bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in taste palatability across the estrous cycle are modulated by hypothalamic estradiol signaling
Authors: Stone Bradly T. , Rahamim Oran M. , Katz Donald B. , Lin Jian-You 
Published: April 2024

AbstractFood intake varies across the stages of a rat’s estrous cycle. It is reasonable to hypothesize that this cyclic fluctuation in consumption reflects an impact of hormones on taste palatability/preference, but evidence for this hypothesis has been mixed, and critical within-subject experiments in which rats sample multiple tastes during each of the four main estrous phases (metestrus, diestrus, proestrus, and estrus) have been scarce. Here, we assayed licking for pleasant (sucrose, NaCl, saccharin) and aversive (quinine-HCl, citric acid) tastes each day for 5-10 days while tracking rats’ estrous cycles through vaginal cytology. Initial analyses confirmed the previously-described increased consumption of pleasant stimuli 24-48 hours following the time of high estradiol. A closer look, however, revealed this effect to reflect a general magnification of palatability—higher than normal preferences for pleasant tastes and lower than normal preferences for aversive tastes—during metestrus. We hypothesized that this phenomenon might be related to estradiol processing in the lateral hypothalamus (LH), and tested this hypothesis by inhibiting LH estrogen receptor activity with ICI182,780during tasting. Control infusions replicated the metestrus magnification of palatability pattern; ICI infusions blocked this effect as predicted, but failed to render preferences “cycle free,” instead delaying the palatability magnification until diestrus. Clearly, estrous phase mediates details of taste palatability in a manner involving hypothalamic actions of estradiol; further work will be needed to explain the lack of a flat response across the cycle with hypothalamic estradiol binding inhibited, a result which perhaps suggests dynamic interplay between brain regions or hormones.Significance StatementConsummatory behaviors are impacted by many variables, including naturally circulating hormones. While it is clear that consumption is particularly high during the stages following the high-estradiol stage of the rodent’s estrous (and human menstrual) cycle, it is as of yet unclear whether this phenomenon reflects cycle stage-specific palatability (i.e., whether pleasant tastes are particularly delicious, and aversive tastes particularly disgusting, at particular phases). Here we show that palatability is indeed modulated by estrous phase, and that this effect is governed, at least in part, by the action of estradiol within the lateral hypothalamus. These findings shed light on the mechanisms underlying the adverse impact on human welfare due to irregularities observed across the otherwise cyclic menstrual process.
A conserved function of corepressors is to nucleate assembly of the transcriptional preinitiation complex
Authors: Leydon Alexander R. , Downing Benjamin , Sanchez Janet Solano , Loll-Krippleber Raphael , Belliveau Nathan M. , Rodriguez-Mias Ricard A , Bauer Andrew , Watson Isabella J. , Bae Lena , Villén Judit , Brown Grant W. , Nemhauser Jennifer L. 
Published: April 2024

SummaryThe plant corepressor TPL is recruited to diverse chromatin contexts, yet its mechanism of repression remains unclear. Previously, we have leveraged the fact that TPL retains its function in a synthetic transcriptional circuit in the yeast modelSaccharomyces cerevisiaeto localize repressive function to two distinct domains. Here, we employed two unbiased whole genome approaches to map the physical and genetic interactions of TPL at a repressed locus. We identified SPT4, SPT5 and SPT6 as necessary for repression with the SPT4 subunit acting as a bridge connecting TPL to SPT5 and SPT6. We also discovered the association of multiple additional constituents of the transcriptional preinitiation complex at TPL-repressed promoters, specifically those involved in early transcription initiation events. These findings were validated in yeast and plants through multiple assays, including a novel method to analyze conditional loss of function of essential genes in plants. Our findings support a model where TPL nucleates preassembly of the transcription activation machinery to facilitate rapid onset of transcription once repression is relieved.
Sonic hedgehog medulloblastoma cells in co-culture with cerebellar organoids converge towardsin vivomalignant cell states
Authors: van Essen Max J. , Nicheperovich Alina , Schuster-Böckler Benjamin , Becker Esther B. E. , Jacob John 
Published: April 2024

AbstractBackgroundIn the malignant brain tumour sonic hedgehog medulloblastoma (SHH-MB) the properties of cancer cells are influenced by their microenvironment, but the nature of those effects and the phenotypic consequences for the tumour are poorly understood. The aim of this study was to identify phenotypic properties of SHH-MB cells that were driven by the non-malignant tumour microenvironment.MethodsHuman induced pluripotent cells (iPSC) were differentiated to cerebellar organoids to simulate the non-malignant tumour microenvironment. Tumour spheroids were generated from two distinct, long-established SHH-MB cell lines which were co-cultured with cerebellar organoids. We profiled the cellular transcriptomes of malignant and non-malignant cells by performing droplet-based single-cell RNA-sequencing (scRNA-seq). The transcriptional profiles of tumour cells in co-culture were compared with those of malignant cells cultured in isolation and with public SHH-MB datasets of patient tumours and patient-derived xenograft (PDX) models.ResultsSHH-MB cell lines in organoid co-culture adopted patient tumour-associated phenotypes and showed increased heterogeneity compared to monocultures. Sub-populations of co-cultured SHH-MB cells activated a key marker of differentiating granule cells,NEUROD1that was not observed in tumour monocultures. Other sub-populations expressed transcriptional determinants consistent with a cancer stem cell (CSC)-like state that resembled cell states identifiedin vivo.ConclusionFor SHH-MB cell lines in co-culture, there was a convergence of malignant cell states towards patterns of heterogeneity in patient tumours and PDX models implying these states were non-cell autonomously induced by the microenvironment. Therefore, we have generated an advanced, novelin vitromodel of SHH-MB with potential translational applications.
Level Dependent Subcortical EEG Responses to Continuous Speech
Authors: Kulasingham Joshua P. , Innes-Brown Hamish , Enqvist Martin , Alickovic Emina 
Published: April 2024

AbstractThe auditory brainstem response (ABR) is a measure of subcortical activity in response to auditory stimuli. The wave V peak of the ABR depends on stimulus intensity level, and has been widely used for clinical hearing assessment. Conventional methods to estimate the ABR average electroencephalography (EEG) responses to short unnatural stimuli such as clicks. Recent work has moved towards more ecologically relevant continuous speech stimuli using linear deconvolution models called Temporal Response Functions (TRFs). Investigating whether the TRF waveform changes with stimulus intensity is a crucial step towards the use of natural speech stimuli for hearing assessments involving subcortical responses. Here, we develop methods to estimate level-dependent subcortical TRFs using EEG data collected from 21 participants listening to continuous speech presented at 4 different intensity levels. We find that level-dependent changes can be detected in the wave V peak of the subcortical TRF for almost all participants, and are consistent with level-dependent changes in click-ABR wave V. We also investigate the most suitable peripheral auditory model to generate predictors for level-dependent subcortical TRFs and find that simple gammatone filterbanks perform the best. Additionally, around 6 minutes of data may be sufficient for detecting level-dependent effects and wave V peaks above the noise floor for speech segments with higher intensity. Finally, we show a proof-of-concept that level dependent subcortical TRFs can be detected even for the inherent intensity fluctuations in natural continuous speech.Visual abstractSignificance statementSubcortical EEG responses to sound depend on the stimulus intensity level and provide a window into the early human auditory pathway. However, current methods detect responses using unnatural transient stimuli such as clicks or chirps. We develop methods for detecting level-dependent responses to continuous speech stimuli, which is more ecologically relevant and may provide several advantages over transient stimuli. Critically, we find consistent patterns of level dependent subcortical responses to continuous speech at an individual level, that are directly comparable to those seen for conventional responses to click stimuli. Our work lays the foundation for the use of subcortical responses to natural speech stimuli in future applications such as clinical hearing assessment and hearing assistive technology.
Small molecule telomerase inhibitors are also potent inhibitors of telomeric C-strand synthesis
Authors: Johnson Kaitlin , Seidel Julia M. , Cech Thomas R. 
Published: April 2024

ABSTRACTTelomere replication is essential for continued proliferation of human cells, such as stem cells and cancer cells. Telomerase lengthens the telomeric G-strand, while C-strand replication is accomplished by CST-polymerase α -primase (CST-PP). Replication of both strands is inhibited by formation of G-quadruplex (GQ) structures in the G-rich single-stranded DNA. TMPyP4 and pyridostatin (PDS), which stabilize GQ structures in both DNA and RNA, inhibit telomerasein vitro, and they cause telomere shortening in human cells that has been attributed to telomerase inhibition. Here, we show that TMPyP4 and PDS also inhibit C-strand synthesis by stabilizing DNA secondary structures and thereby preventing CST-PP from binding to telomeric DNA. We also show that these small molecules inhibit CST-PP binding to a DNA sequence containing no consecutive guanine residues, which is unlikely to form GQs. Thus, while these “telomerase inhibitors” indeed inhibit telomerase, they are also robust inhibitors of telomeric C-strand synthesis. Furthermore, given their limited specificity for GQ structures, they may disrupt many other protein-nucleic acid interactions in human cells.
Structural Basis of Non-Latent Signaling by the Anti-Müllerian Hormone Procomplex
Authors: Howard James A , Hok Lucija , Cate Richard L , Sanford Nathaniel J , Hart Kaitlin N , Leach Edmund AE , Bruening Alena S , Pépin David , Donahoe Patricia K , Thompson Thomas B 
Published: April 2024

AbstractMost TGFβ family ligands exist as procomplexes consisting of a prodomain noncovalently bound to a growth factor (GF); Whereas some prodomains confer latency, the Anti-Müllerian Hormone (AMH) prodomain maintains a remarkably high affinity for the GF yet remains active. Using single particle EM methods, we show the AMH prodomain consists of two subdomains: a vestigial TGFβ prodomain-like fold and a novel, helical bundle GF-binding domain, the result of an exon insertion 450 million years ago, that engages both receptor epitopes. When associated with the prodomain, the AMH GF is distorted into a strained, open conformation whose closure upon bivalent binding of AMHR2 displaces the prodomain through a conformational shift mechanism to allow for signaling.
Characterising Aromatic Side Chains in Proteins through the Synergistic Development of NMR Experiments and Deep Neural Networks
Authors: Shukla Vaibhav Kumar , Karunanithy Gogulan , Vallurupalli Pramodh , Hansen D Flemming 
Published: April 2024

AbstractNuclear magnetic resonance (NMR) spectroscopy has become an important technique in structural biology for characterising the structure, dynamics and interactions of macromolecules. While a plethora of NMR methods are now available to inform on backbone and methyl-bearing side-chains of proteins, a characterisation of aromatic side chains is more challenging and often requires specific labelling or13C-detection. Here we present a deep neural network (DNN) named FID-Net-2, which transforms NMR spectra recorded on simple uniformly13C labelled samples to yield high-quality1H-13C correlation spectra of the aromatic side chains. Key to the success of the DNN is the design of a complementary set of NMR experiments that produce spectra with unique features to aid the DNN produce high-resolution aromatic1H-13C correlation spectra with accurate intensities. The reconstructed spectra can be used for quantitative purposes as FID-Net-2 predicts uncertainties in the resulting spectra. We have validated the new methodology experimentally on protein samples ranging from 7 to 40 kDa in size. We demonstrate that the method can accurately reconstruct high resolution two-dimensional aromatic1H-13C correlation maps, high resolution three-dimensional aromatic-methyl NOESY spectra to facilitate aromatic1H-13C assignments, and that the intensities of peaks from the reconstructed aromatic1H-13C correlation maps can be used to quantitatively characterise the kinetics of protein folding. More generally, we believe that this strategy of devising new NMR experiments specifically for analysis using customised DNNs represents a substantial advance that will have a major impact on the study of molecules using NMR in the years to come.
The Role of Cilia in the Development, Survival, and Regeneration of Hair Cells
Authors: Boldizar Hope , Friedman Amanda , Stanley Tess , Padilla María , Galdieri Jennifer , Sclar Arielle , Stawicki Tamara M. 
Published: April 2024

ABSTRACTMutations impacting cilia genes lead to a class of human diseases known as ciliopathies. This is due to the role of cilia in the development, survival, and regeneration of many cell types. We investigated the extent to which disrupting cilia impacted these processes in hair cells. We found that mutations in two intraflagellar transport (IFT) genes,ift88anddync2h1,which lead to the loss of kinocilia, caused increased hair cell apoptosis in the zebrafish lateral line. IFT gene mutants also have a decreased mitochondrial membrane potential, and blocking the mitochondrial uniporter causes a loss of hair cells in wild-type zebrafish but not mutants, suggesting mitochondria dysfunction may contribute to the apoptosis seen in these mutants. These mutants also showed decreased proliferation during hair cell regeneration, but did not show consistent changes in support cell number or proliferation during hair cell development. These results show that disruption of the cilia through either mutations in anterograde or retrograde IFT genes appear to impact hair cell survival but not necessarily development in the lateral line.
Ontology-based modeling, integration, and analysis of heterogeneous clinical, pathological, and molecular kidney data for precision medicine
Authors: He Yongqun Oliver , Barisoni Laura , Rosenberg Avi Z , Robinson Peter N. , Diehl Alexander D. , Chen Yichao , Phuong Jimmy P. , Hansen Jens , Herr Bruce W. , Börner Katy , Bonevich Nikki , Arnous Ghida , Boddapati Saketh , Zheng Jie , Alakwaa Fadhl , Sardar Pinaki , Duncan William D. , Liang Chen , Valerius M. Todd , Jain Sanjay , Iyengar Ravi , Himmelfarb Jonathan , Kretzler Matthias ,   the Kidney Precision Medicine Project
Published: April 2024

AbstractMany resources are now generating, processing, storing, or providing kidney-related molecular, pathological, and clinical data. Reference ontologies offer an opportunity to support knowledge and data organization and integration. The Kidney Precision Medicine Project (KPMP) team contributed to the representation and addition of 329 kidney phenotype terms to the Human Phenotype Ontology (HPO) and identified many subcategories of acute kidney injury (AKI) or chronic kidney disease (CKD). The Kidney Tissue Atlas Ontology (KTAO) imports and integrates kidney-related terms from existing ontologies (e.g., HPO, CL, and Uberon) and represents 259 kidney-related biomarkers. We also developed a precision medicine metadata ontology (PMMO) to integrate 50 variables from KPMP and CellxGene resources and applied PMMO for integrative analysis. The gene expression profiles of kidney gene biomarkers were specifically analyzed in healthy controls or AKI/CKD disease states. This work demonstrates how ontology-based approaches support multi-domain data and knowledge organization and integration to advance precision medicine.
During haptic communication, the central nervous system compensates distinctly for delay and noise
Authors: Eden Jonathan , Ivanova Ekaterina , Burdet Etienne 
Published: April 2024

AbstractConnected humans have been previously shown to exploit the exchange of haptic forces and tactile information to improve their performance in joint action tasks. As human interactions are increasingly mediated through robots and networks it is important to understand the impact that network features such as lag and noise may have on human behaviour. In this paper, we investigated the interaction with a human-like robot controller that provides similar haptic communication behaviour as human-human interaction and examined the influence and compensation mechanisms for delay and noise on haptic communication. The results of our experiments show that participants can distinguish between noise and delay, and make use of compensation mechanisms to preserve performance in both cases. However, while noise is compensated for by increasing co-contraction, delay compensation could not be explained by this strategy. Instead, computational modelling suggested that a feed-forward prediction mechanism is used to compensate for the temporal delay and yield an efficient haptic communication.Author summaryIncreasingly humans are making use of networks and robots to coordinate haptic interactions through teleoperation. However, with networks comes delays and noise that can change both the force that is transmitted and how we perceive that force. The haptic communication involved in joint actions, such as moving a piano or performing a pair spin, has been shown to improve performance, but how does delay affect this behaviour? We tested how participants tracked a moving target with their right hand when connected to a human-like robotic partner, when perturbed by delay or noise.Through a comparison between noise and delay perturbation in experimental performance and in simulation with a computational model, we found that participants could from small values of perturbation identify if the perturbation was from delay or noise and that they adopted different compensation strategies in each case.
A short sequence targets transmembrane proteins to primary cilia
Authors: Macarelli Viviana , Harding Edward , Gershlick David C. , Merkle Florian T. 
Published: April 2024

AbstractPrimary cilia are finger-like sensory organelles that extend from the bodies of most cell types and have a distinct lipid and protein composition from the plasma membrane. This partitioning is maintained by a diffusion barrier that restricts the entry of non-ciliary proteins, and allows the selective entry of proteins harboring a ciliary targeting sequence (CTS). However, CTSs are not stereotyped, and previously-reported sequences are insufficient to drive efficient ciliary localization across diverse cell types. Here, we describe a short peptide sequence that efficiently targets transmembrane proteins to primary cilia in all tested cell types, including human neurons. We generate human induced pluripotent stem cell (hiPSC) lines stably expressing a transmembrane construct bearing an extracellular HaloTag and intracellular fluorescent protein, that enables bright, specific labeling of primary cilia in neurons and other cell types. We demonstrate the utility of this resource by developing an image analysis pipeline for the automated measurement of primary cilia to detect changes in their length.
Solid–liquid phase transition simulated by the lattice Boltzmann model: from pore scale to representative elementary volume scale
Authors: Li Dong , Zhou Yu , Cao Zhan-Wei , Chen Xin , Dai Jia-Peng 
Published: April 2024

Purpose
This paper aims to establish a lattice Boltzmann (LB) method for solid-liquid phase transition (SLPT) from the pore scale to the representative elementary volume (REV) scale. By applying this method, detailed information about heat transfer and phase change processes within the pores can be obtained, while also enabling the calculation of larger-scale SLPT problems, such as shell-and-tube phase change heat storage systems.

Design/methodology/approach
Three-dimensional (3D) pore-scale enthalpy-based LB model is developed. The computational input parameters at the REV scale are derived from calculations at the pore scale, ensuring consistency between the two scales. The approaches to reconstruct the 3D porous structure and determine the REV of metal foam were discussed. The implementation of conjugate heat transfer between the solid matrix and the solid−liquid phase change material (SLPCM) for the proposed model is developed. A simple REV-scale LB model under the local thermal nonequilibrium condition is presented. The method of bridging the gap between the pore-scale and REV-scale enthalpy-based LB models by the REV is given.

Findings
This coupled method facilitates detailed simulations of flow, heat transfer and phase change within pores. The approach holds promise for multiscale calculations in latent heat storage devices with porous structures. The SLPT of the heat sinks for electronic device thermal control was simulated as a case, demonstrating the efficiency of the present models in designing and optimizing SLPT devices.

Originality/value
A coupled pore-scale and REV-scale LB method as a numerical tool for investigating phase change in porous materials was developed. This innovative approach allows for the capture of details within pores while addressing computations over a large domain. The LB method for simulating SLPT from the pore scale to the REV scale was given. The proposed method addresses the conjugate heat transfer between the SLPCM and the solid matrix in the enthalpy-based LB model.
Factors affecting judicial system efficiency: a systematic mapping review with a focus on Italy
Authors: Giancotti Monica , Rotundo Giorgia , Mauro Marianna 
Published: April 2024

PurposeEuropean justice systems are facing a dramatic performance crisis due to the frequent inability to resolve cases without incurring unreasonable delays and backlogs. In this framework, the Italian Judicial system places itself well below the European countries average, in terms of speed of resolution of administrative, civil and criminal trials. The purpose of the paper was to (1) identify factors affecting Italian judicial system efficiency and (2) identify potential actions to manage them, improving judicial system efficiency.Design/methodology/approachIn order to achieve the aims of this paper, a systematic review to map all critical factors discussed in previous studies was performed. Studies were extracted from Google Scholar, Web of Science and SSRN databases. In total, 22 studies were included.FindingsThe identified factors of inefficiency of the Italian judicial system have been divided into three macro-classes depending on whether they concern human resource management, the judicial process or whether they pertain to internal or external outside the judicial organization. For each of these, possible strategies have been developed in a new conceptual framework.Originality/valueThe framework seeks to assist policymakers in forming policy measures that can significantly increase court effectiveness. This is the first attempt to review and map all factors affecting judicial system efficiency systematically, providing a new conceptual framework to manage them.