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Long-term monitoring and treatment of landfill leachate (LFL) and landfill gas (LFG) is required until landfilled municipal solid waste (MSW) is sufficiently stabilized and post-closure care can be terminated. Monitoring data of methane (CH 4 ) emissions in LFG from a marine landfill over 30 years were compared with the IPCC first order decay (FOD) model estimates. The observed changes in CH 4 showed a similar attenuation trend to the estimates, but the observed CH 4 emissions were only about 30% of the estimate over 30 years; LFL is considered to be another pathway for organic carbon to be released to the environment, but the total organic carbon in discharged LFL was only about 0.2% of CH 4 carbon in LFG emission over the same period. The increase in the CO 2 /CH 4 ratio in LFG over time suggests that the discrepancy between estimated and observed emissions is due to methane oxidation in the overlying soil, in addition to the high coefficient values used in the FOD model. Total organic carbon (TOC) in LFL discharged as effluent reached a maximum value in the early stages of the landfill and gradually decreased, but only to about one-third of the maximum value after more than 30 years and a decrease in the amount of effluent. As incineration of MSW is expected to reduce organic carbon and nitrogen, the CH 4 reduction effect of incineration of business and household waste and sewage sludge was investigated using FOD model estimates.

Purpose: To evaluate a vendor-agnostic multiparametric mapping scheme based on 3D quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) for whole-brain T1, T2, and proton density (PD) mapping., Methods: This prospective, multi-institutional study was conducted between September 2021 and February 2022 using five different 3T systems from four prominent MRI vendors. The accuracy of this technique was evaluated using a standardized MRI system phantom. Intra-scanner repeatability and inter-vendor reproducibility of T1, T2, and PD values were evaluated in 10 healthy volunteers (6 men; mean age ± SD, 28.0 ± 5.6 y) who underwent scan-rescan sessions on each scanner (total scans = 100). To evaluate the feasibility of 3D-QALAS, nine patients with multiple sclerosis (nine women; mean age ± SD, 48.2 ± 11.5 y) underwent imaging examination on two 3T MRI systems from different manufacturers., Results: Quantitative maps obtained with 3D-QALAS showed high linearity (R 2  = 0.998 and 0.998 for T1 and T2, respectively) with respect to reference measurements. The mean intra-scanner coefficients of variation for each scanner and structure ranged from 0.4% to 2.6%. The mean structure-wise test-retest repeatabilities were 1.6%, 1.1%, and 0.7% for T1, T2, and PD, respectively. Overall, high inter-vendor reproducibility was observed for all parameter maps and all structure measurements, including white matter lesions in patients with multiple sclerosis., Conclusion: The vendor-agnostic multiparametric mapping technique 3D-QALAS provided reproducible measurements of T1, T2, and PD for human tissues within a typical physiological range using 3T scanners from four different MRI manufacturers., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Peptides are potentially useful modalities of drugs; however, cell membrane permeability is an obstacle in peptide drug discovery. The identification of bioactive peptides for a therapeutic target is also challenging because of the huge amino acid sequence patterns of peptides. In this study, we propose a novel computational method, PEptide generation system using Neural network Trained on Amino acid sequence data and Gaussian process-based optimizatiON (PENTAGON), to automatically generate new peptides with desired bioactivity and cell membrane permeability. In the algorithm, we mapped peptide amino acid sequences onto the latent space constructed using a variational autoencoder and searched for peptides with desired bioactivity and cell membrane permeability using Bayesian optimization. We used our proposed method to generate peptides with cell membrane permeability and bioactivity for each of the nine therapeutic targets, such as the estrogen receptor (ER). Our proposed method outperformed a previously developed peptide generator in terms of similarity to known active peptide sequences and the length of generated peptide sequences., (© 2024 Wiley‐VCH GmbH.)

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and in vivo preparations. Neurochemical activation or optogenetic stimulation of sensory afferents evoked persistent gamma oscillations in the local field potential. These oscillations arose from slower, GABA(A) receptor-independent intracolumnar oscillators coupled by GABA(A)-ergic synapses into a faster, broadly coherent network oscillation. Consistent with the theoretical properties of coupled-oscillator networks, the spatial extent of zero-phase coherence was bounded in slices by the reduced density of lateral interactions. The intact in vivo network, however, exhibited long-range lateral interactions that suffice in simulation to enable zero-phase gamma coherence across the olfactory bulb. The timing of action potentials in a subset of principal neurons was phase-constrained with respect to evoked gamma oscillations. Coupled-oscillator dynamics in olfactory bulb thereby enable a common clock, robust to biological heterogeneities, that is capable of supporting gamma-band spike synchronization and phase coding across the ensemble of activated principal neurons. NEW & NOTEWORTHY Odor stimulation evokes rhythmic gamma oscillations in the field potential of the olfactory bulb, but the dynamical mechanisms governing these oscillations have remained unclear. Establishing these mechanisms is important as they determine the biophysical capacities of the bulbar circuit to, for example, maintain zero-phase coherence across a spatially extended network, or coordinate the timing of action potentials in principal neurons. These properties in turn constrain and suggest hypotheses of sensory coding.

Associating values to environmental cues is a critical aspect of learning from experiences, allowing animals to predict and maximise future rewards. Value-related signals in the brain were once considered a property of higher sensory regions, but their wide distribution across many brain regions is increasingly recognised. Here, we investigate how reward-related signals begin to be incorporated, mechanistically, at the earliest stage of olfactory processing, namely, in the olfactory bulb. In head-fixed mice performing Go/No-Go discrimination of closely related olfactory mixtures, rewarded odours evoke widespread inhibition in one class of output neurons, that is, in mitral cells but not tufted cells. The temporal characteristics of this reward-related inhibition suggest it is odour-driven, but it is also context-dependent since it is absent during pseudo-conditioning and pharmacological silencing of the piriform cortex. Further, the reward-related modulation is present in the somata but not in the apical dendritic tuft of mitral cells, suggesting an involvement of circuit components located deep in the olfactory bulb. Depth-resolved imaging from granule cell dendritic gemmules suggests that granule cells that target mitral cells receive a reward-related extrinsic drive. Thus, our study supports the notion that value-related modulation of olfactory signals is a characteristic of olfactory processing in the primary olfactory area and narrows down the possible underlying mechanisms to deeper circuit components that contact mitral cells perisomatically., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lindeman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aim: This study aimed to explore whether the supervision of community public health nurses (PHNs) and nursery school teachers (NSTs) by a specialist, familiar with Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations (ESSENCE), improved the agreement of ESSENCE-Questionnaire (ESSENCE-Q) scoring, across raters., Methods: A PHN, two NSTs, and a speech-language pathologist (SLP), familiar with ESSENCE, independently assessed 32 children. The ESSENCE-Q results were divided into the first (child 1-18) and second groups (the 19th child and the following children). Changes in score discrepancies were analysed for ESSENCE-Q cutoff scores and total ESSENCE-Q scores across raters. The SLP scores were used as a reference to evaluate sensitivity and specificity., Results: The total ESSENCE-Q scores of the PHN and NSTs showed higher concordance in the second group (p < 0.05). Comparisons of the differences between the PHN/NSTs and SLP in total ESSENCE-Q scores showed a significantly smaller difference in the NSTs' scores in the second group (p < 0.05)., Conclusion: The findings suggest that specialist supervision may lead to a better agreement between PHN and NSTs regarding ESSENCE-Q scores., (© 2023 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

The Objective Structured Clinical Examination (OSCE) is designed to assess medical students' skills and attitude competencies before clinical practice. However, no method of reflective learning using video-based content has been used in OSCE education. This study aimed to confirm whether using smart glasses-based educational content is effective for OSCE reflective learning using multiple views (patient, student, and overall). This educational intervention study included a control group exposed to the traditional learning method and an intervention group exposed to a learning method incorporating smart glasses. Participants were 117 (72 in the control group and 45 in the intervention group) third-year radiological technology students scheduled to take the OSCE and 70 (37 in the control group and 33 in the intervention group) who met the eligibility criteria. Mock OSCEs were administered before and after the educational intervention (traditional and smart glasses-based education) to investigate changes in scores. After the educational intervention, a self-reported comprehension survey and a questionnaire were administered on the effectiveness of the video-based content from different views for student reflective learning. Unexpectedly, the OSCE evaluation score after the preliminary investigation significantly increased for the smart glasses control group (0.36±0.1) compared to the intervention group (0.06±0.1) setting up the radiographic conditions (x-ray center and detector center; p = 0.042). The intervention group's lower score in the mock OSCEs may have been due to the discomfort of wearing the smart glasses to perform the radiography procedure and their unfamiliarity with the smart glasses, which may have affected their concentration. The findings suggest that smart glasses-based education for OSCEs can be improved (e.g., being easy to handle and use and trouble-free)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Muroi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Senescent cells play a detrimental role in age-associated pathogenesis by producing factors involved in senescence-associated secretory phenotype (SASP). The present study was conducted to examine the possibility that senescent cells are present in aged ovaries and, if so, to determine the tissue region where senescent cells accumulate using a mouse model. Female mice at 2-4 and 8-10 months were used as reproductively young and aged models, respectively; the latter included mice with and without reproductive experience. Cells positive for senescence-associated β-galactosidase (SA-β-Gal) staining, one of the markers of cellular senescence, were detected in the stromal region of aged, but not young, ovaries regardless of reproductive experience. Likewise, the localization of cells expressing CDKN2A (cyclin dependent kinase inhibitor 2A), another senescence marker, in the stromal region of aged ovaries was detected with immunohistochemistry. CDKN2A expression detected by western blotting was significantly higher in the ovaries of aged mice with reproductive experience than in those without the experience. Moreover, cells positive for both γH2AX (a senescence marker) and fluorescent SA-β-Gal staining were present in those isolated from aged ovaries. In addition, the transcript levels of several SASP factors were significantly increased in aged ovaries. These results suggest that senescent cells accumulate in the ovarian stroma and may affect ovarian function in aged mice. Additionally, reproductive experience may promote accumulation.

Purpose To evaluate the feasibility of liver MR fingerprinting (MRF) for quantitative characterization and diagnosis of focal liver lesions. Materials and Methods This single-site, prospective study included 89 participants (mean age, 62 years ± 15 [SD]; 45 women, 44 men) with various focal liver lesions who underwent MRI between October 2021 and August 2022. The participants underwent routine clinical MRI, non-contrast-enhanced liver MRF, and reference quantitative MRI with a 1.5-T MRI scanner. The bias and repeatability of the MRF measurements were assessed using linear regression, Bland-Altman plots, and coefficients of variation. The diagnostic capability of MRF-derived T1, T2, T2*, proton density fat fraction (PDFF), and a combination of these metrics to distinguish benign from malignant lesions was analyzed according to the area under the receiver operating characteristic curve (AUC). Results Liver MRF measurements showed moderate to high agreement with reference measurements (intraclass correlation = 0.94, 0.77, 0.45, and 0.61 for T1, T2, T2*, and PDFF, respectively), with underestimation of T2 values (mean bias in lesion = -0.5%, -29%, 5.8%, and -8.2% for T1, T2, T2*, and PDFF, respectively). The median coefficients of variation for repeatability of T1, T2, and T2* values were 2.5% (IQR, 3.6%), 3.1% (IQR, 5.6%), and 6.6% (IQR, 13.9%), respectively. After considering multicollinearity, a combination of MRF measurements showed a high diagnostic performance in differentiating benign from malignant lesions (AUC = 0.92 [95% CI: 0.86, 0.98]). Conclusion Liver MRF enabled the quantitative characterization of various focal liver lesions in a single breath-hold acquisition. Keywords: MR Imaging, Abdomen/GI, Liver, Imaging Sequences, Technical Aspects, Tissue Characterization, Technology Assessment, Diagnosis, Liver Lesions, MR Fingerprinting, Quantitative Characterization Supplemental material is available for this article. © RSNA, 2023.

Acquisition of a behavioral task is influenced by many factors. The relative timing of stimuli is such a factor and is especially relevant for tasks relying on short-term memory, like working memory paradigms, because of the constant evolution and decay of neuronal activity evoked by stimuli. Here, we assess two aspects of stimulus timing on the acquisition of an olfactory delayed nonmatch-to-sample (DNMS) task. We demonstrate that head-fixed male mice learn to perform the task more quickly when the initial training uses a shorter sample-test odor delay without detectable loss of generalizability. Unexpectedly, we observed a slower task acquisition when the odor-reward interval was shorter. The effect of early reward timing was accompanied by a shortening of reaction times and more frequent sporadic licking. Analysis of this result using a drift-diffusion model indicated that a primary consequence of early reward delivery is a lowered threshold to act, or a lower decision bound. Because an accurate performance with a lower decision bound requires greater discriminability in the sensory representations, this may underlie the slower learning rate with early reward arrival. Together, our results reflect the possible effects of stimulus timing on stimulus encoding and its consequence on the acquisition of a complex task. SIGNIFICANCE STATEMENT This study describes how head-fixed mice acquire a working memory task (olfactory delayed nonmatch-to-sample task). We simplified and optimized the stimulus timing, allowing robust and efficient training of head-fixed mice. Unexpectedly, we found that early reward timing leads to slower learning. Analysis of this data using a computational model (drift-diffusion model) revealed that the reward timing affects the behavioral threshold, or how quickly animals respond to a stimulus. But, to still be accurate with early reaction times, the sensory representation needs to become even more refined. This may explain the slower learning rate with early reward timing., (Copyright © 2023 Reuschenbach, Reinert et al.)

Background: Voxel-based morphometry (VBM) using magnetic resonance imaging (MR) has been used to estimate cortical atrophy associated with various diseases. However, there are mis-segmentations of segmented gray matter image in VBM., Purpose: To study a twofold evaluation of single- and multi-channel segmentation using synthetic MR images: (1) mis-segmentation of segmented gray matter images in transverse and cavernous sinuses; and (2) accuracy and repeatability of segmented gray matter images., Material and Methods: A total of 13 healthy individuals were scanned with 3D quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) sequence on a 1.5-T scanner. Three of the 13 healthy participants were scanned five consecutive times for evaluation of repeatability. We used SyMRI software to create images with three contrasts: T1-weighted (T1W), T2-weighted (T2W), and proton density-weighted (PDW) images. Manual regions of interest (ROI) on T1W imaging were individually set as the gold standard in the transverse sinus, cavernous sinus, and putamen. Single-channel (T1W) and multi-channel (T1W + T2W, T1W + PDW, and T1W + T2W + PDW imaging) segmentations were performed with statistical parametric mapping 12 software., Results: We found that mis-segmentations in both the transverse and cavernous sinuses were large in single-channel segmentation compared with multi-channel segmentations. Furthermore, the accuracy of segmented gray matter images in the putamen was high in both multi-channel T1W + PDW and T1W + T2W + PDW segmentations compared with other segmentations. Finally, the highest repeatability of left putamen volumetry was found with multi-channel segmentation T1WI + PDWI., Conclusion: Multi-channel segmentation with T1WI + PDWI provides good results for VBM compared with single-channel and other multi-channel segmentations.

Relaxation times and morphological information are fundamental magnetic resonance imaging-derived metrics of the human brain that reflect the status of the underlying tissue. Magnetic resonance fingerprinting (MRF) enables simultaneous acquisition of T1 and T2 maps inherently aligned to the anatomy, allowing whole-brain relaxometry and morphometry in a single scan. In this study, we revealed the feasibility of 3D MRF for simultaneous brain structure-wise morphometry and relaxometry. Comprehensive test-retest scan analyses using five 1.5-T and three 3.0-T systems from a single vendor including different scanner types across 3 institutions demonstrated that 3D MRF-derived morphological information and relaxation times are highly repeatable at both 1.5 T and 3.0 T. Regional cortical thickness and subcortical volume values showed high agreement and low bias across different field strengths. The ability to acquire a set of regional T1, T2, thickness, and volume measurements of neuroanatomical structures with high repeatability and reproducibility facilitates the ability of longitudinal multicenter imaging studies to quantitatively monitor changes associated with underlying pathologies, disease progression, and treatments., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background Liver MR fingerprinting (MRF) enables simultaneous quantification of T1, T2, T2*, and proton density fat fraction (PDFF) maps in single breath-hold acquisitions. Histopathologic correlation studies are desired for its clinical use. Purpose To compare liver MRF-derived metrics with separate reference quantitative MRI in participants with diffuse liver disease, evaluate scan-rescan repeatability of liver MRF, and validate MRF-derived measurements for histologic grading of liver biopsies. Materials and Methods This prospective study included participants with diffuse liver disease undergoing MRI from July 2021 to January 2022. Participants underwent two-dimensional single-section liver MRF and separate reference quantitative MRI. Linear regression, Bland-Altman plots, and coefficients of variation were used to assess the bias and repeatability of liver MRF measurements. For participants undergoing liver biopsy, the association between mapping and histologic grading was evaluated by using the Spearman correlation coefficient. Results Fifty-six participants (mean age, 59 years ± 15 [SD]; 32 women) were included to compare mapping techniques and 23 participants were evaluated with liver biopsy (mean age, 52.7 years ± 12.7; 14 women). The linearity of MRF with reference measurements in participants with diffuse liver disease ( R 2 value) for T1, T2, T2*, and PDFF maps was 0.86, 0.88, 0.54, and 0.99, respectively. The overall coefficients of variation for repeatability in the liver were 3.2%, 5.5%, 7.1%, and 4.6% for T1, T2, T2*, and PDFF maps, respectively. MRF-derived metrics showed high diagnostic performance in differentiating moderate or severe changes from mild or no changes (area under the receiver operating characteristic curve for fibrosis, inflammation, steatosis, and siderosis: 0.62 [95% CI: 0.52, 0.62], 0.92 [95% CI: 0.88, 0.92], 0.97 [95% CI: 0.96, 0.97], and 0.74 [95% CI: 0.57, 0.74], respectively). Conclusion Liver MR fingerprinting provided repeatable T1, T2, T2*, and proton density fat fraction maps in high agreement with reference quantitative mapping and may correlate with pathologic grades in participants with diffuse liver disease. © RSNA, 2022 Online supplemental material is available for this article.

Cell type-specific labelling and manipulation using Cre-driver lines have become integral to analyses of neuronal circuits in the brain. To study how mitral cells of the olfactory bulb process olfactory information and how they contribute to behavior, an inducible Cre-driver line, Lbhd2-CreER T2 , can be used. In this chapter, we describe two methods for administering tamoxifen. The first method achieves a dense recombination pattern using tamoxifen-containing food, while the second method involving an intraperitoneal injection is suited for sparse labelling., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: None

Volatile chemicals in the environment provide ethologically important information to many animals. However, how animals learn to use this information is only beginning to be understood. This review highlights recent experimental advances elucidating olfactory learning in rodents, ranging from adaptations to the environment to task-dependent refinement and multisensory associations. The broad range of phenomena, mechanisms, and brain areas involved demonstrate the complex and multifaceted nature of olfactory learning., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To develop a rigid real-time prospective motion-corrected multiparametric mapping technique and to test the performance of quantitative estimates., Methods: Motion tracking and correction were performed by integrating single-shot spiral navigators into a multiparametric imaging technique, three-dimensional quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS). The spiral navigator was optimized, and quantitative measurements were validated using a standard system phantom. The effect of motion correction on whole-brain T1 and T2 mapping under different types of head motion during the scan was evaluated in 10 healthy volunteers. Finally, six patients with Parkinson's disease, which is known to be associated with a high prevalence of motion artifacts, were scanned to evaluate the effectiveness of our method in the real world., Results: The phantom study demonstrated that the proposed motion correction method did not introduce quantitative bias. Improved parametric map quality and repeatability were shown in volunteer experiments with both in-plane and through-plane motions, comparable to the no-motion ground truth. In real-life validation in patients, the approach showed improved parametric map quality compared to images obtained without motion correction., Conclusions: Real-time prospective motion-corrected multiparametric relaxometry based on 3D-QALAS provided robust and repeatable whole-brain multiparametric mapping., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to investigate the influence of magnetic resonance fingerprinting (MRF) dictionary design on radiomic features using in vivo human brain scans., Methods: Scan-rescans of three-dimensional MRF and conventional T1-weighted imaging were performed on 21 healthy volunteers (9 males and 12 females; mean age, 41.3 ± 14.6 years; age range, 22-72 years). Five patients with multiple sclerosis (3 males and 2 females; mean age, 41.2 ± 7.3 years; age range, 32-53 years) were also included. MRF data were reconstructed using various dictionaries with different step sizes. First- and second-order radiomic features were extracted from each dataset. Intra-dictionary repeatability and inter-dictionary reproducibility were evaluated using intraclass correlation coefficients (ICCs). Features with ICCs > 0.90 were considered acceptable. Relative changes were calculated to assess inter-dictionary biases., Results: The overall scan-rescan ICCs of MRF-based radiomics ranged from 0.86 to 0.95, depending on dictionary step size. No significant differences were observed in the overall scan-rescan repeatability of MRF-based radiomic features and conventional T1-weighted imaging (p = 1.00). Intra-dictionary repeatability was insensitive to dictionary step size differences. MRF-based radiomic features varied among dictionaries (overall ICC for inter-dictionary reproducibility, 0.62-0.99), especially when step sizes were large. First-order and gray level co-occurrence matrix features were the most reproducible feature classes among different step size dictionaries. T1 map-derived radiomic features provided higher repeatability and reproducibility among dictionaries than those obtained with T2 maps., Conclusion: MRF-based radiomic features are highly repeatable in various dictionary step sizes. Caution is warranted when performing MRF-based radiomics using datasets containing maps generated from different dictionaries., Key Points: • MRF-based radiomic features are highly repeatable in various dictionary step sizes. • Use of different MRF dictionaries may result in variable radiomic features, even when the same MRF acquisition data are used. • Caution is needed when performing radiomic analysis using data reconstructed from different dictionaries., (© 2022. The Author(s).)

Competing Interests: None

Sensory systems are often tasked to analyse complex signals from the environment, separating relevant from irrelevant parts. This process of decomposing signals is challenging when a mixture of signals does not equal the sum of its parts, leading to an unpredictable corruption of signal patterns. In olfaction, nonlinear summation is prevalent at various stages of sensory processing. Here, we investigate how the olfactory system deals with binary mixtures of odours under different brain states by two-photon imaging of olfactory bulb (OB) output neurons. Unlike previous studies using anaesthetised animals, we found that mixture summation is more linear in the early phase of evoked responses in awake, head-fixed mice performing an odour detection task, due to dampened responses. Despite smaller and more variable responses, decoding analyses indicated that the data from behaving mice was well discriminable. Curiously, the time course of decoding accuracy did not correlate strictly with the linearity of summation. Further, a comparison with naïve mice indicated that learning to accurately perform the mixture detection task is not accompanied by more linear mixture summation. Finally, using a simulation, we demonstrate that, while saturating sublinearity tends to degrade the discriminability, the extent of the impairment may depend on other factors, including pattern decorrelation. Altogether, our results demonstrate that the mixture representation in the primary olfactory area is state-dependent, but the analytical perception may not strictly correlate with linearity in summation., Competing Interests: AA, SL, JR, IF No competing interests declared, (© 2022, Adefuin et al.)

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord., (© 2021. The Author(s).)

In sensory systems of the brain, mechanisms exist to extract distinct features from stimuli to generate a variety of behavioral repertoires. These often correspond to different cell types at various stages in sensory processing. In the mammalian olfactory system, complex information processing starts in the olfactory bulb, whose output is conveyed by mitral cells (MCs) and tufted cells (TCs). Despite many differences between them, and despite the crucial position they occupy in the information hierarchy, Cre-driver lines that distinguish them do not yet exist. Here, we sought to identify genes that are differentially expressed between MCs and TCs of the mouse, with an ultimate goal to generate a cell type-specific Cre-driver line, starting from a transcriptome analysis using a large and publicly available single-cell RNA-seq dataset (Zeisel et al., 2018). Many genes were differentially expressed, but only a few showed consistent expressions in MCs and at the specificity required. After further validating these putative markers using ISH, two genes (i.e., Pkib and Lbdh2 ) remained as promising candidates. Using CRISPR/Cas9-mediated gene editing, we generated Cre-driver lines and analyzed the resulting recombination patterns. This indicated that our new inducible Cre-driver line, Lbhd2-CreERT2 , can be used to genetically label MCs in a tamoxifen dose-dependent manner, both in male and female mice, as assessed by soma locations, projection patterns, and sensory-evoked responses in vivo Hence, this is a promising tool for investigating cell type-specific contributions to olfactory processing and demonstrates the power of publicly accessible data in accelerating science. SIGNIFICANCE STATEMENT In the brain, distinct cell types play unique roles. It is therefore important to have tools for studying unique cell types specifically. For the sense of smell in mammals, information is processed first by circuits of the olfactory bulb, where two types of cells, mitral cells and tufted cells, output different information. We generated a transgenic mouse line that enables mitral cells to be specifically labeled or manipulated. This was achieved by looking for genes that are specific to mitral cells using a large and public gene expression dataset, and creating a transgenic mouse using the gene editing technique, CRISPR/Cas9. This will allow scientists to better investigate parallel information processing underlying the sense of smell., (Copyright © 2021 Koldaeva et al.)

There are >120 forms of non-syndromic deafness associated with identified genetic loci. In particular, mutation of the gap junction beta 2 gene (GJB2), which encodes connexin (CX)26 protein, is the most frequent cause of hereditary deafness worldwide. We previously described an induction method to develop functional CX26 gap junction-forming cells from mouse-induced pluripotent stem cells (iPSCs) and generated in vitro models for GJB2-related deafness. However, functional CX26 gap junction-forming cells derived from human iPSCs or embryonic stem cells (ESCs) have not yet been reported. In this study, we generated human iPSC-derived functional CX26 gap junction-forming cells (iCX26GJCs), which have the characteristics of cochlear supporting cells. These iCX26GJCs had gap junction plaque-like formations at cell-cell borders and co-expressed several markers that are expressed in cochlear supporting cells. Furthermore, we generated iCX26GJCs derived from iPSCs from two patients with the most common GJB2 mutation in Asia, and these cells reproduced the pathology of GJB2-related deafness. These in vitro models may be useful for establishing optimal therapies and drug screening for various mutations in GJB2-related deafness., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: The aims of this study were to develop an accelerated multiparametric magnetic resonance imaging method based on 3D-quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) combined with compressed sensing (CS) and to evaluate the effect of CS on the quantitative mapping, tissue segmentation, and quality of synthetic images., Materials and Methods: A magnetic resonance imaging system phantom, containing multiple compartments with standardized T1, T2, and proton density (PD) values; 10 healthy volunteers; and 12 patients with multiple sclerosis were scanned using the 3D-QALAS sequence with and without CS and conventional contrast-weighted imaging. The scan times of 3D-QALAS with and without CS were 5:56 and 11:11, respectively. For healthy volunteers, brain volumetry and myelin estimation were performed based on the measured T1, T2, and PD. For patients with multiple sclerosis, the mean T1, T2, PD, and the amount of myelin in plaques and contralateral normal-appearing white matter (NAWM) were measured. Simple linear regression analysis and Bland-Altman analysis were performed for each metric obtained from the datasets with and without CS. To compare overall image quality and structural delineations on synthetic and conventional contrast-weighted images, case-control randomized reading sessions were performed by 2 neuroradiologists in a blinded manner., Results: The linearity of both phantom and volunteer measurements in T1, T2, and PD values obtained with and without CS was very strong (R2 = 0.9901-1.000). The tissue segmentation obtained with and without CS also had high linearity (R2 = 0.987-0.999). The quantitative tissue values of the plaques and NAWM obtained with CS showed high linearity with those without CS (R2 = 0.967-1.000). There were no significant differences in overall image quality between synthetic contrast-weighted images obtained with and without CS (P = 0.17-0.99)., Conclusions: Multiparametric imaging of the whole brain based on 3D-QALAS can be accelerated using CS while preserving tissue quantitative values, tissue segmentation, and quality of synthetic images., Competing Interests: Conflicts of interest and sources of funding: N.T. is an employee of GE Healthcare Japan. This work was supported by Japan Agency for Medical Research and Development under grant number JP19lk1010025h9902; JSPS KAKENHI grant numbers 19K17150, 19K17177, 18H02772, and 18K07692; Health, Labor and Welfare Policy Research Grants for Research on Region Medical; and a grant-in-aid for special research in subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan; Brain/MINDS beyond program from Japan Agency for Medical Research and Development grant numbers JP19dm0307024 and JP19dm0307101., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Among them, the G45E/Y136X mutation in GJB2 is the third most prevalent in Japan. In this study, we generated two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of siblings with moderate-to-severe hearing loss (patient) or normal hearing (genetic carrier) carrying a homozygous or heterozygous G45E/Y136X mutation in GJB2 gene, respectively. These iPSC lines showed the expression of pluripotency markers and could differentiate into three germ layers. These disease-specific iPSC lines will be a powerful tool for investigating the pathogenesis of GJB2-related deafness., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Odours are transported in turbulent plumes, which result in rapid concentration fluctuations 1,2 that contain rich information about the olfactory scenery, such as the composition and location of an odour source 2-4 . However, it is unclear whether the mammalian olfactory system can use the underlying temporal structure to extract information about the environment. Here we show that ten-millisecond odour pulse patterns produce distinct responses in olfactory receptor neurons. In operant conditioning experiments, mice discriminated temporal correlations of rapidly fluctuating odours at frequencies of up to 40 Hz. In imaging and electrophysiological recordings, such correlation information could be readily extracted from the activity of mitral and tufted cells-the output neurons of the olfactory bulb. Furthermore, temporal correlation of odour concentrations 5 reliably predicted whether odorants emerged from the same or different sources in naturalistic environments with complex airflow. Experiments in which mice were trained on such tasks and probed using synthetic correlated stimuli at different frequencies suggest that mice can use the temporal structure of odours to extract information about space. Thus, the mammalian olfactory system has access to unexpectedly fast temporal features in odour stimuli. This endows animals with the capacity to overcome key behavioural challenges such as odour source separation 5 , figure-ground segregation 6 and odour localization 7 by extracting information about space from temporal odour dynamics.

Mutations in gap junction beta-2 ( GJB2 ), the gene that encodes connexin 26 (CX26), are the most frequent cause of hereditary deafness worldwide. We recently developed an in vitro model of GJB 2-related deafness (induced CX26 gap junction-forming cells; iCX26GJCs) from mouse induced pluripotent stem cells (iPSCs) by using Bone morphogenetic protein 4 (BMP4) signaling-based floating cultures (serum-free culture of embryoid body-like aggregates with quick aggregation cultures; hereafter, SFEBq cultures) and adherent cultures. However, to use these cells as a disease model platform for high-throughput drug screening or regenerative therapy, cell yields must be substantially increased. In addition to BMP4, other factors may also induce CX26 gap junction formation. In the SFEBq cultures, the combination of BMP4 and the Activin/Nodal/TGF-β pathway inhibitor SB431542 (SB) resulted in greater production of isolatable CX26-expressing cell mass (CX26 + vesicles) and higher Gjb2 mRNA levels than BMP4 treatment alone, suggesting that SB may promote BMP4-mediated production of CX26 + vesicles in a dose-dependent manner, thereby increasing the yield of highly purified iCX26GJCs. This is the first study to demonstrate that SB accelerates BMP4-induced iCX26GJC differentiation during stem cell floating culture. By controlling the concentration of SB supplementation in combination with CX26 + vesicle purification, large-scale production of highly purified iCX26GJCs suitable for high-throughput drug screening or regenerative therapy for GJB2 -related deafness may be possible., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fukunaga, Oe, Chen, Danzaki, Ohta, Koike, Ikeda and Kamiya.)

Objectives: Quantitative synthetic magnetic resonance imaging (MRI) enables the determination of fundamental tissue properties, namely, T1 and T2 relaxation times and proton density (PD), in a single scan. Myelin estimation and brain segmentation based on these quantitative values can also be performed automatically. This study aimed to reveal the changes in tissue characteristics and volumes of the brain according to age and provide age-specific reference values obtained by quantitative synthetic MRI., Materials and Methods: This was a prospective study of healthy subjects with no history of brain diseases scanned with a multidynamic multiecho sequence for simultaneous measurement of relaxometry of T1, T2, and PD. We performed myelin estimation and brain volumetry based on these values. We performed volume-of-interest analysis on both gray matter (GM) and white matter (WM) regions for T1, T2, PD, and myelin volume fraction maps. Tissue volumes were calculated in the whole brain, producing brain parenchymal volume, GM volume, WM volume, and myelin volume. These volumes were normalized by intracranial volume to a brain parenchymal fraction, GM fraction, WM fraction, and myelin fraction (MyF). We examined the changes in the mean regional quantitative values and segmented tissue volumes according to age., Results: We analyzed data of 114 adults (53 men and 61 women; median age, 66.5 years; range, 21-86 years). T1, T2, and PD values showed quadratic changes according to age and stayed stable or decreased until around 60 years of age and increased thereafter. Myelin volume fraction showed a reversed trend. Brain parenchymal fraction and GM fraction decreased throughout all ages. The approximation curves showed that WM fraction and MyF gradually increased until around the 40s to 50s and decreased thereafter. A significant decline in MyF was first noted in the 60s age group (Tukey test, P < 0.001)., Conclusions: Our study showed changes according to age in tissue characteristic values and brain volumes using quantitative synthetic MRI. The reference values for age demonstrated in this study may be useful to discriminate brain disorders from healthy brains., Competing Interests: Conflicts of interest and source of funding: We have no conflicts of interest to declare. This work was supported by Japan Agency for Medical Research and Development (AMED) under grant number JP19lk1010025h9902; JSPS KAKENHI grant numbers 19K17150, 19K17177, and 18K07692; Health, Labour, and Welfare Policy Research Grants for Research on Region Medical; a grant-in-aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan; and Brain/MINDS program from AMED grant numbers JP19dm0307024 and JP19dm0307101., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Three-dimensional (3D) Magnetic resonance fingerprinting (MRF) permits whole-brain volumetric quantification of T1 and T2 relaxation values, potentially replacing conventional T1-weighted structural imaging for common brain imaging analysis. The aim of this study was to evaluate the repeatability and reproducibility of 3D MRF in evaluating brain cortical thickness and subcortical volumetric analysis in healthy volunteers using conventional 3D T1-weighted images as a reference standard. Scan-rescan tests of both 3D MRF and conventional 3D fast spoiled gradient recalled echo (FSPGR) were performed. For each sequence, the regional cortical thickness and volume of the subcortical structures were measured using standard automatic brain segmentation software. Repeatability and reproducibility were assessed using the within-subject coefficient of variation (wCV), intraclass correlation coefficient (ICC), and mean percent difference and ICC, respectively. The wCV and ICC of cortical thickness were similar across all regions with both 3D MRF and FSPGR. The percent relative difference in cortical thickness between 3D MRF and FSPGR across all regions was 8.0 ± 3.2%. The wCV and ICC of the volume of subcortical structures across all structures were similar between 3D MRF and FSPGR. The percent relative difference in the volume of subcortical structures between 3D MRF and FSPGR across all structures was 7.1 ± 3.6%. 3D MRF measurements of human brain cortical thickness and subcortical volumes are highly repeatable, and consistent with measurements taken on conventional 3D T1-weighted images. A slight, consistent bias was evident between the two, and thus careful attention is required when combining data from MRF and conventional acquisitions., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Especially, the 235delC mutation in GJB2 is most prevalent in East Asia. In this study, we generated two iPSC lines from PBMCs of siblings carrying homozygous 235delC mutation which exhibits an audiometric phenotype of profound hearing loss. These iPSC lines had normal karyotype, showed expression of pluripotency markers, and could differentiate into three germ layers. These disease specific iPSC lines may be useful for the construction of the disease models and for the elucidation of pathogenesis in GJB2-related deafness., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

For sensory systems of the brain, the dynamics of an animal's own sampling behavior has a direct consequence on ensuing computations. This is particularly the case for mammalian olfaction, where a rhythmic flow of air over the nasal epithelium entrains activity in olfactory system neurons in a phenomenon known as sniff-locking. Parameters of sniffing can, however, change drastically with brain states. Coupled to the fact that different observation methods have different kinetics, consensus on the sniff-locking properties of neurons is lacking. To address this, we investigated the sniff-related activity of olfactory sensory neurons (OSNs), as well as the principal neurons of the olfactory bulb (OB), using 2-photon calcium imaging and intracellular whole-cell patch-clamp recordings in vivo , both in anesthetized and awake mice. Our results indicate that OSNs and OB output neurons lock robustly to the sniff rhythm, but with a slight temporal shift between behavioral states. We also observed a slight delay between methods. Further, the divergent sniff-locking by tufted cells (TCs) and mitral cells (MCs) in the absence of odor can be used to determine the cell type reliably using a simple linear classifier. Using this classification on datasets where morphological identification is unavailable, we find that MCs use a wider range of temporal shifts to encode odors than previously thought, while TCs have a constrained timing of activation due to an early-onset hyperpolarization. We conclude that the sniff rhythm serves as a fundamental rhythm but its impact on odor encoding depends on cell type, and this difference is accentuated in awake mice., (Copyright © 2020 Ackels, Jordan, Schaefer and Fukunaga.)

The gap junction beta-2 (GJB2) gene is the most common genetic cause of hereditary deafness worldwide. Especially, V37I mutation in GJB2 is most prevalent in Southeast Asia including Thailand, Malaysia, and Indonesia. Furthermore, it is the second most prevalent cause in Japan and China, and exhibits an audiometric phenotype of mild-to-moderate hearing loss. In this study, we generated induced pluripotent stem cells (iPSC) from peripheral blood mononuclear cells (PBMCs) of patient with homozygous V37I mutation. This iPSC line will be a powerful tool for investigating the pathogenesis and for developing a treatment for GJB2-related hearing loss., Competing Interests: Declaration of Competing Interest The authors declare to have no conflicts of interest., (Copyright © 2019. Published by Elsevier B.V.)

Food proteins work not only as nutrients but also modulators for the physiological functions of the human body. The physiological functions of food proteins are basically regulated by peptides encrypted in food protein sequences (food peptides). In this study, we propose a novel deep learning-based method to predict the health effects of food peptides and elucidate the mode-of-action. In the algorithm, we estimate potential target proteins of food peptides using a multi-task graph convolutional neural network, and predict its health effects using information about therapeutic targets for diseases. We constructed predictive models based on 21,103 peptide-protein interactions involving 10,950 peptides and 2,533 proteins, and applied the models to food peptides (e. g., lactotripeptide, isoleucyltyrosine and sardine peptide) defined in food for specified health use. The models suggested potential effects such as blood-pressure lowering effects, blood glucose level lowering effects, and anti-cancer effects for several food peptides. The interactions of food peptides with target proteins were confirmed by docking simulations., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Mutation of the gene GJB2, encoding connexin 26 (CX26; also known as gap junction beta 2), is the most frequent cause of hereditary deafness worldwide. CX26 is expressed in cochlear nonsensory cells, such as cochlear supporting cells, and forms gap junction plaques (GJPs) at cell-cell borders. Cochlear CX26-GJP-forming cells (Cx26GJCs) are thought to be an important therapeutic target for treatment of hereditary deafness. Nevertheless, the generation of Cx26GJCs-such as cochlear supporting cells-from embryonic stem/induced pluripotent stem (ES/iPS) cells has not been reported to date. Here, we detail a novel strategy for differentiating iPS cells into functional Cx26GJCs such as are found in cochlea. Several assays to characterize the phenotype of iPS-derived Cx26GJCs are described, including qRT-PCR, immunohistological analysis, morphological analysis, a scrape-loading and dye transfer assay, and calcium imaging. This in vitro model has applications in the establishment of inner-ear cell therapies and in drug screening to target GJB2-related hearing loss. © 2019 by John Wiley & Sons, Inc. Basic Protocol: Induction of mouse stem cells to create CX26-GJP-forming cells Support Protocol 1: Maintenance and passage of mouse induced pluripotent stem cells Support Protocol 2: Screening for high GJB2 and GJB6 expression in SFEBq culture using quantitative real-time PCR Support Protocol 3: Characterization of cells at different stages of differentiation by immunostaining Support Protocol 4: Ultrastructural analyses of cells at different stages of CX26-GJP-forming cell induction Support Protocol 5: Functional analyses of stem cell-derived CX26-GJP-forming cells., (© 2019 John Wiley & Sons, Inc.)

Background: Previous quantitative synthetic MRI of the brain has been solely performed in 2D., Purpose: To evaluate the feasibility of the recently developed sequence 3D-QALAS for brain cortical thickness and volumetric analysis., Study Type: Reproducibility/repeatability study., Subjects: Twenty-one healthy volunteers (35.6 ± 13.8 years)., Field Strength/sequence: 3D T 1 -weighted fast spoiled gradient recalled echo (FSPGR) sequence was performed once, and 3D-QALAS sequence was performed twice with a 3T scanner., Assessment: FreeSurfer and FIRST were used to measure cortical thickness and volume of subcortical structures, respectively. Agreement with FSPGR and scan-rescan repeatability were evaluated for 3D-QALAS., Statistical Tests: Percent relative difference and intraclass correlation coefficient (ICC) were used to assess reproducibility and scan-rescan repeatability of the 3D-QALAS sequence-derived measurements., Results: Percent relative difference compared with FSPGR in cortical thickness of the whole cortex was 3.1%, and 89% of the regional areas showed less than 10% relative difference in cortical thickness. The mean ICC across all regions was 0.65, and 74% of the structures showed substantial to almost perfect agreement. For volumes of subcortical structures, the median percent relative differences were lower than 10% across all subcortical structures, except for the accumbens area, and all structures showed ICCs of substantial to almost perfect agreement. For the scan-rescan test, percent relative difference in cortical thickness of the whole cortex was 2.3%, and 97% of the regional areas showed less than 10% relative difference in cortical thickness. The mean ICC across all regions was 0.73, and 80% showed substantial to almost perfect agreement. For volumes of subcortical structures, relative differences were less than 10% across all subcortical structures except for the accumbens area, and all structures showed ICCs of substantial to almost perfect agreement., Data Conclusion: 3D-QALAS could be reliably used for measuring cortical thickness and subcortical volumes in most brain regions., Level of Evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1834-1842., (© 2019 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Previous methods for the quantification of brain tissue properties by magnetic resonance imaging were mainly based on two-dimensional acquisitions and were thus limited to a relatively low resolution in the slice direction compared to three-dimensional (3D) acquisitions. The 3D-quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) sequence may allow for simultaneous acquisition of relaxometry parameters in high spatial resolution., Purpose: To evaluate bias, linearity, and day-to-day repeatability of relaxometry parameters, as well as tissue fraction maps, acquired with 3D-QALAS., Materials and Methods: Scan-rescan test of the 3D-QALAS sequence was performed on a 1.5-T scanner with the International Society for Magnetic Resonance in Medicine/National institute of Standards and Technology system phantom and 10 healthy volunteers (7 male, 3 female; mean age, 23.2 ± 3.6 years). Simple linear regression analysis, Bland-Altman plots, and intrasubject coefficients of variation (CV) were used to assess the reliability of 3D-QALAS sequence-derived parameters. The T1, T2, proton density (PD), and myelin volume fraction (MVF) of in vivo brain regions were compared with values obtained using the multidynamic multi-echo sequence., Results: In the phantom study, the T1, T2, and PD values measured by 3D-QALAS showed strong linearity with the reference values (R 2  = 0.998, 0.998, and 0.960 for T1, T2, and PD, respectively) and high repeatability (mean CV of 1.2%, 2.8%, and 2.9% for T1, T2, and PD, respectively). The T1, T2, PD, and MVF values of in vivo brain regions obtained with 3D-QALAS were highly consistent within subjects, with mean intrasubject CVs of 0.5%, 0.5%, 0.4%, and 1.6% for the T1, T2, PD, and MVF values, respectively., Conclusion: 3D-QALAS enables reliable measurement of T1, T2, PD, and MVF values of the whole brain in high spatial resolution across a clinically-relevant dynamic range., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)