bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inducible, virus-free direct lineage reprogramming enhances scalable generation of human inner ear hair cell-like cells
Authors: Rainey Robert N. , Houman Sam D. , Menendez Louise , Chang Ryan , Tao Litao , Bugacov Helena , McMahon Andrew P. , Kalluri Radha , Oghalai John S. , Groves Andrew K. , Segil Neil 
Published: February 2025

AbstractMammalian inner ear sensory hair cells are highly sensitive to environmental stress and do not regenerate, making hearing loss progressive and permanent. The paucity and extreme inaccessibility of these cells hinder the development of regenerative and otoprotective strategies, Direct lineage reprogramming to generate large quantities of hair cell-like cells in vitro offers a promising approach to overcome these experimental bottlenecks. Previously, we identified four transcription factors—Six1,Atoh1,Pou4f3, andGfi1(SAPG)—capable of converting mouse embryonic fibroblasts, adult tail tip fibroblasts, and postnatal mouse supporting cells into induced hair cell-like cells through retroviral or lentiviral transduction (Menendezet al., 2020). Here, we developed a virus-free, inducible system using a stable human induced pluripotent stem (iPS) cell line carrying doxycycline-inducible SAPG. Our inducible system significantly increases reprogramming efficiency compared to retroviral methods, achieving a ∼19-fold greater conversion to a hair cell fate in half the time. Immunostaining, Western blot, and single-nucleus RNA-seq analyses confirm the expression of hair cell-specific markers and activation of hair cell gene networks in reprogrammed cells. The reprogrammed hair cells closely resemble developing fetal hair cells, as evidenced by comparison with a human fetal inner ear dataset. Electrophysiological analysis reveals that the induced hair cell-like cells exhibit diverse voltage-dependent ion currents, including robust, quick-activating, slowly inactivating currents characteristic of primary hair cells. This virus-free approach improves scalability, reproducibility, and the modeling of hair cell differentiation, offering significant potential for hair cell regenerative strategies and preclinical drug discovery targeting ototoxicity and otoprotection.
Procurement of Pancreatic Islet Cells from Deceased Donors: Updated Data and Gaps in Reporting
Authors: Goldberg David S , Tewksbury Erin , Wadsworth Matthew 
Published: February 2025

ABSTRACTIn 2020, CMS updated the ‘Final Rule’ for organ procurement organizations (OPO) in 2020 to include new metrics of OPO performance with a carveout whereby pancreata procured for research count as a “donor” to reward OPOs procuring pancreata for islet cell research or transplantation. Yet data suggested OPOs took advantage of this loophole, leading to updated guidance in 2024 to require OPOs classify whether procured research pancreata were “accepted for islet cell research.” Based on updated data using the new CMS codes, the increase in research pancreas procurement was nearly half previously reported, but far greater than prior to 2020. Importantly, the number of pancreata OPOs reported were accepted for islet cell research were an order of magnitude greater than what was used by the Integrated Islet Cell Distribution Program (IIDP) and the Network for Pancreatic Organ Donors with Diabetes (nPOD), the two largest sources of islet cell/pancreata for qualified researchers in the US. Inappropriate procurement of organs, and mislabeling them as being used for “islet cell research” raises questions of fraud, waste, and abuse that requires further investigation and transprancy.
Exploring intra-specific variation in photosynthesis of maize and sorghum
Authors: Almeida Rafael L. , Silveira Neidiquele M. , Sartori Heitor L. , Carvalho Camila C. , Scarpari Maximiliano S. , Duarte Aildson P. , Sawazaki Eduardo , Machado Eduardo C. , Ribeiro Rafael V. 
Published: February 2025

AbstractEnhancing crop yield through improved photosynthesis is a key for feeding the global population and providing feedstock for a sustainable green economy. However, effectively linking photosynthetic performance and biomass production in C4species requires an integrative approach at plant canopy. This study aimed to characterize photosynthesis along the canopy of five maize (BM3069-PRO2, AG8701-PRO4, K7500-VIP3, DKB355-PRO3 and B2401-PWU) and sorghum (DKB560, Enforcer, IAC 7021, Brandelisa and Santa Elisa) cultivars, focusing on leaf gas exchange and chlorophyll fluorescence evaluations in three canopy strata: top; middle and bottom. Photosynthetic responses to increasing intercellular CO2concentration and light (A–CiandA–PAR curves, respectively) were performed and key photosynthetic traits estimated. We found a significant variability in the maximum photosynthetic rates across the canopies. Modern maize cultivars exhibited high CO2assimilation in the top and middle canopy leaves, demonstrating physiological adjustments for increasing canopy homogeneity in terms of photosynthesis. Such adjustments included high maximum quantum efficiency of CO2assimilation (ϕ), stomatal conductance, carboxylation rates of PEPC and Rubisco, and leaf nitrogen content (LNC) along the canopy. In contrast, sorghum cultivars showed significant interactions between canopy strata, with DKB560 and Brandelisa standing out for their enhanced CO2uptake and ϕ throughout the plant canopy. Our findings highlight maize as an efficient C4crop, characterized by a high photosynthetic capacity and relative uniform photosynthesis across the canopy. This is attributed to reduced stomatal limitation and higher stomatal conductance, carboxylation of Rubisco (Vcmax) and LNC in the top and middle canopy, along with higher ϕ in middle and bottom layers. Overall, physiological adjustments such as nitrogen redistribution to upper canopy leaves and the optimization of light-use efficiency in lower layers are key for enhancing canopy-level photosynthesis in maize and sorghum cultivars.
Co-adaptive training improves performance during fMRI decoded neurofeedback
Authors: Abdennour Najemeddine , Margolles Pedro , Soto David 
Published: February 2025

AbstractA significant challenge for neurofeedback training research and related clinical applications, is participants’ difficulty in learning to induce specific brain patterns during training. Here, we address this issue in the context of fMRI-based decoded neurofeedback (DecNef). Arguably, discrepancies between the data used to construct the decoder and the data used for neurofeedback training, such as differences in data distributions and experimental contexts, neural and non-neural noise, are likely the cause of aforementioned participants’ difficulties. Hare, we developed a co-adaptation procedure using standard machine learning algorithms. The procedure involves an adaptive decoder algorithm that is updated in real time based on its predictions across neurofeedback trials. First, we tested the procedure via simulations using a previous DecNef dataset. We then collected real time fMRI data in a DecNef training procedure to provide proof of concept evidence that co-adaptation enhances participant’s ability to induce the target state during training. Thus, personalized decoders through co-adaptation can improve the precision and reliability of DecNef training protocols to target specific brain representations, with ramifications in translational research. The tools are made openly available to the scientific community.
Ultra-High Resolution TR-external EPIK with Deep Learning Image Reconstruction for Enhanced Characterisation of Cortical Depth-dependent Neural Activity
Authors: Yun Seong Dae , Cho Jaejin , Pais-Roldán Patricia , Shah N. Jon 
Published: February 2025

AbstractThe detection of neural signals using functional MRI at the laminar or columnar level enables non-invasive exploration of fundamental brain function processing and the interconnected pathways within intracortical tissues. The growing interest in this research area is driven by advancements in fMRI acquisition techniques that enhance spatial resolution for high-fidelity mapping. However, the submillimetre voxel sizes commonly employed in layer-specific fMRI studies raise concerns about relatively low signal-to-noise ratios and increased image artefacts in reconstructed images, ultimately limiting the precise delineation of cortical depth-dependent functional activities.This work aims to address this issue by incorporating a deep learning technique for enhanced image reconstruction of the submillimetre fMRI data, acquired with echo-planar-imaging with keyhole (EPIK) combined with the repetition-time-external (TR-external) EPI phase correction scheme. Our network was trained in a self-supervised, scan-specific manner using the sampling strategy from zero-shot self-supervised learning (ZS-SSL) method, which has gained attention for high-resolution MR image reconstruction.Healthy volunteers participated in this study, and the performance of the developed method was evaluated in direct comparison to the conventional reconstruction method using datasets acquired at 7T. The deep learning reconstruction produced reconstructed images with significantly higher SNR than the conventional method, which was further quantitatively validated through histogram analysis. This enhancement was consistent across all slice locations, demonstrating the reliability of the scan-specific deep learning technique.
N-terminal region of PetD is essential for cytochromeb6ffunction and controls STT7 kinase activity via STT7-dependent feedback loop phosphorylation
Authors: Zaeem Afifa , Milrad Yuval , Bütfering Simon , Stoffel Carolyne , Burlacot Adrien , Scholz Martin , Buchert Felix , Hippler Michael 
Published: February 2025

AbstractThe cytochromeb6fcomplex (b6f) links photosystem I (PSI) and photosystem II (PSII) in the photosynthetic electron transfer chain and is distributed across appressed and non-appressed thylakoid membranes. Theb6falso activates the state-transition 7 kinase (STT7), which phosphorylates light-harvesting complex proteins, triggering their migration to enable energy redistribution between PSII and PSI. STT7-dependent phosphorylation has also been observed at T4 in the N-terminal domain of theb6fsubunit-IV (PetD), though its functional significance has remained unclear. To investigate its role, we generated several chloroplast mutants. The phosphomimic mutation PetD T4E inhibited STT7 kinase activity, as indicated by the absence of STT7-dependent phosphorylation and the strain being locked in State 1. This reveals a novel feedback mechanism regulating phosphorylation facilitated by STT7. The deletion of five N-terminal amino acids resulted in a comparable inhibition of STT7 activity and, additionally, in the disruption of electron transfer which underscores a crucial role of the PetD N-terminus inb6ffunction.
Flagellin in the human gut microbiome is a diet-adjustable adjuvant for vaccination
Authors: Huus Kelsey E. ,   µHEAT Clinical Study Group, Tan Yi Han , Abo Hirohito , Keller Ronald , Atay Ezgi , Vu Dai Long , Dauser Silke , Prokipchuk Alina , Tyakht Alexander V. , Youngblut Nicholas , Chassaing Benoit , Kang Sang-Moo , Parsonnet Julie , Kremsner Peter G. , Maier Lisa , Gewirtz Andrew T. , Esen Meral , Ley Ruth E. 
Published: February 2025

ABSTRACTThe intestinal microbiota is thought to modulate immune responsiveness to vaccines. Human studies on this topic, however, have yielded inconsistent results1,2. We hypothesized that the microbiome would influence innate immune responses, and thus vaccine reactogenicity, more directly than vaccine immunogenicity. To test this, we established the µHEAT (Microbial-Human Ecology And Temperature) study, which longitudinally profiled the fecal microbiota, oral body temperature and serum antibody responses of 171 healthy adults (18-40 years old) before and after vaccination for SARS-CoV-2. Increased temperature after vaccination (ΔT) was associated with habitual diet and with baseline metabolic and immune markers. The microbiomes of ΔT-high (ΔThi) participants were characterized by high expression of flagellin and an overabundance of the flagellated bacteriumWaltera. Fecal samples from ΔThiparticipants induced more inflammation in human cells and stronger post-vaccine temperature responses in mice compared to ΔTlosamples, suggesting a causal role for the microbiome. Moreover,Walteraflagellin replicated the inflammatory phenotypesin vitroand was modulable via a dietary additive. Overall, these data suggest that flagellin from the gut microbiome stimulates innate immunity and vaccine reactogenicity, and that this axis can be manipulated via diet. These findings have implications for improving human vaccine tolerance and immunogenicity.
Synthetic Diffusion Tensor Imaging Maps Generated by 2D and 3D Probabilistic Diffusion Models: Evaluation and Applications
Authors: Chattopadhyay Tamoghna , Jagad Chirag , Kush Rudransh , Desai Vraj Dharmesh , Thomopoulos Sophia I. , Villalón-Reina Julio E. , Ambite Jose Luis , Steeg Greg Ver , Thompson Paul M. 
Published: February 2025

AbstractDiffusion tensor imaging (DTI) is a key neuroimaging modality for assessing brain tissue microstructure, yet high-quality acquisitions are costly, time-intensive, and prone to artifacts. To address data scarcity and privacy concerns – and to augment the available data for training deep learning methods – synthetic DTI generation has gained interest. Specifically, denoising diffusion probabilistic models (DDPMs) have emerged as a promising approach due to their superior fidelity, diversity, controllability, and stability compared to generative adversarial networks (GANs) and variational autoencoders (VAEs). In this work, we evaluate the quality, fidelity and added value for downstream applications of synthetic DTI mean diffusivity (MD) maps generated by 2D slice-wise and 3D volume-wise DDPMs. We evaluate their computational efficiency and utility for data augmentation in two downstream tasks: sex classification and dementia classification using 2D and 3D convolutional neural networks (CNNs). Our findings show that 3D synthesis outperforms 2D slice-wise generation in downstream tasks. We present a benchmark analysis of synthetic diffusion-weighted imaging approaches, highlighting key trade-offs in image quality, diversity, efficiency, and downstream performance.
Investigating the effectiveness of cannabidiol to mitigate the adverse consequences of exposure to neonatal procedural pain
Authors: Timmerman Brian , Honeycutt Jennifer A. , Skully Jordan , Patel Deep , Khan Waris , Neagu Alan , Baez Eshani , Battagliese Quinn , Brummelte Susanne 
Published: February 2025

AbstractRepeated painful procedures are associated with a multitude of effects on neurodevelopment in preterm infants, and current methods of neonatal pain management are unable to prevent the distress and long-term changes induced by these procedures. Cannabidiol (CBD) may be particularly effective for neonatal pain management because it reduces pain unpleasantness ratings, mitigates biological stress responses, and has minimal side effects in adults. However, there is limited research on the effects of neonatal CBD exposure. The present study investigated the efficacy of CBD treatment in mitigating behavioral responses to neonatal pain exposure. This was measured acutely through changes in ultrasonic vocalization (USV) emissions, as well as across development on long-term behavioral outcomes. We show that neonatal pain exposure decreased USV emission and increased adult anxiety-like behavior in male rats. Neonatal CBD treatment also decreased USVs in male pups but was unable to rescue the increased anxiety-like behavior in adulthood. Additionally, neonatal CBD increased baseline corticosterone levels in adult male subjects and decreased adult female body weight. More research is needed to determine whether CBD may be a safe and effective neonatal pain management medication.HighlightsCBD reduced USV emissions on PD 2 and 3 in males, but not on later daysPain exposure increased adult anxiety-like behavior in malesNeonatal CBD exposure resulted in decreased adult female body weight.CBD had no permanent effects on measurements of neurodevelopment or adult behaviorCBD does not seem to mitigate effects of neonatal pain exposure
Development and Characterization of aSf-1-Flp Mouse Model
Authors: Galvan Marco , Fujitani Mina , Heaselgrave Samuel R. , Thomas Shreya , Chen Bandy , Lee Jenny J. , Wyler Steven C. , Elmquist Joel K. , Fujikawa Teppei 
Published: February 2025

AbstractThe use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enable the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons (Sf-1-Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterizedSf-1-Flp mice and demonstrated its utility. Flp sequence was inserted intoSf-1locus with P2A. This insertion did not affectSf-1mRNA expression levels andSf-1-Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV)-bearing Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α inSf-1-Flp mice. This was similar to SF-1 neuronal activation usingSf-1-BAC-Cre and AAV-bearing Cre-dependent ChR2. Finally, we generatedSf-1-Flp mice that lackβ2-adrenergic receptors(Adrβ2) only in skeletal muscle with a combination of Cre/LoxP technology (Sf-1-Flp::SKMΔAdrβ2). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α inSf-1-Flp::SKMΔAdrβ2mice, suggesting thatAdrβ2in skeletal muscle isrequiredfor augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate thatSf-1-Flp mice are useful for interrogating complex physiology.
Motivating Effects of Negative-hedonic Valence Encoded in Engrams
Authors: Nedelescu Hermina , Meamari Elias , Rajaei Nami , Grey Alexus , Bullard Ryan , O’Connor Nathan , Suto Nobuyoshi , Weiss Friedbert 
Published: February 2025

ABSTRACTEngrams are neuronal alterations that encode associations between environmental contexts and subjectively rewarding or aversive experiences within sparsely activated neuronal assemblies that regulate behavioral responses. How positive- or negative-hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate or maladaptive behavior, respectively. It is well-known that animals avoid noxious stimuli and experiences. Little is known, however, how the conditioning of environmental or contextual stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations leading to compulsive maladaptive behavior. Here we have studied engrams that encode the conditioned effects of alcohol-related stimuli associated with the reversal of the dysphoric withdrawal state in alcohol dependent rats and document the recruitment of engrams in the paraventricular nucleus of the thalamus (PVT), the central nucleus of the amygdala (CeA), and the Dorsal Striatum (DS). The findings suggest that the encoding of associations between reversal of negative hedonic states and environmental contexts in these engrams may serve as a neural mechanism for compulsive alcohol seeking and vulnerability to relapse associated with dysregulation of reward to a pathological allostatic level.
Targeting the ferroptosis pathway: A novel compound, AZD1390, protects the brain after ischemic stroke
Authors: Lee Han Kyu , Lin Chao-Chieh , Dunn Denise E. , Chen Yubin , Chen Ssu-Yu , Marchuk Douglas A. , Floyd Scott R. , Chi Jen-Tsan 
Published: February 2025

AbstractBackgroundFerroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. This process has been implicated in various diseases, including ischemic stroke. Ischemic stroke leads to oxidative stress, iron overload, and reactive oxygen species (ROS) accumulation, which collectively may trigger ferroptotic neuronal cell death. However, the regulatory mechanisms of ferroptosis in stroke remain poorly understood. Previous studies have identified ataxia telangiectasia mutated (ATM), a DNA damage kinase, as a critical regulator of ferroptosis. However, the therapeutic potential of this discovery remains unknown.MethodsWe investigated the effect of ATM inhibitors, including the brain-penetrant AZD1390, on ferroptosis usingin vitro, ex vivo, andin vivomodels of ischemic stroke. Our analysis included assessments of cell viability, lipid peroxidation, ferroptosis marker expression, and infarct volume.ResultATM inhibitors significantly alleviated ferroptosis-induced cell death in cultured cells andex vivomurine brain slice cultures. In the oxygen-glucose deprivation (OGD) stroke model, treatment with AZD1390 reduced the expression of ferroptosis markers (xCT and PTGS2) and diminished neuronal cell death in rat and mouse brain slices. Furthermore, in a mouse model of ischemic stroke, AZD1390 decreased infarct volume confirming its therapeutic efficacyin vivo.ConclusionsThis study identifies ferroptosis as a critical mechanism in ischemic stroke-induced neuronal cell death and highlights ATM inhibition, particularly with AZD1390, as a promising therapeutic candidate for mitigating stroke-associated damage. Targeting ferroptosis may provide a translationally relevant strategy to mitigate neuronal injury and improve clinical outcomes for stroke patients.
Transcriptome differentiation inCryptomeria japonicatrees with different origins growing in the north and south of Japan
Authors: Ujino-Ihara Tokuko , Uchiyama Kentaro , Kanetani Seiichi , Suyama Yoshihisa , Tsumura Yoshihiko 
Published: February 2025

AbstractCryptomeria japonicais a coniferous species widely distributed throughout Japan and therefore adapted to various environments. To seek genes involved in the local adaptation of this species, individuals with different origins growing at three common gardens located in the south, central and north of Japan were subjected to transcriptome analysis. The transcriptome assembly, guided by whole-genome sequence ofC. japonica, resulted in 77,212 transcripts from 56,203 genes. Individuals were clustered into three genetic groups based on single nucleotide polymorphisms (SNPs) detected in 12,389 genes among them. Weighted gene co-expression network analysis (WGCNA) identified 25 gene modules. Comparison of representative gene expression patterns for each co-expression gene module with genetic differentiation predicted by SNPs revealed that one module exhibited a negative correlation and another a positive correlation across all three common gardens. While defense response genes were highly expressed in individuals from the Pacific Ocean side of Japan (omote-sugi), terpenoid metabolism genes were more expressed in individuals originating from the Sea of Japan side (ura-sugi). These results suggest that local adaptation associated with the alteration of gene regulation occurred in biotic stress response genes inC. japonica.