonal phase of Eu3+ : NaYF4 and different phases of Eu3+ : BiPO4. Spectral and temporal interactions are interrelated and reduced by about 2 times due to two-photon nested dressing in contrast to the sum of each laser excitation. As the lifetime of photons increases, off-resonance profile cross-interaction decreases because cross-interaction reverses the signal at the near time gate position and keeps it consistent at the far time gate position. Moreover, the thermal phonon dressing at 300 K exhibits 6 times more eminent and obvious temporal interaction than that at 77 K. In a different phase of Eu3+ : BiPO4, there are three dark dips having stronger self-interaction; however, Eu3+ : NaYF4 has two dark dips as Eu3+ : BiPO4 has two phonon dressing. Further, the pure hexagonal phase of Eu3+ : BiPO4 demonstrates the strongest cross-interaction and longest coherent time under the dressing effect due to the smallest dressing phonon detuning and off-resonance profile cross-interaction at PMT2 because the angle quantization is the strongest. Such results can be used for designing novel quantum devices and have potential applications in quantum memory devices.

Cholecystokinin receptor antagonist challenge elicits brain-wide functional connectome modulation with micronetwork hippocampal decreased calcium transients.

The cortical distribution and functional role of cholecystokinin (CCK) are largely unknown. Here, a CCK receptor antagonist challenge paradigm was developed to assess functional connectivity and neuronal responses. Structural-functional magnetic resonance imaging and calcium imaging were undertaken in environmental enrichment (EE) and standard environment (SE) groups (naïve adult male mice, n = 59, C57BL/B6J, P = 60). Functional connectivity network-based statistics and pseudo-demarcation Voronoi tessellations to cluster calcium signals were used to derive region of interest metrics based on calcium transients, firing rate, and location. The CCK challenge elicited robust changes to structural-functional networks, decreased neuronal calcium transients, and max firing rate (5 s) of dorsal hippocampus in SE mice. However, the functional changes were not observed in EE mice, while the decreased neuronal calcium transients and max firing rate (5 s) were similar to SE mice. Decreased gray matter alterations were observed in multiple brain regions in the SE group due to CCK challenge, while no effect was observed in the EE group. The networks most affected by CCK challenge in SE included within isocortex, isocortex to olfactory, isocortex to striatum, olfactory to midbrain, and olfactory to thalamus. The EE group did not experience network changes in functional connectivity due to CCK challenge. Interestingly, calcium imaging revealed a significant decrease in transients and max firing rate (5 s) in the dorsal CA1 hippocampus subregion after CCK challenge in EE. Overall, CCK receptor antagonists affected brain-wide structural-functional connectivity within the isocortex, in addition to eliciting decreased neuronal calcium transients and max firing rate (5 s) in CA1 of the hippocampus. Future studies should investigate the CCK functional networks and how these processes affect isocortex modulation. Significance Statement  Cholecystokinin is a neuropeptide predominately found in the gastrointestinal system. Albeit abundantly expressed in neurons, the role and distribution of cholecystokinin are largely unknown. Here, we demonstrate cholecystokinin affects brain-wide structural-functional networks within the isocortex. In the hippocampus, the cholecystokinin receptor antagonist challenge decreases neuronal calcium transients and max firing rate (5 s) in CA1. We further demonstrate that mice in environmental enrichment do not experience functional network changes to the CCK receptor antagonist challenge. Environmental enrichment may afford protection to the alterations observed in control mice due to CCK. Our results suggest that cholecystokinin is distributed throughout the brain, interacts in the isocortex, and demonstrates an unexpected functional network stability for enriched mice.

Lithium in breast milk transiently affects the renal electrolytic balance of infants.

BACKGROUND: The use of lithium during breast-feeding has not been comprehensively investigated in humans due to concerns about lithium toxicity. PROCEDURE: We analyzed lithium in the kidneys of nursed pups of lithium medicated mothers, using analytical spectroscopy in a novel rat model. The mothers were healthy rats administered lithium via gavage (1000 mg/day Li2 CO3 per 50 kg body weight). RESULTS: Lithium was detected in the breast milk, and in the blood of pups (0.08 mM), of lithium-exposed dams at post-natal day 18 (P18), during breast-feeding. No lithium was detected after breast-feeding, at P25 (4 days after cessation of nursing). The lithium pups blood had elevated urea nitrogen at P18 and reduced total T4 at P18 and P25, indicating a longer-term effect on the kidneys and the thyroid gland. Multivariate machine-learning analysis of spectroscopy data collected from the excised kidneys of pups showed elevated potassium in lithium-exposed animals both during- and after breast-feeding. The elevated renal potassium was associated with low nephrin expression in the kidneys measured immunohistochemically during breast-feeding. After lithium exposure is stopped, the filtration of lithium from the kidneys reverses these effects. Our study showed that breastfeeding during lithium use has an effect on the kidneys of the offspring in rats.

Omics approach to reveal the effects of obesity on the protein profiles of the exosomes derived from different adipose depots.

BACKGROUND: Obesity affects the cargo packaging of the adipocyte-derived exosomes. Furthermore, adipocytes in different adipose tissues have different genetic makeup, the cargo contents of the exosomes derived from different adipose tissues under obesity conditions should be different, and hence their impacts on the pathophysiological conditions. METHODS AND RESULTS: iTRAQ-based quantitative proteomics show that obesity has more prominent effects on the protein profiles of the exosomes derived from subcutaneous adipose tissue (SAT-Exos) in the high fat diet-induced obesity (DIO) mice than those derived from epididymal adipose tissue (EAT-Exos) and visceral adipose tissue (VAT-Exos). The differentially expressed proteins (DEPs) in SAT-Exos and VAT-Exos are mainly involved in metabolism. Subsequent untargeted metabolomic and lipidomics analyses reveal that injection of these SAT-Exos into the B6/J-Rab27a-Cas9-KO mice significantly affects the mouse metabolism such as fatty acid metabolism. Some of the DEPs in SAT-Exos are correlated with fatty acid metabolism including ADP-ribosylation factor and mitogen-activated protein kinase kinase kinase-3. Pathway analysis also shows that SAT-Exos affect adipocyte lipolysis and glycerophospholipid metabolism, which is in parallel with the enhanced plasma levels of fatty acids, diglycerides, monoglycerides and the changes in glycerophospholipid levels in DIO mice. CONCLUSION: Our data provide scientific evidence to suggest SAT-Exos contribute to the changes in plasma lipid profiles under obesity conditions.

Environmental enrichment leads to behavioral circadian shifts enhancing brain-wide functional connectivity between sensory cortices and eliciting increased hippocampal spiking.

Environmental enrichment induces widespread neuronal changes, but the initiation of the cascade is unknown. We ascertained the critical period of divergence between environmental enriched (EE) and standard environment (SE) mice using continuous infrared (IR) videography, functional magnetic resonance imaging (fMRI), and neuron level calcium imaging. Naïve adult male mice (n = 285, C57BL/6J, postnatal day 60) were divided into SE and EE groups. We assessed the linear time-series of motion activity using a novel structural break test which examined the dataset for change in circadian and day-by-day motion activity. fMRI was used to map brain-wide response using a functional connectome analysis pipeline. Awake calcium imaging was performed on the dorsal CA1 pyramidal layer. We found the preeminent behavioral feature in EE was a forward shift in the circadian rhythm, prolongation of activity in the dark photoperiod, and overall decreased motion activity. The crepuscular period of dusk was seen as the critical period of divergence between EE and SE mice. The functional processes at dusk in EE included increased functional connectivity in the visual cortex, motor cortex, retrosplenial granular cortex, and cingulate cortex using seed-based analysis. Network based statistics found a modulated functional connectome in EE concentrated in two hubs: the hippocampal formation and isocortical network. These hubs experienced a higher node degree and significant enhanced edge connectivity. Calcium imaging revealed increased spikes per second and maximum firing rate in the dorsal CA1 pyramidal layer, in addition to location (anterior-posterior and medial-lateral) effect size differences between EE and SE. The emergence of functional-neuronal changes due to enrichment consisted of enhanced hippocampal-isocortex functional connectivity and CA1 neuronal increased spiking linked to a circadian shift during the dusk period. Future studies should explore the molecular consequences of enrichment inducing shifts in the circadian period.

Development of a carboxyl-terminated indium tin oxide electrode for improving cell adhesion and facilitating low noise, real-time impedance measurements.

The working electrode's surface property is crucial to cell adhesion and signal collection in electric cell-substrate impedance sensing (ECIS). To date, the indium tin oxide (ITO)-based working electrode is of interest in ECIS study due to its high transparency and biocompatibility. Of great concern is the impedance signal loss, distortion, and data interpretation conflict profoundly created by the movement of multiple cells during ECIS study. Here, a carboxyl-terminated ITO substrate was prepared by stepwise surface amino silanization, with N-hydroxy succinimide (NHS) and 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (EDC) treatment, respectively. We investigated the stepwise changes in the property of the treated ITO, cell-substrate adhesion, collective cell mobility, and time course of change in absolute impedance from multiple Chinese hamster ovary (CHO) cells [(Δt-Δ|Z|)CELLS]. The carboxyl-terminated ITO substrate with a surface roughness of 6.37 nm shows enhanced conductivity, 75% visible light transparency, improved cell adherence, reduced collective cell migration speed by approximately twofold, and diminished signal distortion in the [(Δt-Δ|Z|)CELLS]. Thus, our study provides an ITO surface-treatment strategy to reduce multiple cell movement effects and to obtain essential cell information from the ECIS study of multiple cells through undistorted (Δt-Δ|Z|)CELLS.

Hearing loss impacts gray and white matter across the lifespan: Systematic review, meta-analysis and meta-regression.

Hearing loss is a heterogeneous disorder thought to affect brain reorganization across the lifespan. Here, structural alterations of the brain due to hearing loss are assessed by using unique effect size metrics based on Cohen's d and Hedges' g. These metrics are used to map coordinates of gray matter (GM) and white matter (WM) alterations from bilateral congenital and acquired hearing loss populations. A systematic review and meta-analysis revealed m = 72 studies with structural alterations measured with magnetic resonance imaging (MRI) (bilateral = 64, unilateral = 8). The bilateral studies categorized hearing loss into congenital and acquired cases (n = 7,445) and control cases (n = 2,924), containing 66,545 datapoint metrics. Hearing loss was found to affect GM and underlying WM in nearly every region of the brain. In congenital hearing loss, GM decreased most in the frontal lobe. Similarly, acquired hearing loss had a decrease in frontal lobe GM, albeit the insula was most decreased. In congenital, WM underlying the frontal lobe GM was most decreased. In congenital, the right hemisphere was more negatively impacted than the left hemisphere; however, in acquired, this was the opposite. The WM alterations most frequently underlined GM alterations in congenital hearing loss, while acquired hearing loss studies did not frequently assess the WM metric. Future studies should use the endophenotype of hearing loss as a prognostic template for discerning clinical outcomes.

Lithium from breast-milk inhibits thyroid iodine uptake and hormone production, which are remedied by maternal iodine supplementation.

BACKGROUND: Lithium is especially taken as a maintenance medication for Bipolar Disorder. In women with bipolar disorder, lithium is often effective during postpartum period, but breast-feeding for medicated mothers is controversial because of harmful effects for her child. At present, the biological mechanisms of lithium are not well-understood, affecting its usage and overall health implications. PROCEDURE: We developed a rat lithium and breast-feeding model at human therapeutic levels to study the effects of lithium exposure through breast-milk on pups' thyroid function. Novel laser analytical spectroscopy, along with traditional blood and immunohistochemical tests, were applied to further investigate the mechanisms behind the thyroid dysfunction. Maternal iodine supplementation was evaluated as a therapeutic method to address the pups' thyroid dysfunction. RESULTS: Pups exposed to lithium via breastmilk, even with the dam on a sub-therapeutic level, experienced weight gain, reduced blood thyroxine (T4 ), and elevated blood urea nitrogen, indicating effects on thyroid and kidney function. We show that lithium inhibited iodine uptake by thyroid follicles, initiating a mechanism that reduced iodination of tyrosine, thyroglobulin cleavage, and thyroid hormone production. Importantly, infant thyroid function can be significantly improved by administering supplementary iodine to the medicated dam's diet during breast-feeding. CONCLUSION: These results elucidate the mechanisms of lithium in thyroid function, provide valuable information on use postpartum, and suggest a clinically applicable remedy to side-effects. The results are particularly important for patients (and their infants) who respond well to lithium and need, or choose, to breast-feed.

FROZEN! Intracellular multi-electrolyte analysis measures millimolar lithium in mammalian cells.

Lithium salts are commonly used as medication for Bipolar Disorder (BD) and depression. However, there are limited methods to quantify intracellular lithium. Most methods to analyze intracellular electrolytes require tedious sample processing, specialized and often expensive machinery, sometimes involving harmful chemicals, and a bulk amount of the sample. In this work, we report a novel method (FROZEN!) based on cell isolation (from the surrounding medium) through rapid de-ionized water cleaning, followed by flash freezing for preservation. SKOV3 cells were cultured in normal medium and a medium containing 1.0 mM lithium. Lithium and other intracellular electrolytes in the isolated and preserved cells were simultaneously analyzed with laser-induced breakdown spectroscopy (LIBS) and X-ray fluorescence spectroscopy (XRF). Key electrolytes such as sodium, potassium, and magnesium, along with lithium, were detectable at the single-cell level. We found that cells cultured in the lithium medium have an intracellular lithium concentration of 0.5 mM. Concurrently, the intracellular concentrations of other positively charged electrolytes (sodium, potassium, and magnesium) were reduced by the presence of lithium. FROZEN! will greatly facilitate research in intracellular electrolyte balance during drug treatment, or other physiological stresses. In particular, the cell isolation and preservation steps can be easily performed by many laboratories worldwide, after which the samples are sent to an analytical laboratory for electrolyte analysis.

Rapid trace element analysis of microgram soft materials with cryogenic milling and laser ablation spectroscopy.

Trace element analysis of soft materials, to determine the content of low concentration elements, is important in many industries such as food quality control and medical biopsy analysis. Many of these applications would benefit from faster analysis with smaller sample requirements. Further, some natural samples are soft and have high water content, which brings challenges to element analysis. Here, we develop a cryogenic pelletization pretreatment to address those challenges. The soft samples are cryogenically milled, freeze-dried, and pelletized before elemental analysis. Analysis is performed by laser ablation spectroscopy, the combination of laser-induced breakdown spectroscopy (LIBS) and laser ablation inductively coupled plasma mass spectroscopy (LA-ICP-MS), to rapidly analyze light and heavy analytes. For this initial study, aluminum (Al) content in soft samples is determined by LIBS and lead (Pb) content by LA-ICP-MS. The standard addition method is performed to build calibration curves for element quantification. The measurements are compared with a Hong Kong government certified acid digestion and ICP-MS procedure. The experiment is performed on standard reference materials and selected food samples. The relative errors compared with certified measurements are less than 10% for all samples, with Al content ranging from 63-1466 µg/g and Pb content from 0.37-2.35 µg/g (dry mass). Microscopy of pellets shows that laser ablation spectroscopy can be performed with 100 µg of sample (dry mass). Total analysis time from raw sample to final measurement, including preparation, is under 1 h. The results indicate that the laser ablation spectroscopy with cryogenic pelletization is a promising technique for many applications such as screening of small food samples for toxic metals and trace element analysis of millimeter biopsies.

Stability improvement for dried droplet pretreatment by suppression of coffee ring effect using electrochemical anodized nanoporous tin dioxide substrate.

A novel nanoporous analytical platform is reported to improve the stability of the dried droplet method (DDM). This nanoporous platform was made of tin dioxide (Np SnO2) substrate by electrochemical anodization from tin (Sn) slide. The DDM is a widely used sample pretreatment in analytical chemistry that involves placing a droplet of solution onto the substrate and drying for analytical testing. However, during the droplet drying process, the solutes would converge at the droplet edge and cause inhomogeneous solutes distribution. This is the coffee ring effect (CRE). The Np SnO2 has irregular nanopores, which allows droplet solutions to penetrate into the substrate rather than spreading out, effectively suppressing CRE. Theoretical models were built to explain the formation of CRE on blank tin (Sn) substrate and suppression of CRE on Np SnO2. Better results were obtained in detecting lithium (Li) using the Np SnO2 by laser-induced breakdown spectroscopy (LIBS). The line scanning results indicated that the Li emission line (670.8 nm) intensities on Np SnO2 substrate had lower relative standard deviation (RSD = 3.3%) than those on Sn substrate (RSD = 31.5%), which illustrate suppression of CRE and stability improvement on Np SnO2 substrate. Furthermore, Li calibration curves were built for LIBS with DDM. The curve using Np SnO2 substrate had better linearity (R2 = 0.997), higher precision (RSD = 4.2%), and higher sensitivity (LOD = 0.13 mg/L) than that by Sn substrate (R2 = 0.954, RSD = 17%, and LOD = 1.21 mg/L). All in all, the anodic Np SnO2 substrate can suppress CRE in DDM and hence improve the stability and precision of subsequent analysis. Graphical abstract.

The pineal gland of the shrew (Blarina brevicauda and Blarina carolinensis): a light and electron microscopic study of pinealocytes.

The pineal gland structure and ultrastructure in the Northern (Blarina brevicauda) and Southern short-tailed shrew (Blarina carolinensis) are described by light and electron microscopy. Results observed were similar to other mammals of Insectivora described previously, specifically, the hedgehog (Erinaceus europaeus) and the Old World mole (Talpa europea). Two different types of pinealocytes were noticed by electron microscopy, in addition to relatively few glial cells. Granular vesicles were not noticed in abundance. The granular endoplasmic reticulum was observed and studded with vesicles. The golgi apparatus was well developed and appeared often. Synaptic ribbons were observed in several different formations consisting of ribbons and/or rods. The ciliary derivative, the rudimentary photoreceptor structures found in the pinealocytes of population I, was noticed in a 9 + 0 tubular pattern. Within these semifossorial shrews, the relationship between specific intracellular organelles and their function was discussed.

Collagen formation observed from healing calvarial defects with principal component analysis of Raman scattering.

Bone healing is a complex process involving molecular changes. Bone matrix consists of collagen proteins that serve as the framework and minerals, calcium and phosphate, are deposited into the matrix accordingly. Raman spectroscopy is a promising technique to study bone mineral and matrix environments simultaneously. We studied the bone composition using 785 nm excitation during healing of subcritical calvarial defects without disrupting the fracture. Calvarial defects (in vivo) were created using a 1 mm burr drill on the parietal bones of Sprague-Dawley rats (n = 12). After 7 days, subjects were sacrificed and an additional defect (control) was created. Principal component analysis was utilized for the analysis of Raman spectra and helped in classifying normal and healing bone. Principal component 1 (PC1) shows that the major variation between in vivo and control defects and normal bone surface is at 958 cm-1 (ν1 phosphate band). PC2 shows a major variation at 1448 cm-1 (CH2 deformation). PC2 score distinguishes in vivo defects from normal surface and control defects. The decrease in crystallinity and mineral to matrix ratio at the healing site as revealed by Raman confirms the new bone formation. Scanning electron and optical microscopy show the formation of newly generated matrix by means of bony bridges of collagens. The surface roughness increases by 23% from control to in vivo defects, as revealed by optical profiler. Histology shows the decreased depth of in vivo defects and new blood vessels formation. Overall, the new collagen formation shows the scaffolding of the bone is growing during healing.

Reduction of sound-evoked midbrain responses observed by functional magnetic resonance imaging following acute acoustic noise exposure.

Short duration and high intensity acoustic exposures can lead to temporary hearing loss and auditory nerve degeneration. This study investigates central auditory system function following such acute exposures after hearing loss recedes. Adult rats were exposed to 100 dB sound pressure level noise for 15 min. Auditory brainstem responses (ABRs) were recorded with click sounds to check hearing thresholds. Functional magnetic resonance imaging (fMRI) was performed with tonal stimulation at 12 and 20 kHz to investigate central auditory changes. Measurements were performed before exposure (0D), 7 days after (7D), and 14 days after (14D). ABRs show an ∼6 dB threshold shift shortly after exposure, but no significant threshold differences between 0D, 7D, and 14D. fMRI responses are observed in the lateral lemniscus (LL) and inferior colliculus (IC) of the midbrain. In the IC, responses to 12 kHz are 3.1 ± 0.3% (0D), 1.9 ± 0.3% (7D), and 2.9 ± 0.3% (14D) above the baseline magnetic resonance imaging signal. Responses to 20 kHz are 2.0 ± 0.2% (0D), 1.4 ± 0.2% (7D), and 2.1 ± 0.2% (14D). For both tones, responses at 7D are less than those at 0D (p < 0.01) and 14D (p < 0.05). In the LL, similar trends are observed. Acute exposure leads to functional changes in the auditory midbrain with timescale of weeks.

Health risk communication message comprehension is influenced by image inclusion.

The impact of images on risk communications such as public service announcements is unknown. Whether images contained within a printed message such as a food safety warning alters the comprehension of the underlying text, has not previously been explored. The present study examined three factors of a risk communication in the print form: (1) the role images play in promoting comprehension of risk messages, (2) how demographic variables such as gender impacts message reception and (3) the need for cognition, or the degree to which some individuals are innately motivated to comprehend and understand information. Examples of risk communications in the print form are warnings on food or tobacco and alcohol warnings. In the present study, students at an undergraduate university (N = 92, 61 females, age 19.89 (SD =1.94) years, range 18-32), read risk communications with and without images. The purpose of the study was to ascertain the affect images have on message comprehension and receptivity. Comprehension was assessed by the structural knowledge test. Negative/fear-arousing images increase message receptivity and subsequent learning when accompanying printed risk communications. Gender alone did not significantly impact message receptivity, although males tended to show greater change in structural knowledge pre- to post-test. This was true especially for the negative fear-arousing images condition. Need for cognition plays a significant role in message receptivity. Nevertheless, for risk communications illustrated with fear arousing images, it appears that the need for cognition is not a necessary condition to learn the message. Further research is needed to determine how these factors impact the degree or depth of message processing.

The multi-level impact of chronic intermittent hypoxia on central auditory processing.

During hypoxia, the tissues do not obtain adequate oxygen. Chronic hypoxia can lead to many health problems. A relatively common cause of chronic hypoxia is sleep apnea. Sleep apnea is a sleep breathing disorder that affects 3-7% of the population. During sleep, the patient's breathing starts and stops. This can lead to hypertension, attention deficits, and hearing disorders. In this study, we apply an established chronic intermittent hypoxemia (CIH) model of sleep apnea to study its impact on auditory processing. Adult rats were reared for seven days during sleeping hours in a gas chamber with oxygen level cycled between 10% and 21% (normal atmosphere) every 90s. During awake hours, the subjects were housed in standard conditions with normal atmosphere. CIH treatment significantly reduces arterial oxygen partial pressure and oxygen saturation during sleeping hours (relative to controls). After treatment, subjects underwent functional magnetic resonance imaging (fMRI) with broadband sound stimulation. Responses are observed in major auditory centers in all subjects, including the auditory cortex (AC) and auditory midbrain. fMRI signals from the AC are statistically significantly increased after CIH by 0.13% in the contralateral hemisphere and 0.10% in the ipsilateral hemisphere. In contrast, signals from the lateral lemniscus of the midbrain are significantly reduced by 0.39%. Signals from the neighboring inferior colliculus of the midbrain are relatively unaffected. Chronic hypoxia affects multiple levels of the auditory system and these changes are likely related to hearing disorders associated with sleep apnea.

Diffusion tensor imaging reveals changes in the adult rat brain following long-term and passive moderate acoustic exposure.

This study investigated neuroanatomical changes following long-term acoustic exposure at moderate sound pressure level (SPL) under passive conditions, without coupled behavioral training. The authors utilized diffusion tensor imaging (DTI) to detect morphological changes in white matter. DTIs from adult rats (n = 8) exposed to continuous acoustic exposure at moderate SPL for 2 months were compared with DTIs from rats (n = 8) reared under standard acoustic conditions. Two distinct forms of DTI analysis were applied in a sequential manner. First, DTI images were analyzed using voxel-based statistics which revealed greater fractional anisotropy (FA) of the pyramidal tract and decreased FA of the tectospinal tract and trigeminothalamic tract of the exposed rats. Region of interest analysis confirmed (p < 0.05) that FA had increased in the pyramidal tract but did not show a statistically significant difference in the FA of the tectospinal or trigeminothalamic tract. The results of the authors show that long-term and passive acoustic exposure at moderate SPL increases the organization of white matter in the pyramidal tract.

Chronic exposure to broadband noise at moderate sound pressure levels spatially shifts tone-evoked responses in the rat auditory midbrain.

Noise-induced hearing disorders are a significant public health concern. One cause of such disorders is exposure to high sound pressure levels (SPLs) above 85 dBA for eight hours/day. High SPL exposures occur in occupational and recreational settings and affect a substantial proportion of the population. However, an even larger proportion is exposed to more moderate SPLs for longer durations. Therefore, there is significant need to better understand the impact of chronic, moderate SPL exposures on auditory processing, especially in the absence of hearing loss. In this study, we applied functional magnetic resonance imaging (fMRI) with tonal acoustic stimulation on an established broadband rat exposure model (65 dB SPL, 30 kHz low-pass, 60 days). The auditory midbrain response of exposed subjects to 7 kHz stimulation (within exposure bandwidth) shifts dorsolaterally to regions that typically respond to lower stimulation frequencies. This shift is quantified by a region of interest analysis that shows that fMRI signals are higher in the dorsolateral midbrain of exposed subjects and in the ventromedial midbrain of control subjects (p<0.05). Also, the center of the responsive region in exposed subjects shifts dorsally relative to that of controls (p<0.05). A similar statistically significant shift (p<0.01) is observed using 40 kHz stimulation (above exposure bandwidth). The results suggest that high frequency midbrain regions above the exposure bandwidth spatially expand due to exposure. This expansion shifts lower frequency regions dorsolaterally. Similar observations have previously been made in the rat auditory cortex. Therefore, moderate SPL exposures affect auditory processing at multiple levels, from the auditory cortex to the midbrain.

Long-term, passive exposure to non-traumatic acoustic noise induces neural adaptation in the adult rat medial geniculate body and auditory cortex.

Exposure to loud sounds can lead to permanent hearing loss, i.e., the elevation of hearing thresholds. Exposure at more moderate sound pressure levels (SPLs) (non-traumatic and within occupational limits) may not elevate thresholds, but could in the long-term be detrimental to speech intelligibility by altering its spectrotemporal representation in the central auditory system. In support of this, electrophysiological and behavioral changes following long-term, passive (no conditioned learning) exposure at moderate SPLs have recently been observed in adult animals. To assess the potential effects of moderately loud noise on the entire auditory brain, we employed functional magnetic resonance imaging (fMRI) to study noise-exposed adult rats. We find that passive, pulsed broadband noise exposure for two months at 65 dB SPL leads to a decrease of the sound-evoked blood oxygenation level-dependent fMRI signal in the thalamic medial geniculate body (MGB) and in the auditory cortex (AC). This points to the thalamo-cortex as the site of the neural adaptation to the moderately noisy environment. The signal reduction is statistically significant during 10 Hz pulsed acoustic stimulation (MGB: p<0.05, AC: p<10(-4)), but not during 5 Hz stimulation. This indicates that noise exposure has a greater effect on the processing of higher pulse rate sounds. This study has enhanced our understanding of functional changes following exposure by mapping changes across the entire auditory brain. These findings have important implications for speech processing, which depends on accurate processing of sounds with a wide spectrum of pulse rates.

Elevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions.

The cargo content in small extracellular vesicles (sEVs) changes under pathological conditions. Our data shows that in obesity, extracellular matrix protein 1 (ECM1) protein levels are significantly increased in circulating sEVs, which is dependent on integrin-ß2. Knockdown of integrin-ß2 does not affect cellular ECM1 protein levels but significantly reduces ECM1 protein levels in the sEVs released by these cells. In breast cancer (BC), overexpressing ECM1 increases matrix metalloproteinase 3 (MMP3) and S100A/B protein levels. Interestingly, sEVs purified from high-fat diet-induced obesity mice (D-sEVs) deliver more ECM1 protein to BC cells compared to sEVs from control diet-fed mice. Consequently, BC cells secrete more ECM1 protein, which promotes cancer cell invasion and migration. D-sEVs treatment also significantly enhances ECM1-mediated BC metastasis and growth in mouse models, as evidenced by the elevated tumor levels of MMP3 and S100A/B. Our study reveals a mechanism and suggests sEV-based strategies for treating obesity-associated BC.